The present invention provides a medical device, preferably a contact lens, which comprises an antimicrobial coating including at least one layer of polyquat of formula (I) or (II). The antimicrobial coating on the medical device of the invention has a high antimicrobial efficacy against microorganisms including Gram-positive and Gram-negative bacterial, a low toxicity, low coefficient of friction, and increased hydrophilicity while maintaining the desired bulk properties such as oxygen permeability and ion permeability of lens material. Such lenses are useful as extended-wear contact lenses. In addition, the invention provides a method for making a medical device, preferably a contact lens, having an antimicrobial coating thereon.

Description of the Invention

SUMMARY OF THE INVENTION

These and other objects of the invention are met by the various aspects of the invention described herein.

The invention, in one aspect, provides a medical device having an antimicrobial surface coating and the following surface properties: a low coefficient of friction characterized by having an averaged value of less than 1.4 and a hydrophilicity characterized by having an averaged contact angle of less than 80 degree. The antimicrobial coating preferably comprises at least one layer of polymeric quaternary ammonium group-containing compound (polyquats) and has a balance of high antimicrobial efficacy and low cytotoxicity.

The invention, in another aspect, provides a method for forming an antimicrobial coating on a medical device. The method comprises applying at least one layer of polymeric quaternary ammonium group-containing compound on a medical device.

These and other aspects of the invention will become apparent from the following description of the presently preferred embodiments. The detailed description is merely illustrative of the invention and does not limit the scope of the invention, which is defined by the appended claims and equivalents thereof. As would be obvious to one skilled in the art, many variations and modifications of the invention may be effected without departing from the spirit and scope of the novel concepts of the disclosure.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In general, the present invention is directed to a medical device having a core material and an antimicrobial surface coating (hereinafter antimicrobial coating) formed thereon and the following surface properties: a low coefficient of friction characterized by having an averaged value of less than 1.4 and a hydrophilicity characterized by having an averaged contact angle of less than 80 degree. The antimicrobial coating can comprise any known suitable antimicrobial agents. Exemplary antimicrobial agents include, without limitation, antibiotics, lactoferrin, metal chelating agents, substituted and unsubstituted polyhydric phenols, amino phenols, alcohols, acid and amine derivatives, and quaternary ammonium group-containing compounds. Antimicrobial agents in the antimicrobial coating of a medical device can be covalent bound to or entrapped to the medical device.

In particular, the present invention is directed to a medical device, preferably an ophthalmic lens, more preferably a contact lens, having an antimicrobial coating comprising at least one layer, preferably one capping layer, of polymeric quaternary ammonium salt compounds or the like. Surprisingly, it has been discovered that a previously known polymeric quaternary ammonium salt compound (polyquat) of formula (I) or (II)  -- see Original Patent -- can be used to form on a contact lens an antimicrobial coating having a high antimicrobial efficacy and low cytotoxicity. Especially, when such antimicrobial coating is formed on a contact lens which is made from ophthalmically compatible materials, for example, materials disclosed in U.S. Pat. No. 5,849,811, it provides high antimicrobial activity coupled with low cytotoxicity, increases surface hydrophilicity, decreases coefficient of friction, and has a minimal adverse effects on the desirable bulk properties of the lens, such as oxygen permeability, ion permeability, and optical properties. Coefficient of friction may be one of important parameters that may affect the on-eye movement and thereby the wearer's comfort. High coefficient of friction may increase the likelihood of damaging mechanically the ocular epithelia and/or may lead to ocular discomfort. An antimicrobial coating of the present invention may find particular use in extended-wear contact lenses.

In formula (I) (see Original Patent), R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are identical or different from one another. They are C.sub.1-C.sub.10 hydrocarbon radicals, preferably C.sub.1 to C.sub.6 alkyl radicals or C.sub.1 to C.sub.6 alkyl radicals having one or more hydroxyl groups, more preferably methyl, ethyl, or benzyl radicals, even more preferably methyl radicals.

In formula (I) (see Original Patent), A and B are identical or different from one another. They are n-alkylene groups having 3 to 15 carbon atoms or n-alkylene groups having 3 to 15 carbon atoms and one or more hydroxyl groups. Preferably, either one of A and B is hexamethylene radical (--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--). More preferably, either one of A and B is hexamethylene radical (--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) and the respective other one is an n-alkylene group having 6 to 10 carbon atoms. Even more preferably, either one of A and B is hexamethylene radical (--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) and the respective other one is an n-alkylene group having 8 to 10 carbon atoms.

Where either one of A and B is hexamethylene radical (--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--) and the respective other one is an n-alkylene radical having 6 to 12 carbon atoms, the polyquat of formula (I) will be represented by PQ6-x, in which x represents the number of carbon atoms of n-alkylene radical.

It is possible as well to provide the polymer chains with varying proportions of alkylene groups of different lengths. For example, one of A and B may be hexamethylene radical (--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--), while the respective other one is n-alkylene radical having 6, 8, 10, or 12 carbon atoms, and these being present in different proportions. It is possible, for example, to produce polymers which contain 80% of hexamethylene units and 10% each of decamethylene and dodecamethylene groups. Depending on the starting material used, these different alkylene groups may be distributed statistically or in a more or less orderly fashion throughout the polymer chain.

In formula (I), the index y characterizes the chain length of the polymer of formula (I) and is a number from about 10 to 500, preferably a number from 25 to 400, and more preferably a number from 50 to 300. X is chlorine, bromine, or iodine.

In formula (II) (see Original Patent), X is chlorine, bromine, or iodine. The index n characterizes the chain length of the polymer of formula (II) and is a number from about 100 to 5000, preferably a number from 500 to 4000, and more preferably a number from 500 to 3000. R.sub.5 and R.sub.6 are identical or different from one another. They are n-alkyl groups having 1 to 10 carbon atoms or n-alkyl groups having 1 to 10 carbon atoms and one or more hydroxyl groups. Preferably, R.sub.5 and R.sub.6 are identical and methyl groups.

Methods for making a polymer of formula (I) are well known in the art. Reference is made in this context to U.S. Pat. Nos. 2,261,002, 2,271,378 and 3,898,188. Generally, a polymer of formula (I) can be synthesized by reacting a diamine having of formula (III) -- see Original Patent.

It has also been discovered that an unleachable antimicrobial coating can be formed on a medical device made from a core material by covalently attaching at least one layer of polymers of polyquat of formula (I) to the surface of the medical device or by non-covalently applying at least one layer of polyquat of formula (I) onto the surface of the medical device using a layer-by-layer polyelectrolyte deposition technique. The antimicrobial activity of the polyquat of formula (I) is not diminished significantly in the antimicrobial coating formed on the medical device.

In a preferred embodiment, a medical device of the invention comprises a core material and an antimicrobial LbL coating including at least one polyquat-polyanionic bilayer which is composed of one layer of a polyanionic material and one layer of polyquat of formula (I) or (II). In a more preferred embodiment, the medical device of the invention further comprises a plurality of polyelectrolyte bilayers. A polyelectrolyte bilayer is composed of a first layer of a first polyionic material and a second layer of a second polyionic material having charges opposite of the charges of the first polyionic material.

A polycationic material used in the present invention can generally include any material known in the art to have a plurality of positively charged groups along a polymer chain. For instance, suitable examples of such polycationic materials can include, but are not limited to, poly(allylamine hydrochloride) (PAH), poly(ethyleneimine) (PEI), poly(vinylbenzyltriamethylamine) (PVBT), polyaniline (PAN or PANI) (p-type doped) [or sulphonated polyaniline], polypyrrole (PPY) (p-typed doped), and poly(pyridinium acetylene).

A polyanionic material used in the present invention can generally include any material known in the art to have a plurality of negatively charged groups along a polymer chain. For example, suitable polyanionic materials can include, but are not limited to, polymethacrylic acid (PMA), polyacrylic acid (PAA), poly(thiophene-3-acetic acid) (PTAA), poly(4-styrenesulfonic acid) (PSS), sodium poly(styrene sulfonate) (SPS) and poly(sodium styrene sulfonate) (PSSS).

The foregoing lists are intended to be exemplary, but clearly are not exhaustive. A person skilled in the art, given the disclosure and teaching herein, would be able to select a number of other useful polyionic materials.

In order to alter various characteristics of the coating, such as thickness, the molecular weight of the polyionic materials including polyquats can be varied. In particular, as the molecular weight is increased, the coating thickness generally increases. However, if the increase in molecular weight increase is too substantial, the difficulty in handling may also increase. As such, polyionic materials used in a process of the present invention will typically have a molecular weight M.sub.n of about 2,000 to about 150,000. In some embodiments, the molecular weight is about 5,000 to about 100,000, and in other embodiments, from about 75,000 to about 100,000.

In another preferred embodiment, a medical device of the invention comprises a core material and an antimicrobial LbL coating including a capping layer of polyquat of formula (I) or (II). With such capping layer of polyquat of formula (I) or (II), an antimicrobial coating on a medical device of the invention can provide a direct contact with the antimicrobial agents, polyquat of formula (I) or (II) for microorganisms and thereby have a higher antimicrobial efficacy.

In another preferred embodiment, a medical device of the invention comprises a core material and an antimicrobial LbL coating including a plurality of layers of polyquat of formula (I) or (II). Such antimicrobial coating may provide higher concentration of antimicrobial agents and thereby increase antimicrobial efficacy.

In accordance with the present invention, the core material of a medical device may be any of a wide variety of polymeric materials. Exemplary core materials include, but are not limited to, hydrogels, silicone-containing hydrogels, polymers and copolymers of styrene and substituted styrenes, ethylene, propylene, acrylates and methacrylates, N-vinyl lactams, acrylamides and methacrylamides, acrylonitrile, acrylic and methacrylic acids. A preferred group of polymeric materials forming ophthalmic lenses are those materials which are highly oxygen permeable, such as fluorine- or siloxane-containing polymers. In particular, the polymeric materials described in U.S. Pat. No. 5,760,100 are an exemplary group, and the teachings of this patent are incorporated herein by reference.

One embodiment of the invention is a method for producing a medical device having a core material and an antimicrobial coating including a capping layer of polyquats of formula (I) or (II), comprising covalently coupling the polyquats of formula (I) or (II) to the core material.

Any known suitable method for covalent coupling of polyquats to the core material can be used. For example, a contact lens made from a hydrogel, such as lotrafilcon A, lotrafilcon B, or balafilcon, is dipped into or sprayed with a solution containing a diaziridine compound, which is subsequently attached covalently to the surface of the contact lens via a thermal process, so as to functionalize the contact lens. Such functionalized lenses can be placed in a container containing a polyquat solution and then irradiated with blue light for 30 minutes so that polyquats are covalently attached to the functionalized lens.

It should be understood that the surface of the medical device can be chemically modified before covalently coupling polyquats to the medical device or a different material can be first grafted onto or bound to the core material and then covalently coupled with polyquats.

Another embodiment of the invention is a method for producing a medical device having a core material and an antimicrobial LbL coating including a capping layer of polyquats of formula (I) or (II) comprising applying the antimicrobial LbL coating onto the core material using a layer-by-layer polyelectrolyte deposition technique.

It has been discovered and disclosed in U.S. application Ser. No. 09/005,317 that complex and time-consuming pretreatment of a core material (medical device) is not required prior to non-covalently binding of a polyionic material to the core material. By simply contacting a core material of a medical device, for example, a contact lens, with one or more solutions each containing one or more polyionic materials, an LbL coating can be formed on a medical device to modify the surface properties of the core material of the medical device. An LbL coating can be a single layer or a bilayer or multiple bilayers.

Application of an LbL coating may be accomplished in a number of ways as described in pending U.S. patent application (application Ser. Nos. 09/005,317, 09/774,942, 09/775,104), herein incorporated by reference in their entireties. One coating process embodiment involves solely dip-coating and dip-rinsing steps. Another coating process embodiment involves solely spray-coating and spray-rinsing steps. However, a number of alternatives involve various combinations of spray- and dip-coating and rinsing steps may be designed by a person having ordinary skill in the art.

One dip-coating alternative involves the steps of applying a coating of a first polyionic material to a core material of a medical device by immersing said medical device in a first solution of a first polyionic material; rinsing the medical device by immersing the medical device in a rinsing solution; and, optionally, drying the medical device. This procedure can be repeated using a second polyionic material, with the second polyionic material having charges opposite of the charges of the first polyionic material, in order to form a polyionic bilayer. This bilayer formation process may be repeated a plurality of times in order to produce a thicker LbL coating. A preferred number of bilayers is about 5 to about 20 bilayers. While more than 20 bilayers are possible, it has been found that delamination may occur in some LbL coatings having an excessive number of bilayers.

The immersion time for each of the coating and rinsing steps may vary depending on a number of factors. Preferably, immersion of the core material into the polyionic solution occurs over a period of about 1 to 30 minutes, more preferably about 2 to 20 minutes, and most preferably about 1 to 5 minutes. Rinsing may be accomplished in one step, but a plurality of rinsing steps can be quite efficient.

Another embodiment of the coating process is a single dip-coating process as described in U.S. application Ser. No. 09 775104, herein incorporated by reference in its entirety. Such single dip-coating process involves dipping a core material of a medical device in a solution containing a negatively charged polyionic material and a positively charged polyionic material in an amount such that the molar charge ratio of said solution is from about 3:1 to about 100:1. Multiple bilayers can be formed on a medical device by using this single dip-coating process.

Another embodiment of the coating process involves a series of spray coating techniques. The process generally includes the steps of applying a coating of a first polyionic material to a core material of a medical device with a first solution of a first polyionic material; rinsing the medical device by spraying the medical device with a rinsing solution; and optionally, drying the medical device. Similar to the dip-coating process, the spray-coating process may be repeated with a second polyionic material, with the second polyionic material having charges opposite of the charges of the first polyionic material.

The contacting of the medical device with solution, either polyionic material or rinsing solution, may occur by a variety of methods. For example, the medical device may be dipped into both solutions. One preferred alternative is to apply the solutions in a spray or mist form. Of course, various combinations may be envisioned, e.g., dipping the medical device in the polyionic material followed by spraying the rinsing solution.

The spray coating application may be accomplished via a number of methods. For example, a conventional spray coating arrangement may be used, i.e., the liquid material is sprayed by application of fluid, which may or may not be at elevated pressure, through a reduced diameter nozzle which is directed towards the deposition target.

Preferably, a spraying process is selected from the group consisting of an air-assisted atomization and dispensing process, an ultrasonic-assisted atomization and dispensing process, a piezoelectric assisted atomization and dispensing process, an electro-mechanical jet printing process, a piezo-electric jet printing process, a piezo-electric with hydrostatic pressure jet printing process, and a thermal jet printing process; and a computer system capable of controlling the positioning of the dispensing head of the spraying device on the ophthalmic lens and dispensing the coating liquid. Those spraying coating processes are described in U.S. Application No. 60/312,199, herein incorporated by reference in its entirety. By using such spraying coating processes, an asymmetrical coating can be applied to a medical device. For example, the back surface of a contact lens can be coated with a hydrophilic and/or lubricous coating material and the front surface of the contact lens can be coated with an antimicrobial material. It is also possible to produce a coating on a contact lens, the coating having a functional pattern so as to provide simultaneously multiple benefits to a wearer.

In accordance with the present invention, polyionic material solutions can be prepared in a variety of ways. In particular, a polyionic solution of the present invention can be formed by dissolving the polyionic material(s) in water or any other solvent capable of dissolving the materials. When a solvent is used, any solvent that can allow the components within the solution to remain stable in water is suitable. For example, an alcohol-based solvent can be used. Suitable alcohols can include, but are not limited to, isopropyl alcohol, hexanol, ethanol, etc. It should be understood that other solvents commonly used in the art can also be suitably used in the present invention.

Whether dissolved in water or in a solvent, the concentration of a polyionic material in a solution of the present invention can generally vary depending on the particular materials being utilized, the desired coating thickness, and a number of other factors. However, it may be typical to formulate a relatively dilute aqueous solution of polyionic material. For example, a polyionic material concentration can be between about 0.001% to about 0.25% by weight, between about 0.005% to about 0.10% by weight, or between about 0.01% to about 0.05% by weight.

In general, the polyionic solutions mentioned above can be prepared by any method well known in the art for preparing solutions. For example, in one embodiment, a polyanionic solution can be prepared by dissolving a suitable amount of the polyanionic material, such as polyacrylic acid having a molecular weight of about 90,000, in water such that a solution having a certain concentration is formed. In one embodiment, the resulting solution is a 0.001 M PAA solution. Once dissolved, the pH of the polyanionic solution can also be adjusted by adding a basic or acidic material. In the embodiment above, for example, a suitable amount of 1 N hydrochloric acid (HCl) can be added to adjust the pH to 2.5.

Polycationic solutions can also be formed in a manner as described above. For example, in one embodiment, poly(allylamine hydrochloride) having a molecular weight of about 50,000 to about 65,000 can be dissolved in water to form a 0.001 M PAH solution. Thereafter, the pH can also be adjusted to 2.5 by adding a suitable amount of hydrochloric acid.

In some embodiments of the present invention, it may be desirable to apply a solution containing both polyanionic and polycationic materials within a single solution. For example, a polyanionic solution can be formed as described above, and then mixed with a polycationic solution that is also formed as described above. In one embodiment, the solutions can then be mixed slowly to form the coating solution. The amount of each solution applied to the mix depends on the molar charge ratio desired. For example, if a 10:1 (polyanion:polycation) solution is desired, 1 part (by volume) of the PAH solution can be mixed into 10 parts of the PAA solution. After mixing, the solution can also be filtered if desired.

A medical device of the invention can also be made by first applying an antimicrobial coating to a mold for making a medical device and then transfer-grafting the antimicrobial coating to the medical device made from the mold, in substantial accordance with the teachings of U.S. patent application (Ser. No. 09/774,942), herein incorporated by reference in its entirety.

Methods of forming mold sections for cast-molding a contact lens are generally well known to those of ordinary skill in the art. The process of the present invention is not limited to any particular method of forming a mold. In fact, any method of forming a mold can be used in the present invention. However, for illustrative purposes, the following discussion has been provided as one embodiment of forming a mold on which a color image can be printed in accordance with the present invention.

In general, a mold comprises at least two mold sections (or portions) or mold halves, i.e. first and second mold halves. The first mold half defines a first optical surface and the second mold half defines a second optical surface. The first and second mold halves are configured to receive each other such that a contact lens forming cavity is formed between the first optical surface and the second optical surface. The first and second mold halves can be formed through various techniques, such as injection molding. These half sections can later be joined together such that a contact lens-forming cavity is formed therebetween. Thereafter, a contact lens can be formed within the contact lens-forming cavity using various processing techniques, such as ultraviolet curing.

Examples of suitable processes for forming the mold halves are disclosed in U.S. Pat. No. 4,444,711 to Schad; U.S. Pat. No. 4,460,534 to Boehm et al.; U.S. Pat. No. 5,843,346 to Morrill; and U.S. Pat. No. 5,894,002 to Boneberger et al., which are also incorporated herein by reference.

Virtually all materials known in the art for making molds can be used to make molds for making contact lenses. For example, polymeric materials, such as polyethylene, polypropylene, and PMMA can be used. Other materials that allow UV light transmission could be used, such as. quartz glass.

Once a mold is formed, a transferable antimicrobial LbL coating, which comprises at least one layer of polyquat of formula (I) or (II), can be applied onto the optical surface (inner surface) of one or both mold portions by using the above-described LbL deposition techniques. The inner surface of a mold portion is the cavity-forming surface of the mold and in direct contact with lens-forming material. A transferable antimicrobial LbL coating can be applied onto the mold portion defining the posterior (concave) surface of a contact lens or on the mold section defining the anterior surface of a contact lens or on both mold portions.

Once a transferable antimicrobial LbL coating is applied onto the optical surface of one or both mold portions, a lens material can then be dispensed into the contact lens forming cavity defined by the assembled mold halves. In general, a lens material can be made from any polymerizable composition. In particular, when forming a contact lens, the lens material may be an oxygen-permeable material, such as flourine- or siloxane-containing polymer. For example, some examples of suitable substrate materials include, but are not limited to, the polymeric materials disclosed in U.S. Pat. No. 5,760,100 to Nicolson et al., which is incorporated herein by reference. The lens material can then be cured, i.e. polymerized, within the contact lens-forming cavity to form the contact lens, whereby at least a portion of the transferable coating detaches from the optical surface and reattaches to the formed contact lens.

Thermal curing or photo curing methods can be used to curing a polymerizable composition in a mold to form an ophthalmic lens. Such curing methods are well-known to a person skilled in the art.
 

Claim 1 of 9 Claims

1. A medical device, comprising a core material and an antimicrobial surface coating, wherein said antimicrobial surface coating is an LbL coating obtained by using a layer-by-layer deposition technique and comprises at least one polyanionic-polyquat bilayer composed of one layer of a polyanionic material and one layer of the polyquat of formula (1), -- see Original Patent.

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