Methods for making and using contact lenses containing pharmaceutical agents and stabilizers for unstable components such as drugs

Abstract

The present invention recognizes that medical devices, such as, but not limited to, contact lenses, can be fabricated with at least one coating fabricated at least in part using printing techniques to provide a drug storage and release structure, particularly for hydrophobic drugs, and that such hydrophobic drugs can be stabilized with respect to hydrolysis, heating, and combinations thereof. A first aspect of the present invention includes a packaged medical device comprising at least one drug delivery contact lens. A second aspect of the present invention includes a drug delivery contact lens. A third aspect of the present invention includes a method of fabricating a drug delivery contact lens. A fourth aspect of the present invention includes an ink. A fifth aspect of the present invention includes a method of treating or preventing an ocular disease, disorder, or condition using a drug delivery contact lens.

Description

[Technical Field]

[0001] Priority Statement This application claims the benefit of priority to U.S. Provisional Application No. 63 / 368,515, filed July 15, 2022, and now pending. each of which is incorporated herein by reference in its entirety.

[0002] The present invention relates generally to the field of medical devices, including but not limited to contact lenses, that contain pharmaceutical agents or drugs in a coating layer, and methods of making and using such medical devices. The coating layer is preferably made, at least in part, using printing, preferably, but not limited to, digital printing. [Background technology]

[0003] Medical devices containing pharmaceutical agents are known. Examples include contact lenses and stents for the treatment or prevention of various diseases, disorders, or conditions, such as contact lenses for the treatment of glaucoma and stents for the treatment or prevention of restenosis. Existing medical devices containing pharmaceutical agents have traditionally been fabricated using relatively simple drug coating or drug impregnation techniques that do not allow for controlled release of the pharmaceutical agent from the coating. The present invention addresses these limitations and also provides additional advantages.

[0004] Various medical devices, particularly contact lenses, have been described that contain pharmaceutical agents. For example, U.S. Patent No. 7,638,137 (B2) to Chuahan et al. describes a drug delivery system that relies on transparent encapsulated drugs dispersed within the lens. However, such dispersion within the lens can alter the physical properties of the polymeric lens material. Also, the encapsulated drug, while visually clear in certain cases, can interfere with the optical properties of the lens. Additionally, the drug within the lens may be released from either or both the anterior and posterior surfaces of the lens, thus not providing the desired dosage of drug to the cornea or other areas of the ocular structure and surrounding tissues. This document also provides a literature survey regarding issues related to drug release.

[0005] U.S. Published Patent Application No. 2009 / 07504245(A1) to Orilla et al. describes masking the color of a drug by applying a color layer on top of the drug. This document is not directed to controlling the rate of drug release from the lens.

[0006] Also, U.S. Published Patent Application No. 2009 / 0004244 to Burke et al. describes ejecting drugs in an iris-like pattern to provide an aesthetic appearance for lenses for drug delivery. This document does not address how the rate of drug release can be controlled.

[0007] Additionally, U.S. Patent No. 6,887,858 to Yerxa describes a formulation for the treatment of dry eye disease. This document does not relate to drug release from medical devices such as contact lenses.

[0008] Additionally, U.S. Patent No. 6,294,553 to Gil et al. describes a drug for ocular surface pain, however, Gil et al. is not directed to controlled drug delivery rates.

[0009] US Patent No. 3,786,812 to Neefe describes the use of contact lenses for drug delivery, however, this document is not concerned with achieving a desired release rate of the drug from the lens.

[0010] Also, U.S. Patent Nos. 3,618,604 and 3,828,777 describe polymeric plastics in which drugs are retained to provide controlled drug release rates, however the documents are silent about the ability to tailor the drug release rate.

[0011] Additionally, US Pat. No. 10,463,677 generally relates to the stabilization of latanoprost with cyclodextrins.

[0012] Also, published U.S. patent application 2012 / 0021013 generally relates to the stabilization of latanoprost with cyclodextrins.

[0013] Furthermore, Rodriguez-Aller et al. “New Prostaglandin analog formations for glaucoma treatment containing cyclodextrins for improved stability, solubility and ocular tolerance” European Journal of Pharmaceutics and Biopharmaceuticals, Volume 95, Part B, Pg 203-214 (2015) (abstract only) https: / / www.sciencedirect.com / science / article / abs / pii / S093964111500212X?via%3Dihub.

[0014] Additionally, US Pat. No. 9,539,262 generally relates to prostaglandin derivatives such as latanoprost formulated with polyethylene glycol hyroxystearate, which has reduced absorption that was not addressed by the addition of oil.

[0015] EP 1681059 also generally relates to the effect of different formulation conditions, such as pH, on the degradation of latanoprost.

[0016] Additionally, US Patent Nos. 9,931,296 and 10,413,506 to Doshi all relate generally to drug-releasing contact lenses.

[0017] Additionally, U.S. Patent No. 10,617,559, U.S. Patent No. 11,173,064, and U.S. Published Application No. 2002 / 0192975 to Yang all relate generally to drug-releasing contact lenses. [Brief explanation of the drawings]

[0018] [Figure 1] Generally, the proposed mechanism of latanoprost hydrolysis to latanoprost free acid is shown: The isopropyl ester on carbon 1 is readily hydrolyzed at ambient room temperature to produce latanoprost free acid. [Figure 2] Generally, the proposed mechanism of hydrolysis of atropine to tropine and tropic acid is shown. [Figure 3] Generally, a proposed scheme for the inclusion complex of latanoprost and 2-hydroxypropyl-β-cyclodextrin is shown. [Figure 4] Generally, a proposed scheme for the formation of a latanoprost-cyclodextrin oil-in-water microemulsion system is shown. [Figure 5] Generally, latanoprost (the drug) is shown dissolved in oil droplets in a microemulsion system. [Figure 6] Generally, a proposed scheme for the atropine and 2-hydroxypropyl-β-bicyclodextrin inclusion complex is shown. [Figure 7] 1 shows the stability of the latanoprost packaging solution at 5° C. in general. [Figure 8] 1 shows the stability of the latanoprost packaging solution at 25° C. in general. [Figure 9] Generally, the daily release of latanoprost printed onto the lens over a one week period is shown. [Figure 10]Generally, the cumulative release of latanoprost in the lenses over a one week period is shown. Summary of the Invention

[0019] The present invention recognizes that medical devices, such as, but not limited to, contact lenses, can be fabricated with at least one coating fabricated at least in part using printing techniques to provide drug storage and drug release structures, particularly for hydrophobic drugs, and that such hydrophobic drugs can be stabilized with respect to hydrolysis, heating, and combinations thereof.

[0020] A first aspect of the present invention generally comprises a medical device incorporating at least one agent in at least one coating.

[0021] A second aspect of the present invention generally comprises a method of making a medical device that incorporates at least one agent in at least one coating.

[0022] A third aspect of the invention generally includes methods of treating or preventing a disease, disorder, or condition using the medical devices of the invention.

[0023] A fourth aspect of the present invention includes a packaged medical device that includes at least one drug delivery contact lens.

[0024] A fifth aspect of the invention includes a drug delivery contact lens.

[0025] A sixth aspect of the invention includes a method of making a drug delivery contact lens.

[0026] A seventh aspect of the present invention comprises an ink.

[0027] An eighth aspect of the invention includes a method of treating or preventing an ocular disease, disorder, or condition using a drug delivery contact lens. DETAILED DESCRIPTION OF THE INVENTION

[0028] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the nomenclature used herein and laboratory procedures that are well known and commonly employed in the art. These procedures are described in the art and in U.S. Pat. Nos. 5,160,463, 5,271,874, 5,018,849, 5,034,166, 5,414,477, 6,315,410, 6,899,426(B2), 7,638,137(B2), U.S. Published Patent Application No. 2009 / 0062381(A1), Day et al., Current Optometric Information and Terminology, Third Edition, American Optometric Association (1980), Howley's Condensed Chemical Dictionary (1981), Federation of Societies for Coatings Technology, and "Contact Lenses for Drug Delivery: Achieving Sustained Release with Novel Systems," Alvarez Lorenzo et al., American Journal of Drug Conventional methods are used, such as those provided in various general references, such as "Delivery," (2006) 4(3)(3)(5). Where a term is provided in the singular, the inventors also contemplate the plural of that term. The nomenclature used herein and the laboratory procedures described below are those well known and commonly used in the art. As used throughout this disclosure, the following terms shall be understood to have the following meanings, unless otherwise indicated:

[0029] "Directly" refers to the direct causation of a process without the need for intermediate steps.

[0030] "Indirectly" refers to an indirect causal relationship that requires an intermediate step.

[0031] A "digitally encoded image" or "digital image" refers to an image created or stored in digital form. A digitally encoded image may be created using methods known in the art, such as technical representations, scanning, or image translation. A digitally encoded image may be stored on a suitable storage medium, such as a magnetic medium, or a polymer, such as a cyclo-olefin copolymer. Multiple digitally encoded images may be stored together or separately and accessible individually or in combination to form a database of digitally encoded images. Such digitally encoded images may be modified using established methods, such as technical representations or image modification software. Multiple images may also be merged to form a new digitally encoded image.

[0032] "Solvent" refers to an aqueous organic or inorganic solvent such as water, isopropanol, tetrahydrofuran, or acetone.

[0033] "Surfactant" refers to a surface active agent as that term is known in the art, for example, an acetylene glycol or a polyoxyethylene alkyl.

[0034] "Dispersant" refers to dispersants known in the art, such as, for example, the Tergitol series from Union Carbide, polyoxylated alkyl ethers, alkyldiamino quaternary salts, or "Pecegal 'O'" from GAF (U.S. Patent No. 5,560,766). Dispersants are preferably used at about 0.1% to about 10%, more preferably about 0.5% to about 5%.

[0035] As used herein, "lens" refers to a composition of matter that can transmit light. The lens is preferably capable of acting as an optical lens, such as a contact lens. In certain aspects of the invention, the lens need not act as an optical lens, such as a contact lens, that is used for therapeutic purposes, as opposed to purposes related to correcting, improving, or altering the vision of a user.

[0036] "Contact lens" refers to a structure that can be placed on or in a wearer's eye. A contact lens can, but need not, correct, improve, or alter the user's vision. A contact lens can be of any suitable material known in the art or later developed, and can be a soft lens, a hard lens, or a hybrid lens. A contact lens can be in a dry or wet state.

[0037] "Soft lens" refers to a variety of soft lenses known in the art that are characterized, for example, as having at least one of the following properties: oxygen permeability, hydrophilicity, or flexibility.

[0038] "Hard lens" refers to a variety of hard lenses known in the art that are characterized, for example, as having at least one of the following properties: hydrophobicity, gas permeability, or rigidity.

[0039] "Hybrid lens" refers to a variety of hybrid lenses known in the art, such as, for example, lenses with a soft skirt and a hard center.

[0040] "Dry state" refers to the state of an article of manufacture or a portion thereof prior to hydration, or the state of an article of manufacture or a portion thereof under storage or use conditions.

[0041] "Wet state" refers to an article of manufacture or portion thereof in a hydrated state.

[0042] "Transparent" refers to a substantial portion of visible light being transmitted through the structure, such as 90% or more of the incident light.

[0043] "Opaque" refers to a substantial portion of visible light being reflected or absorbed by a structure, such as 90% or more of the incident light.

[0044] "Partially opaque" refers to a combination of transparent and opaque.

[0045] "Hydrogel" refers to a polymer that swells in an aqueous solution due to absorption of water. A hydrogel contains water or an aqueous solution as part of its structure.

[0046] "Polymer" refers to a linkage of monomers. Preferably, the polymer is a polymer suitable for use in a lens, such as a contact lens. The polymer can be, for example, a homopolymer, a heteropolymer, a copolymer, a hydrophobic polymer, a hydrophilic polymer, or any combination thereof.

[0047] "Hydrophobic polymer" refers to a polymer that does not absorb significant amounts of water or aqueous solutions (see US Pat. No. 5,034,166).

[0048] "Hydrophilic polymer" refers to a polymer that absorbs a significant amount of water or aqueous solutions (see U.S. Patent No. 5,034,166). Lens-forming materials suitable for the manufacture of contact lenses are disclosed in U.S. Patent Nos. 2,976,576, 3,220,960, 3,937,680, 3,948,871, 3,949,021, 3,983,083, 3,988,274, 4,018,853, 3,875,211, 3,503,942, 3,532,679, 3,621,079, 3,639,524, 3,640,525, 3,650,526, 3,660,527, 3,670,528, 3,680,529, 3,700,529, 3,710,529, 3,875,211, 3,503,942, 3,532,679, 3,621,079, 3,639,524, 3,720,529, 3,730,529, 3,740,529, 3,750,529, 3,760,529, 3,875,211, 3,875,211, 3,503,942, 3,532,679, 3,621,079, 3,639,524, 3,770,529, 3,780,529, 3,875,211, 3,875,211, 3,87 and 5,034,166.

[0049] "Hydrophilic monomer" refers to a monomer used to make soft lenses, such as hydroxyethyl methacrylate, methacrylic acid, or N-vinylpyrrolidone (US Pat. No. 5,271,874, US Pat. No. 5,272,010).

[0050] "Hydrophilic monomer" refers to a monomer used to make hard lenses, such as methyl methacrylate, ethoxyethyl methacrylate, styrene, or silicone (US Pat. No. 5,271,874, US Pat. No. 5,272,010).

[0051] "Homopolymer" refers to a polymer that contains a single type of monomer, such as hydroxyethyl methacrylate.

[0052] "Heteropolymer" refers to a polymer that contains two or more types of monomers, such as hydroxyethyl methacrylate and methacrylic acid.

[0053] "Copolymer" refers to the use of two different polymers to make a polymer chain.

[0054] "Acrylic polymer" or "acrylic" refers to various polymers of that genus and species known in the art, such as, for example, hydroxyethyl methacrylate.

[0055] "Silicone polymer" or "silicone" refers to various polymers of that genus and species known in the art, such as, for example, tris(tris(pentamethyldisiloxyanyl)-3-methacrylate-propylsilane or 3-methacryloxypropytris(trimethylsiloxy)silane).

[0056] "Polycarbonate polymer" or "polycarbonate" refers to various polymers of that genus and species known in the art, such as, for example, Lexan.

[0057] "Initiator" in the context of polymerization refers to an initiator as that term is known in the art, e.g., a chemical that starts a polymerization reaction.

[0058] "UV initiator" in the context of polymerization refers to UV initiators as that term is known in the art, such as, for example, chemicals that become reactive or activated by the adsorption of energy, such as, for example, UV energy, such as, for example, benzoin methyl ether.

[0059] "Binder" or "adhesive," as those terms are known in the art, refers to compounds used that function to increase the interaction between moieties, such as between a monomer and a polymer. An example of a binder or adhesive is hexamethylene diisocyanate or other isocyanate compounds.

[0060] "Thickener" refers to a compound used to increase the viscosity of a liquid or partially liquid mixture or solution, as that term is known in the art. An example of a thickener is polyvinyl alcohol.

[0061] "Anti-stick agent" or "non-stick agent" refers to a compound that facilitates the printing process utilizing a nozzle, as such terms are known in the art.

[0062] "Dispersant" refers to a surfactant added to a suspension medium to promote the distribution and separation of fine or very fine solid particles.

[0063] "Thermal initiator" in the context of polymerization refers to thermal initiators as that term is known in the art, e.g., chemicals that become activated or reactive upon absorption of thermal energy, such as, for example, Vazo-64 or azobisisobutyronitrile.

[0064] "Anti-bacterial agent" refers to a compound or composition that can act as a bactericide or bacteriostat or reduce the rate of growth of bacteria, such as tetrabutylammonium chloride.

[0065] "Antifungal agent" refers to a compound or composition that can act as a fungicide or bacteriostatic agent or reduce the rate of growth of fungi, such as benzalkonium chloride salicylic acid.

[0066] "Disinfectant" refers to a compound or composition that can reduce the type, number, or diversity of microorganisms.

[0067] "Humectant" refers to a compound that reduces evaporation, such as ethylene glycol.

[0068] "Printing" refers to the application of at least one printing formulation to a surface or structure. Printing can use any suitable device or method known in the art that is later developed for a particular purpose.

[0069] "Printing device" refers to any suitable device for printing onto a surface or structure known in the art or later developed for a particular purpose. Preferably, the printing device involves dispensing microdroplets of liquid. The size or volume of the microdroplets can vary, but generally, the smaller the microdroplets, the better the quality of the print produced. Preferred microdroplets are from about 1 picoliter to about 1,000 microliters, preferably from about 10 picoliters to about 10 microliters, or from about 100 picoliters to about 1 microliter. Preferred microdroplets can also be in the microliter range.

[0070] "Inkjet printing" refers to printing using a printing device that includes at least one inkjet. Such printing devices are commercially available through, for example, Hewlett Packard Corporation (e.g., DeskJet 560C printer cartridges) and Encad Corporation.

[0071] "Piezo printing" refers to printing using a printing device that includes at least one piezo printing structure. Such piezo printing structures are known in the art, such as those available through Packard Instruments and Hewlett Packard Corporation or Canon Inc.

[0072] "Thermal printing" refers to printing using a printing device that includes at least one thermal printing structure. Such thermal printing structures are known in the art, such as those available through Hewlett Packard Corporation.

[0073] "Laser printing" refers to printing using a printing device employing at least one laser printing structure, such as those known in the art, such as those available through Cannon or Hewlett Packard Corporation.

[0074] "Pad transfer printing" refers to printing using a pad transfer printing device. Such pad transfer printing devices are known in the art, particularly for printing in the field of contact lenses. Briefly, a layer is disposed or printed on the pad transfer device, and the layer on the pad transfer device is transferred to another surface, such as a polymer or a lens or other surface (see U.S. Pat. No. 3,536,386 issued Oct. 27, 1970 to Spivack; U.S. Pat. No. 4,582,402 issued Apr. 15, 1986 to Knapp; U.S. Pat. No. 4,704,017 issued Nov. 3, 1987 to Knapp; U.S. Pat. No. 4,704,017 issued Jul. 1991 to Knapp). No. 5,034,166 issued to Rawlings et al. on April 23, 1992; U.S. Pat. No. 5,106,182 issued to Briggs et al. on April 21, 1992; U.S. Pat. No. 5,352,245 issued to Su et al. on October 4, 1994; U.S. Pat. No. 5,452,658 issued to Shell on September 26, 1995; and U.S. Pat. No. 5,637,265 issued to Misciagno et al. on June 10, 1997.

[0075] "Impregnation" refers to an agent contacting a surface, such as a polymer, and the agent diffuses into the polymer (EP 0357062 to Pfortner, published March 7, 1990).

[0076] "Chemical bond" refers to a covalent or non-covalent bond.

[0077] A "polymer-polymer bond" refers to two polymers that form a covalent or non-covalent bond, such as by cross-linking the polymers, such as formed between two polymers, such as hydroxyethyl methyl acrylate and ethylene glycol dimethacrylate.

[0078] "Dry state" refers to a polymer that is not fully hydrated.

[0079] "Wet state" refers to a polymer that is fully hydrated.

[0080] "Forming a lens" or "manufacturing a lens" refers to any method or structure known in the art or later developed that is used to form a lens. Such forming may be done using, for example, cast molding, spin casting, cutting, grinding, laser cutting, stamping, trimming, engraving, etching, etc. (U.S. Patent No. 4,558,931, issued December 17, 1985 to Fuhrman).

[0081] "Casting," in the context of forming a lens, refers to forming at least a portion of a lens using a mold (see U.S. Patent No. 3,536,386 issued to Spivak on October 27, 1970; U.S. Patent No. 3,712,718 issued to LeGrand et al. on January 23, 1973; U.S. Patent No. 4,582,402 issued to Knapp on April 15, 1986; U.S. Patent No. 4,582,402 issued to Knapp on November 3, 1987). U.S. Patent No. 4,704,017 issued to Briggs et al. on April 21, 1992; U.S. Patent No. 5,106,182 issued to Briggs et al. on April 21, 1992; U.S. Patent No. 5,160,463 issued to Evans et al. on November 3, 1992; U.S. Patent No. 5,271,874 issued to Osipo et al. on December 21, 1993; and EP 0357062 issued to Pfortner on March 7, 1990.

[0082] "Spin casting" in the context of forming lenses refers to the formation of lenses using centrifugal force (U.S. Patent No. 3,557,261, issued January 19, 1971 to Wichterle and U.S. Patent No. 5,034,166, issued July 23, 1991 to Rawlings et al.).

[0083] "Information storage medium" refers to any medium of expression capable of permanently or temporarily storing information in any suitable form. Preferred information storage media include paper, electronic media, magnetic media, or polymers such as cyclo-olefin copolymers.

[0084] "Electronic media" refers to information storage media capable of storing information in electronic form. For example, electronic media includes magnetic storage media such as diskettes.

[0085] "Machine-readable form" refers to information stored on or within an information storage medium in a form, language, or arrangement that allows a machine, such as a central processing unit (CPU), to access and use the information.

[0086] A "database" refers to a collection of information, such as digital images. The information is preferably provided on or in an information storage medium and may be separate from or integrated with the central processing unit.

[0087] "Printable formulation" refers to a printable formulation that can be used in conjunction with a printing technique or printing device to provide at least one structure, at least one layer, or a combination thereof, of the present invention.

[0088] "Subject" refers to, but is not limited to, a human or non-human primate; a companion animal, such as, but not limited to, a dog, cat, bird, fish, reptile, amphibian, fox, wolf, pig, horse, or other companion known in the art; a laboratory animal, such as, but not limited to, a mouse, rat, guinea pig, rabbit, dog, cat, ferret, pig, or other laboratory animal known in the art; a working animal, such as, but not limited to, a dog, horse, or other working animal known in the art; or any other animal known in the art that may require or for testing the techniques of the present invention.

[0089] "Digital printing" refers to printing at least a portion of the layers of the present invention using at least one digital image printing technique.

[0090] "3D printing" or "three-dimensional printing" refers to the printing of three-dimensional structures using suitable printing technology and printers known in the art or later developed. 3D printing is useful in creating parts, products, or layers one or more layers at a time using a computer-driven additive process. 3D printing can build parts or other structures, such as layers, directly from CAD drawings or other digital images that have been preferably cross-sectioned into many, if not hundreds or thousands of layers, using any suitable material, such as plastic or metal. 3D printing offers a faster and cheaper alternative to machining, including but not limited to, cutting, turning, grinding, and drilling materials, such as solid materials. While various techniques are used in 3D printing in related fields, 3D printers use additive manufacturing, i.e., building a part or structure one layer at a time, with thicknesses ranging from about 1 millimeter to less than 1 / 1000 of an inch. The build material may be in any suitable form, such as, but not limited to, a liquid, powder, or sheet material that is cured by heat, UV light, chemical reaction, or other suitable method.

[0091] Other technical terms used herein have their ordinary meaning in the technical field in which they are used, as exemplified by various technical dictionaries.

[0092] Prologue The present invention recognizes that medical devices, such as, but not limited to, contact lenses, can be fabricated with at least one coating fabricated at least in part using printing techniques to provide drug storage and drug release structures, particularly for hydrophobic drugs, and that such hydrophobic drugs can be stabilized with respect to hydrolysis, heating, and combinations thereof.

[0093] As an important non-limiting introduction to the present invention, the present invention includes several general and useful aspects, including the following. 1) Generally, medical devices, including pharmaceuticals. 2) Generally, a method for making a medical device containing a pharmaceutical agent. 3) Generally, methods of treating or preventing diseases, disorders, or conditions using the medical devices of the present invention. 4) A packaged medical device comprising at least one drug delivery contact lens. 5) Drug delivery contact lenses. 6) A method for making drug delivery contact lenses. 7) Ink. 8) Methods of treating or preventing ocular diseases, disorders, or conditions using drug delivery contact lenses.

[0094] These aspects of the invention, as well as other aspects described herein, can be achieved using the methods, articles of manufacture, and compositions of matter described herein. It will be further recognized that various aspects of the invention can be combined to create desirable embodiments of the invention, to gain a full appreciation of the scope of the invention.

[0095] I. Medical Devices Including Pharmaceuticals - General The present invention includes an article of manufacture comprising: a) a medical device comprising at least one surface; and b) one or more coatings disposed on at least a portion of the at least one surface. The one or more coatings may include at least one pharmaceutical agent.

[0096] Additionally, U.S. Patent No. 9,931,296 and U.S. Patent No. 10,413,506 to Doshi all relate generally to medical devices containing pharmaceutical agents, particularly drug delivery contact lenses, and are hereby incorporated by reference for purposes specifically directed to medical devices containing pharmaceutical agents, particularly drug delivery contact lenses.

[0097] A. Medical Devices The medical device of the present invention can be any known in the art or later developed, and can be implanted into a subject, as is the case with many medical devices known in the art, such as cardiac stents, joint replacements, especially hip and knee replacements, birth control sticks, pacemakers, breast implants, facial implants for reconstructive or cosmetic purposes, such as cheek and chin implants, intrauterine devices (IUDs), pins and meshes and resorbable materials (such as, but not limited to, polylactic acid (PLA)) such as those known in the art for bone reconstruction or fixation, dental implants, intravascular filters for trapping blood clots, optical lens replacements for cataract treatment, and voice boxes for laryngeal cancer patients.

[0098] The medical devices of the present invention may also be non-implantable types known in the art, such as, for example, contact lenses, dental appliances, drug patches, transdermal drug patches, including, but not limited to, contraception, Alzheimer's disease patches, smoking cessation patches, hearing aids, earplugs, or other devices inserted into the ear to treat swimmer's ear and ear infections, etc.

[0099] The medical devices of the present invention can be made of any suitable material or combination of materials appropriate for the purpose and location in or on the subject where the medical device will ultimately reside. The choice of material for a medical device can be determined by one skilled in the art, and there are many examples in the prior art for one to follow. In the present invention, it is generally the surface of the medical device that is provided with the coating, although this need not be an exclusive requirement.

[0100] B. Surface The surface of a medical device coated in the manner of the present invention can be of any suitable material and will generally be determined or influenced by the nature of the medical device and its location and duration of implantation or non-implantation in or on a subject.

[0101] Many medical devices exhibit metals on their surfaces. Examples include, but are not limited to, bone pins and meshes for bone repair and stabilization. Metals that can be used as surfaces include, for example, steel, stainless steel, gold, silver, etc.

[0102] Some medical devices present plastics or polymers on their surfaces. Examples include, but are not limited to, contact lenses, IUDs, and implantable contraceptive sticks. The polymers and plastics available for use in medical devices are diverse and too numerous to list. Individual polymers and plastics are discussed further herein and are intended as a non-exhaustive list of such materials.

[0103] Other medical devices exhibit partially polymerized polymers during their manufacture, but they may not necessarily be present in the final product. Partially polymerized polymers may be used as intermediates to facilitate bonding with other components of the device. Examples include, but are not limited to, contact lenses.

[0104] Still other medical devices present polymeric matrices on their surfaces. Examples include, but are not limited to, materials that allow for skin or other tissue regeneration for trauma, disease, disorders, conditions, etc., such as burn treatment, such as, but not limited to, those containing fibronectin or other structural proteins. The polymeric or protein matrix can be any suitable material, such as, but not limited to, proteins, nucleic acids, and carbohydrates.

[0105] Additionally, still other medical devices present silicone, ceramic, glass, carbon (including nanotubes and graphite), and fabrics on their surfaces. Examples include, but are not limited to, breast implants, penal implants, hip replacement parts, knee replacement parts, dressings for burns and trauma wounds, etc. The silicone, ceramic, glass, carbon (including, but not limited to, graphite, including sheets, carbon nanostructures such as tubes, balls, sheets, and other structures), and fabrics can be any suitable and art-implemented material.

[0106] The surface of the medical device may also, in some cases, be pretreated or modified by various processes to clean or prepare the surface to accept the coating of the present invention. Some pretreatments, such as abrading, scarring, or scoring, may be physical in nature, while other pretreatments may be chemical in nature. Preferred chemical processes include, but are not limited to, chemical coating, chemical cleaning, chemical texture modification, chemical or electrochemical activation, or the creation of reactive groups on or in the at least one surface, the application of one or more chemicals to the at least one surface, and combinations thereof.

[0107] C. Drug reservoir layer The drug reservoir layer functions to store a drug for later release from the coating. The drug reservoir layer is preferably porous or otherwise capable of containing a drug for this purpose. In one aspect of the invention, the drug reservoir layer is a solid or semi-solid, such as a gel or sol, that can reversibly entrap a drug for later release. The drug reservoir layer can be initially provided without a drug, and the drug can be added in a later step. Alternatively, the drug reservoir layer can be provided with the drug in one step. The drug reservoir layer is preferably fabricated using a printing technique. The choice of polymer depends on several factors, including, for example, the printing technique used to print the drug reservoir layer.

[0108] The drug reservoir layer may comprise a polymer having the above properties. Preferred polymers include, but are not limited to, polyHEMA, polyGMA, polyvinyl alcohol, polyDMA, PMMA (polymethylacrylic acid), polycarbonate, PVP (polyvinylpyrrolidone), siloxane, etc. Depending on the polymer and printing technique selected, the polymer may be provided in a monomeric state and later polymerized, or alternatively, may be provided in a partially polymerized state.

[0109] The drug reservoir layer may also comprise a partially polymerized polymer having the above properties, and may be any suitable one. Preferred polymers include, but are not limited to, polyHEMA, polyGMA, polyvinyl alcohol, polyDMA, PMMA (polymethylacrylic acid), polycarbonate, PVP (polyvinylpyrrolidone), siloxane, etc. Depending on the partially polymerized polymer and printing technique selected, the partially polymerized polymer may be provided in a monomeric state and later partially polymerized, or alternatively, may be provided in a partially polymerized state.

[0110] The drug reservoir layer can comprise a polymer matrix having the above properties, and can be any suitable one. Preferred polymer matrices include, but are not limited to, proteins, nucleic acids, and carbohydrates. Depending on the polymer and printing technique selected, the polymer matrix can be provided in a monomeric state and subsequently polymerized, or alternatively, can be provided in a polymerized state.

[0111] Additionally, still other materials can be used for the drug reservoir layer, such as, but not limited to, silicone, ceramic, glass, carbon (including nanotubes and graphite), and fabric. The silicone, ceramic, glass, carbon, and fabric can be any suitable material practiced in the art, and the selection will generally relate to their physical properties, such as their ability to accept and retain the drug for later release, as well as the printing technique selected to print the drug reservoir layer, as well as other materials used in the drug reservoir layer.

[0112] Preferred materials for the drug reservoir layer include derivatized oligomers. Preferred derivatized oligomers include, but are not limited to, HEMA (mydroxyethyl methyl acrylate), DMA (dimethylacrylamide), GMA (glycidol methyl acylate), PVA (polyvinyl alcohol), silicone, or siloxane. As with other materials used, the choice of derivatized oligomer depends on the physical properties of the material and the printing technique used to create the drug reservoir layer.

[0113] If the material used in the drug reservoir layer needs to be polymerized and cured, a polymerization or curing initiator must be used. The requirements for the polymerization or curing initiator depend on the specific type of polymer / monomer utilized, and the selection is well established in the art. Preferred polymerization or curing initiators include, but are not limited to, at least one of UV curing, thermal curing, room temperature curing, simultaneous printing, and UV curing, or e-beam.

[0114] As depicted in the figures, the drug reservoir layer can release drug in one or more directions. For example, with a contact lens, when the contact lens is engaged on the eye, the drug receiving layer can release drug toward the cornea or toward the eyelid. The use of layers, or the lack thereof, allows for the design of a structure that allows drug to be released in one or both directions.

[0115] The material used for the drug receiving layer may be bonded to the surface, permanently bonded to the surface, or not bonded to the surface. Certain materials that can be used for the drug reservoir layer may be inherently bonded to the surface or not bonded to the surface, depending on the nature of the surface. As explained above, the surface may be modified, such as through chemical agents or other methods or techniques, to allow the drug reservoir layer to chemically bond or react with the drug receiving layer components.

[0116] D. Drug-receptor layer Fabrication of the drug reservoir layer may include the use of a drug receiving layer. In this case, the drug receiving layer is applied to a surface by a suitable means or method, such as printing. The drug receiving layer may or may not contain a drug at this point. The drug receiving layer has physical and chemical properties to allow efficient and localized reception of the applied drug using a suitable method, preferably printing. Once the drug receiving layer is applied to the surface, the drug or additional drug is applied to the drug receiving layer to entrap the drug or additional drug therein for later release.

[0117] The drug receiving layer can be of any suitable material with the appropriate physical and chemical properties to achieve a structure with the desired properties discussed herein. The drug receiving layer can be a chemical. Preferred materials for the drug receiving layer include, but are not limited to, superabsorbent polymers such as polyvinylpyrrolidone homopolymer, polyvinylpyrrolidone copolymer, polyacrylamide homopolymer, polyacrylamide copolymer, polyacrylate homopolymer, polyacrylate copolymer, proteinaceous materials, carbohydrates, or combinations thereof.

[0118] Since there may be other layers applied to the surface before the drug-receiving layer, the drug-receiving layer may be applied to such previous layers using any suitable method. As with the other layers of the coating of the present invention, the drug-receiving layer may be applied by any suitable method, preferably by printing techniques.

[0119] When the drug-receiving layer comprises a polymer, it may contain an adhesive or crosslinking agent to help trap or immobilize the drug for subsequent release from the drug reservoir layer. Preferred adhesives include, but are not limited to, methylacrylate, titanate, and silane. Preferred crosslinking agents include, but are not limited to, HDI, and derivatized oligomers of HEMA, GMA, DMA, and PVA, polyfunctional aziridines, and polyfunctional carbodiimides.

[0120] In one preferred embodiment of the present invention, the drug receiving layer comprises a superabsorbent polymer, including, but not limited to, polyvinylpyrrolidine homopolymer, polyvinylpyrrolidone copolymer, polyacrylamide homopolymer, polyacrylamide copolymer, polyacrylate homopolymer, polyacrylate copolymer, proteinaceous material, carbohydrate, or combinations thereof.

[0121] Preferred methods of application of the drug-receiving layer of the present invention are printing and coating techniques, including but not limited to direct coating, droplet or microdroplet application, inkjet printing, dipping, immersion, spin coating, drip coating, screen coating, silk screen coating, or pad printing, such as methods known in the art.

[0122] E. Drugs The drug provided in the drug reservoir is a matter of choice for one of ordinary skill in the art, depending on the disease, disorder, or condition to be treated or prevented, along with the location of the article of manufacture on or within the subject, and along with the nature of the medical device being used. For example, a drug for the treatment or prevention of glaucoma would be provided by a contact lens, while a drug for the treatment or prevention of restenosis would be provided by a stent.

[0123] The drug released from the article of manufacture should be of an appropriate amount, duration, and dosage to be effective for preventing or treating at least one disease, disorder, or condition. The amount, duration, and dosage of drug for a particular location for such treatment or prevention are available to those skilled in the art. The present invention allows for localized and controlled administration in terms of amount and duration of administration, and can allow for continuous or intermittent release of drug for drug delivery regimes.

[0124] One preferred aspect of the present invention is the delivery of a drug to the eye to treat or prevent or cure an ocular disease, condition, or disorder. Drugs known to treat or prevent various diseases and conditions exist with appropriate regimes of dose, time course of administration, and route of administration. The present invention allows for variable dose and time course regimes, as well as providing a highly localized route of administration. Preferred drugs that are antibiotics useful for treating ocular infections include, but are not limited to, gentamicin, tobramycin, erythromycin, polytrim, cirproflizacin, viamox, and xymar. Preferred drugs used to treat glaucoma include, but are not limited to, timolol, alphagan, axopt, cosopt, lumigan, travatan, xalatan, and combigan. Preferred anti-inflammatory agents used to treat ocular diseases, disorders, and conditions include, but are not limited to, perdforte, lotemax, flurometholone, nevanac, acular, and xibrom. Other agents known in the art for treating or preventing ocular diseases, conditions, or disorders include, but are not limited to, pilocarpine, dexamethasone, pilocarpine nitrate, tropicamide, timolol, timolol nitrate, timolol maleate, methylprednisolone, flurbiprofen, penillin G, gentamicin, ciprofloxacin, tobramycin, sulfacetamine sodium, indomethacin, hydrocortisone, indomethacin, pilocarpine hydrochloride, ciprofloxacin hydrochloride, insulin, indomethacin, and ketorolac tromethamine, either alone or in combination.(For example, Yasmin Sultana,Rahul Jain,Rahul Rathod,Asgar Ali,M.Aqil,Department of Pharmaceutics,Faculty of Pharmacy,Hamdard University,New Delhi 110062,INDIA.“Advances in Ophthalmic Drug Delivery Systems:Part I”By-04 / 12 / 2005,in Latest Reviews Vol.3 Issue 2,2005,www.pharmmainfo.net / reviews / advances-opthalmic-drug-delivery-systems-part-i, and Yasmin Sultana,Rahul Jain,Rahul Rathod,Asgar Ali,M.Aqil,Department of Pharmaceutics,Faculty of Pharmacy,Hamdard University,New Delhi 110062,INDIA,“Advances in Ophthalmic Drug Delivery Systems:Part II” By-04 / 12 / 2005, in Latest Reviews Vol. 3 Issue 2, 2005, www.pharmmainfo.net / reviews / advances-opthalmic-drug-delivery-systems-part-ii(4-1-2011) (see “Sultana et al. Part II”). Sultana et al. Part I and Sultana et al. Part II provide a discussion and listing of drugs and their combinations for treating or preventing various diseases, conditions, and disorders of the eye. The patent literature also provides ocular drug delivery devices and methods provided by Sultana et al. Part I and Sultana et al. Part II.See, for example, U.S. patents and U.S. published patent application serial numbers 4,925,581, 5,227,372, 5,296,228, 5,480,914, 5,578,638, 5,705,194, 5,888,493, 6,242,442, 6,297,240, 6,316,441, 6,410,045, 6,416,740, 2002 / 0071874, 2002 / 0197300, 2003 / 0017199, 5,837,226, 6,017,875, 6,1 No. 54,671, No. 6,217,896, No. 6,319,240, No. 6,335,335, No. 6,410,045, No. 6 ,539,251, 6,579,519, 2002 / 0026176, 2003 / 0147849, 2002 / 00 See Patent Publications Nos. 64513, 2002 / 0114778, 2002 / 0119941, 2002 / 0197300, 2003 / 0175324, 2003 / 0185892, 2003 / 0191426, and 2004 / 0037889.

[0125] In one aspect of the invention, the drug is provided in a drug reservoir layer that releases the drug from the drug reservoir, either alone or in combination with other components. Alternatively, the drug may be provided in the drug reservoir layer along with such other components and then released from the drug reservoir layer without such other components. In a preferred embodiment of the present invention, the drug is provided at least partially as the sole active ingredient, without association with any other components that may alter the activity or deliverability of at least one drug. That is, the drug is provided or released alone and without other components, such as, but not limited to, those used to encapsulate, microencapsulate, or emulsify the drug.

[0126] Drugs can be provided or released from the drug-receiving layers and coatings of the present invention in an encapsulated form. Drug encapsulation is well known in the art and is within the skill of those skilled in the art. Preferred encapsulation materials include, but are not limited to, biodegradable polycyanoacrylate, biodegradable poly(alkyl cyanoacrylate), biodegradable calcium phosphate, legumin, polyester-grafted polysaccharides (amphiphilic copolymers), poly(methylidene malonate), gelatin, poly(E-caprolactone), sodium alginate, agarose hydrogel, PMMA, biotinylated poly(ethylene glycol) conjugated with lactobionic acid, poly(vinyl alcohol) hydrogel, biotinylated pullulan acetate, diblock copolymers, and mixtures thereof. Polycyanoacrylates are preferably, but not limited to, polybutyl cyanoacrylate, polyhexyl cyanoacrylate, polyethyl cyanoacrylate, polyisobutyl cyanoacrylate, and mixtures thereof.

[0127] The drug may be provided or released from the drug-receiving layer and coating of the present invention in microencapsulated form. Microencapsulation of drugs is known in the art and within the skill of a person skilled in the art, e.g., "Microencapsulation Techniques, Factors Influencing Encapsulation Efficiency: A Review," Jyothi et al., Journal of Microencapsulation, Informa Health Care, Volume 27, Issue 3, pp. 187-197.

[0128] Drugs can be delivered or released from the drug-receiving layers and coatings of the present invention nanoencapsulated in nanoparticles with an encapsulating material. Nanoencapsulation of drugs is known in the art and within the skill of those skilled in the art. Non-limiting examples of nanoencapsulating materials include chitosan nanoparticles, human serum albumin nanoparticles; silica nanospheres, PEGylated core-shell nanoparticles, biodegradable PGGA (poly(D,L-lactide-co-glycolide)) particles, PLA (polylactic acid), PGA, PLG (poly-(D,L-glycolide)) polymeric nanoparticles, biocompatible gliadin nanoparticles, low pH-sensitive PEG-stabilized plasmid-lipid nanoparticles, tocopherol derivative-stabilized nanosized emulsion particles, PLA-PEG nanoparticles, nanoparticles composed of hydrophilic proteins bound to apolipoprotein E, biodegradable poly(vesiln-caproline) nanoparticles, biotinylated poly(ethylene glycol) conjugated with lactobionic acid, carboxymethyl dextran magnetic nanoparticles, and mixtures thereof.

[0129] The drug may be provided or released from the drug-receiving layers and coatings of the present invention in an emulsion, a water-in-oil emulsion, an oil-in-water emulsion, or a liposome. Drug-containing emulsions, water-in-oil emulsions, oil-in-water emulsions, and liposomes are known in the art, such as U.S. Pat. No. 7,638,137 (B2), and are within the skill of one of ordinary skill in the art.

[0130] The agents of the present invention can take any suitable form, such as small molecules or biological or biomimetics, as those terms are known in the art. As previously mentioned, a wide variety of agents in various forms are known for treating or preventing diseases, disorders, or conditions. The present invention is not limited to any particular type or class of agent. The structure of the coating of the present invention can be tailored for the storage and release of any suitable agent. For example, the porosity of the drug reservoir layer tends to be greater for larger molecules and similarly tends to be smaller for small molecules. Exemplary small molecules include hormones for hormone replacement therapy or nucleoside analogs as antiviral agents. Exemplary biological agents and related biomimetics include the general classes of enzymes, transport proteins, structural proteins, storage proteins, hormone proteins, receptor proteins, contractile proteins, defense proteins, cytokines, clotting factors, and vaccines. Examples of preferred proteins include, but are not limited to, insulin for the treatment of diabetes, and antibodies and monoclonal antibodies for the treatment of infectious diseases or for the targeted delivery of related agents.

[0131] Essentially, virtually any drug may be useful in the present invention, and an enumerated list is beyond the scope of this document. By way of example, the following is a non-limiting and non-exhaustive list of general classes of drugs useful in the present invention: anti-inflammatory drugs, anti-allergic drugs, and antibiotics, drugs for the treatment of glaucoma, drugs for the treatment of macular degeneration, ophthalmic drugs, hydrophilic drugs, hydrophobic drugs, antiparasitic drugs, steroids, antibiotics and drugs for the treatment of dry eye, and drugs for the treatment of ocular discomfort.

[0132] F. Printing A wide variety of printing techniques are applicable to applying the various layers of the coating of the present invention. The choice of which printing technique to use is a matter of choice for those skilled in the art based on the particular size, shape, thickness, and other properties of the layer to be applied. In addition, if a portion of the layer is printed in a liquid or semi-solid form and then converted to a solid or semi-solid form, for example, but not limited to, by polymerization or partial polymerization, the properties of the printing liquid or semi-solid should be taken into consideration. As a preferred embodiment of the present invention, the compositions of Doshi et al., published U.S. Application No. 2008 / 0062381(A1), published March 13, 2008, are applicable, especially when a pigment is optionally present in such a formulation and at least one drug is optionally provided in such a formulation.

[0133] Preferred printing methods are digital in nature, such as those described by Doshi et al. (US 2008 / 0062381(A1)), which is incorporated herein by reference in its entirety, to enable relatively accurate methods and means for providing high-quality, well-defined printed products. Because the methods and associated devices are digital in nature, the printing process is adaptable to computer control and product design. Preferred digital printing methods and structures are discussed herein. As a non-limiting introduction to digital printing methods and devices, the following digital printing methods are preferred: inkjet printing, three-dimensional printing (3D printing), piezo printing, thermal printing, laser printing, and MEMS printing (micromachined electromechanical systems), where the printing head or related or associated structures are rotary or non-rotary. Generally, although not exclusively, the printing solution of the present invention replaces the ink solution of existing commercially available printing devices, specifically within the printing cartridge.

[0134] Similarly, preferred printing methods include pad printing, including but not limited to pad transfer printing, which are known in the art. Pad printing is less precise than digital printing, but is the preferred printing method for the present invention. Pad printing for printing an image of the iris of the eye onto a contact lens is known in the art (see, for example, U.S. Patent Nos. 5,302,978, 5,414,477, and 4,668,240).

[0135] Inkjet printing is known in the art and can take a variety of forms and associated structures, as discussed herein. Generally, inkjet printing refers to printing devices and methods that utilize high-precision printing methods and structures that allow for the production of high-quality, precise structures. Generally, available inkjet printing devices and structures can be utilized with minimal modification, where the ink solution normally present in an inkjet cartridge or reservoir is replaced with a solution containing a polymerizable monomer and an associated polymerization initiator, as needed. After being dispensed from the inkjet printing structure, the polymerizable monomer can be polymerized purposefully and at a rapid rate.

[0136] Three-dimensional printing is primarily, though not exclusively, based on inkjet printing technology. These methods and devices allow for the production of one-off or multiple copies of a structure. Generally, a polymerizable solution is placed in a printing device, dispensed under computer control, and polymerized in repeated printing cycles or steps to produce a three-dimensional structure. Examples of available and preferred 3D printing devices and associated structures and cartridges include, but are not limited to, those disclosed herein and those known in the art or later developed.

[0137] Piezo printing is a subtype of inkjet printing and is the preferred printing method of the present invention. Examples of available and preferred piezo printing devices and related structures and cartridges include, but are not limited to, those disclosed herein and those known in the art or later developed.

[0138] Thermal printing is a subtype of inkjet printing and is the preferred printing method of the present invention. Examples of available and preferred thermal printing devices and associated structures and cartridges include, but are not limited to, those disclosed herein and those known in the art or later developed.

[0139] Laser printing is a subtype of inkjet printing and is the preferred printing method of the present invention. Examples of laser printing devices and associated structures and cartridges include, but are not limited to, those disclosed herein and those known in the art or later developed.

[0140] Optionally, the inkjet printing device may include a rotating printer head, which may allow for improved printing on curved surfaces.

[0141] Another preferred printing method is MEMS printing, where MEMS stands for micromachined electromechanical systems, a technology that allows for the printing of integrated circuit substrates but is applicable to the fabrication of very small functional structures. Examples of functional structures made by MEMS printing include mechanical gears and other mechanical devices, lab-on-chip structures for performing chemical reactions and laboratory procedures, including diagnostic procedures.

[0142] G. Modulation of Drug Release The combination of components of the coatings of the present invention, particularly the at least one drug reservoir layer containing at least one drug, allows for controlled release of at least one drug from the coating. The coating structure allows for the manufacture of coating layers that can specifically tailor the release of at least one drug from the coating layer for desired characteristics, including, but not limited to, dose, regime, time course of delivery, and route of administration. Because the article of manufacture can be localized to a specific location on a subject, the drug can be delivered in a specific regimen and in a specific, focused manner, which can allow for less drug to be administered to the subject than would be the case if administered via a more systematic route of administration. While specific physicochemical phenomena associated with drug release from coating layers are discussed herein, the list should not be considered limiting.

[0143] In one aspect of the invention, the release of at least one drug from the coating layer can be controlled by diffusion out of the drug reservoir layer. Determining the effect of diffusion on the transport of chemicals out of the substrate can be accomplished through routine experimentation using established methods and procedures.

[0144] In another embodiment of the present invention, the release of at least one drug from the coating layer can be controlled by diffusion out of the drug reservoir layer. Determining the effect of diffusion on chemical transport out of the coating layer of the present invention can be accomplished through routine experimentation using established methods and procedures.

[0145] In another embodiment of the present invention, the release of at least one drug from the coating layer can be regulated by mass action out of the drug reservoir layer. Determining the effect of mass action on the transport of chemicals out of the coating layer of the present invention can be accomplished through routine experimentation using established methods and recipes.

[0146] In yet another aspect of the present invention, the release of at least one drug from the coating layer can be controlled by a concentration gradient of the at least one drug out of the drug reservoir layer. Determining the effect of a chemical gradient on chemical transport out of the coating layer of the present invention can be accomplished through routine experimentation using established methods and procedures.

[0147] In yet another aspect of the present invention, the release of at least one drug from the coating layer can be controlled by the solubility of the at least one drug in the environment from the drug reservoir layer. Determining the effect of solubility on chemical migration from the coating layer of the present invention can be accomplished through routine experimentation using established methods and procedures.

[0148] In yet another aspect of the invention, the release of at least one agent from the coating layer can be regulated by the temperature at which the article of manufacture is maintained (either at a storage temperature or during use) at which the at least one agent leaves the drug reservoir layer. Determining the effect of temperature on chemical migration out of the coating layers of the invention can be accomplished through routine experimentation using established methods and recipes.

[0149] In yet another aspect of the present invention, the release of at least one drug from the coating layer can be controlled by the molecular weight of the at least one drug exiting the drug reservoir layer. Determining the effect of molecular weight on chemical transport out of the coating layer of the present invention can be accomplished through routine experimentation using established methods and procedures.

[0150] In yet another aspect of the present invention, the release of at least one drug from the coating layer can be controlled by a concentration gradient of the at least one drug from the drug reservoir layer. Determining the effect of chemical gradient transition on chemical release from the coating layer of the present invention can be accomplished through routine experimentation using established methods and procedures.

[0151] In a further aspect of the present invention, the release of at least one drug from the coating layer can be controlled by the thickness of the coating layer and its components, i.e., the drug reservoir layer. Determining the effect of the thickness of the coating and its components on the migration of chemicals out of the coating layer of the present invention can be accomplished through routine experimentation using established methods and recipes.

[0152] In yet a further aspect of the present invention, the release of at least one drug from the coating layer can be controlled by the porosity of the coating layer and its components, i.e., the drug reservoir layer. Determining the effect of the porosity of the coating and its components on the migration of chemicals out of the coating layer of the present invention can be accomplished through routine experimentation using established methods and recipes.

[0153] In yet a further aspect of the present invention, the release of at least one agent from the coating layer can be controlled by the pore size of the coating layer. The effect of the pore size of the coating layer and its components on the migration of chemicals out of the coating layer of the present invention can be determined through routine experimentation using established methods and recipes.

[0154] In yet a further aspect of the present invention, the release of at least one drug from the coating layer can be controlled by the molecular exclusion size of the coating layer and its components, i.e., the drug reservoir layer. Determining the effect of the molecular exclusion size of the coating and its components on the migration of chemicals out of the coating layer of the present invention can be accomplished through routine experimentation using established methods and recipes.

[0155] In another aspect of the present invention, the release of at least one drug from the coating layer can be controlled by the moisture content of the coating layer and its components, i.e., the drug reservoir layer. Determining the effect of moisture content of the coating and its components on chemical migration out of the coating layer of the present invention can be accomplished through routine experimentation using established methods and recipes.

[0156] In yet another aspect of the present invention, the release of at least one drug from the coating layer can be controlled by the concentration of the drug in the coating layer and its components, i.e., the drug reservoir layer. Determining the effect of the concentration of the drug in the coating and its components on the migration of chemicals out of the coating layer of the present invention can be accomplished through routine experimentation using established methods and recipes.

[0157] In a further aspect of the present invention, the release of at least one drug from the coating layer can be controlled by the concentration of the drug in the coating layer and its components, i.e., the drug reservoir layer. Determining the effect of the drug concentration in the coating and its components on the transport of our chemicals through the coating layer of the present invention can be accomplished through routine experimentation using established methods and recipes.

[0158] In yet a further aspect of the present invention, the release of at least one drug from the coating layer can be controlled by the packaging environment of the coating layer and its components, i.e., the drug reservoir layer (such as the concentration of the drug in the packaging solution, if present). Determining the effect of the packaging environment of the coating and its components on the migration of our chemicals from the coating layer of the present invention can be accomplished through routine experimentation using established methods and recipes.

[0159] In one aspect of the invention, the drug can exhibit sustained release from the coating layer over time. This can be achieved by first establishing the relationship of release rate for a given drug with a given material of the layer in terms of thickness variation, drug solubility, and concentration. In another aspect of the invention, the drug can exhibit intermittent release from the coating layer over time.

[0160] In yet another embodiment of the present invention, two or more drugs may be released from the coating layers of the present invention. Alternatively, two or more drugs may be provided within a single drug reservoir layer.

[0161] H. Contact lenses In one preferred embodiment of the present invention, the medical device comprises a contact lens. Contact lenses containing a drug on or within the contact lens are known in the art. However, these contact lenses do not provide the structure of the present invention, such as at least one coating including at least one drug reservoir layer that may contain at least one drug, and at least one layer that may include a structure, wherein the release of at least one drug from at least one coating layer is regulated by

[0162] A variety of materials for making contact lenses are known in the art and are useful in the present invention. Preferred materials include, but are not limited to, acrylics, silicones, polyvinyl alcohol, and combinations thereof.

[0163] There are various general types of contact lenses known in the art that are useful in the present invention. Preferred general types of contact lenses include, but are not limited to, hybrid lenses, hydrophilic lenses, and hydrophilic lenses.

[0164] In addition, there are other common types of contact lenses known in the art that are useful in the present invention, including, but not limited to, spherical lenses, toric lenses, multifocal lenses, tinted lenses, corrective optical power lenses, and lenses without ametropia correction.

[0165] There are a variety of methods that can be used to make lenses useful in the present invention. Preferred methods of making contact lenses, at least in part or in combination, include, but are not limited to, lathing, casting, spin casting, and inkjet printing.

[0166] Once a contact lens is manufactured, various secondary or finishing operations may be utilized and are useful in the present invention. Preferred secondary or finishing operations include, but are not limited to, edging, polishing, tinting, hydration, extraction, and sterilization.

[0167] In one aspect of the present invention, at least one drug in at least one coating layer can be provided on the surface of a contact lens. In another aspect of the present invention, at least one drug in at least one coating layer can be provided within a contact lens. In another aspect of the present invention, at least one drug can be provided on the inside of a contact lens in combination with at least one drug in at least one coating layer on the surface of the lens, without the structure of at least one coating layer. In yet another aspect of the present invention, at least one coating layer containing at least one drug can be provided both on the surface of the lens and on the inside of the lens.

[0168] In some cases, the agent provided in at least one coating may have optical properties that may interfere with the optical function of the contact lens, such as agents having color or opacity. Preferred agents for use in the present invention do not have such optical properties, but this need not be the case, as agents having such optical properties are useful in the present invention.

[0169] In another aspect of the invention, the one or more coatings may optionally have dispersed therein nanoparticles having a particle size of less than about 50 nm, nanoencapsulated ophthalmic agents that allow the ophthalmic agent to diffuse and migrate through the contact lens into the post-lens tear film or toward the eyelid when the contact lens is placed on the eye, the nanoparticles being dispersed within or on at least one surface of the contact lens in an amount such that the lens optionally remains substantially optically clear (see, e.g., U.S. Patent No. 7,638,137(B2) issued to Chauhan et al. on December 29, 2009).

[0170] In another aspect of the invention, the one or more coatings may optionally have dispersed therein nanoparticles having a particle size of less than about 50 nm, nanoencapsulated ophthalmic agents that allow the ophthalmic agent to diffuse and migrate away from the contact lens into the under-lens tear film or toward the eyelid when the contact lens is placed on the eye, nanoparticles dispersed within or on at least one surface of the contact lens in an amount such that the lens optionally remains substantially optically clear (see, e.g., U.S. Patent No. 7,638,137(B2) issued to Chauhan et al. on December 29, 2009).

[0171] In yet another aspect of the present invention, when at least one agent is provided with or without a drug delivery composition described herein, the at least one agent provided with or without the drug delivery composition is substantially optically transparent. However, this need not be the case. In one aspect of the present invention, when the at least one agent provided with or without the drug delivery composition is substantially optically transparent, or is not substantially optically transparent, the optical properties of the at least one agent or other structures of the at least one coating layer can be masked with an opaque material or coloring, such as coloring known in the art.

[0172] A. Packaging The articles of manufacture of the present invention can be provided in a variety of forms and current packaging formats and solutions, many of which are established packaging formats, while others are unique to the present invention.

[0173] The articles of manufacture of the present invention may be provided in a packaged state in a dry state, preferably in a dehydrated or lyophilized state, using methods known in the art. The articles of manufacture of the present invention may also be provided in a packaged state in a wet state, i.e., in a suitable solution and, where appropriate, in a hydrated state.

[0174] The packaging format can be any format desired. For example, the manufactured article can be provided in suitable and conventional packaging for manufactured articles, such as a vial, box, or other container, such as a plastic container, or in a vial. Vial and blister packaging are preferred, but not necessarily for, for example, contact lenses.

[0175] When present, the solution present in the packaging format, particularly in the wet packaging format, may contain at least one agent present in at least one coating layer, an agent different from that provided in the coating layer, or a combination thereof.

[0176] In one case, the concentration of the drug in the packaging solution is less than the concentration of the drug in the coating layer, in which case it is likely that the drug in the coating layer can migrate from the coating layer to the packaging layer and eventually reach a steady-state equilibrium, which is not the case here.

[0177] In other cases, the concentration of the drug in the packaging solution is equal to the drug in the coating layer, in which case the drug in the packaging solution is likely to be at steady state with the drug in the coating layer, but this need not be the case.

[0178] Alternatively, the concentration of drug in the packaging solution is higher than the concentration of drug in the coating layer, in which case the drug in the packaging solution will likely migrate into the coating layer and eventually reach a steady-state equilibrium, although this need not be the case.

[0179] Yet another example may be where there is a drug provided in the packaging layer that is not present in the coating layer, in which case it is likely, but not necessary, that the drug in the packaging solution will migrate to the contact lens and eventually reach a steady state equilibrium.

[0180] II. Methods for Making Medical Devices Containing Pharmaceuticals - General The present invention also includes a method of making an article of manufacture comprising: a) providing a medical device comprising at least one surface; and b) depositing one or more coatings on at least a portion of the at least one surface, the one or more coatings comprising: 1) at least one drug reservoir layer deposited at least in part by printing onto the at least one surface, the at least one drug reservoir layer comprising at least one drug.

[0181] The present invention also includes a method of making an article of manufacture, the method comprising: a) providing a medical device comprising at least one surface; and b) depositing one or more coatings on at least a portion of the at least one surface.

[0182] Having discussed the specific structures of the present invention, what they are made from, how they are preferably made, how they interact, how they are assembled, and how they are selected based on their physical and chemical properties, we now turn to a consideration of how articles of manufacture are made, with exemplary and preferred examples provided in the Examples section below.

[0183] Additionally, U.S. Patent No. 9,931,296 and U.S. Patent No. 10,413,506 to Doshi all relate generally to methods of making medical devices containing pharmaceutical agents, particularly methods of making drug delivery contact lenses, and are incorporated herein by reference, particularly for purposes of methods of making medical devices containing pharmaceutical agents, particularly methods of making drug delivery contact lenses.

[0184] A. Medical Devices First, a medical device to be coated is selected. Essentially, any medical device can be used in the present invention. The selection of a medical device is within the skill of one of ordinary skill in the art, and the state of the art provides a vast literature on a wide variety of medical devices and their implantation locations, as well as the agents that may be usefully delivered by the coatings of the present invention to treat or prevent any number of diseases, conditions, or disorders that a subject may suffer from.

[0185] Medical devices can be implantable or non-implantable, as these terms are known in the art and described above. In one preferred aspect of the invention, the medical device includes a cardiac stent or joint replacement device, or other implantable medical device. In another preferred aspect of the invention, the medical device includes a contact lens or skin patch drug delivery medical device, or other non-implantable medical device.

[0186] B. Surface The medical device presents a surface onto which the coating of the present invention is created. The surface of the medical device selected is usually, but need not be, an inherent property of the medical device. The surface may be modified by any number of methods or techniques, including chemical or physical modification, which may be known in the art and discussed herein.

[0187] In certain preferred aspects of the present invention, as discussed herein, surfaces presented for application of the coatings of the present invention include, but are not limited to, at least one metal, at least one plastic, at least one polymer, at least one partially polymerized polymer, at least one polymer matrix, at least one protein matrix, at least one silicone, at least one ceramic, at least one glass, at least one carbon-containing compound, at least one fabric, or combinations thereof.

[0188] In another preferred embodiment of the present invention, as discussed herein, surfaces presented for application of the coating of the present invention may be modified by various methods before the coating of the present invention is applied. Preferred surface modification methods include, but are not limited to, one or more chemical processes or one or more physical processes. Preferred chemical processes include, but are not limited to, chemical coating, chemical cleaning, chemical texture modification, chemical or electrochemical activation, or generation of reactive groups on or within the at least one surface, application of one or more chemicals to the at least one surface, and combinations thereof. Preferred physical processes include, but are not limited to, etching, scoring, spraying a material onto a surface, sputtering a material onto a surface, corona treatment, and combinations thereof.

[0189] C. Drug reservoir layer The coatings of the present invention include a drug reservoir layer, which contains at least one drug for later release to or onto a subject where the medical device is provided to the subject. The drug reservoir layer, as discussed herein, is preferably disposed directly on at least a portion of the surface of the medical device and is the first component of the coatings of the present invention. However, in certain aspects of the present invention where directional release of the drug from the coatings of the present invention is desired, such as when a medical device such as a contact lens, in which the drug can be released toward the eye, toward the eyelid, or both, presents multiple surfaces for drug release from the coatings of the present invention, at least one layer may be disposed prior to the at least one drug reservoir layer.

[0190] The drug reservoir layer can be made of any suitable material or combination of materials, and the selection of materials is generally within the skill of one in the art, influenced by various factors, including, but not limited to, the printing method used to provide the drug reservoir layer, the size, thickness, and shape of the desired drug receiving layer, the physical and chemical properties desired for the drug reservoir, which are influenced by the chemical and physical properties of the drug provided in the drug receiving layer so that the drug can be released at a desired rate, etc.

[0191] Preferred materials for the drug-receiving layer include, but are not limited to, at least one polymer, at least one partially polymerized polymer, at least one polymer matrix, at least one protein matrix, at least one silicone, at least one ceramic, at least one glass, at least one carbon-containing compound, at least one fabric, or a combination thereof. Other preferred materials include, but are not limited to, derivatized oligomers, such as, but not limited to, HEMA, DMA, GMA, PVA, silicones, and siloxanes, or a combination thereof.

[0192] In certain embodiments of the present invention, during the printing process used to create the drug reservoir layer, a non-polymerized or partially polymerized printing formulation that can include at least one drug is applied to the surface. The non-polymerized or partially polymerized formulation is then polymerized or cured to stabilize the drug-receiving layer, which in certain embodiments of the present invention functions to confine or localize the drug in the drug reservoir layer for later release. Preferred methods for polymerizing or curing the drug reservoir, if needed or desired, include, but are not limited to, at least one UV curing or polymerization, at least one thermal curing or polymerization, at least one room temperature curing or polymerization, at least one simultaneous printing and curing or polymerization, at least one e-beam curing or polymerization, or a combination thereof.

[0193] In certain aspects of the present invention, the drug reservoir layer is bonded, permanently bonded, or not bonded to the surface. In this case, reactive groups on the surface or drug-receiving layer can chemically or physically interact to form chemical bonds, such as covalent bonds, or physical bonds, such as short-range interactions, including but not limited to hydrogen bonds, van der Waals interactions, hydrophobic interactions, hydrophilic interactions, ionic interactions, etc. The formation of these chemical or physical interactions depends on the chemical properties of the surface and the drug reservoir layer and can be determined by one skilled in the art based on the state of the art.

[0194] In another aspect of the present invention, as discussed herein, the drug receiving layer may release the drug in one or more directions. In certain cases, the drug receiving layer may release the drug only in one direction based on the characteristics of the medical device and surface, such that the surface prevents or blocks drug release in one direction, and the drug is not substantially able to migrate to the surface or medical device based on the materials provided. As discussed herein, a barrier layer may be provided to prevent drug migration in one direction. As discussed herein, the drug may be released in two or more directions, such as in the case of contact lenses.

[0195] D. Drug-receptor layer In one aspect of the present invention, the at least one drug reservoir comprises at least one drug receiving layer. In this aspect of the present invention, the drug reservoir layer containing at least one drug is as described herein, and the drug receiving layer is printed onto a surface such that at least one drug is provided to the at least one drug receiving layer to form the drug reservoir layer. The drug is provided to the drug receiving layer by any suitable method, such as printing as described herein, although other methods of applying a drug to the drug receiving layer, such as, but not limited to, immersion, dipping, and spin coating, may be used. As with the other layers of the coating of the present invention, the drug receiving layer may be made of any suitable material or combination of materials, and the selection of materials is generally within the skill of one of ordinary skill in the art, influenced by various factors, including, but not limited to, the printing method used to provide the drug reservoir layer, the desired size, thickness, and shape of the drug receiving layer, and the physical and chemical properties desired for the drug reservoir, which are influenced by the chemical and physical properties of the drug provided in the drug receiving layer so that the drug can be released at a desired rate.

[0196] In one embodiment of the present invention, at least one drug reservoir layer comprises a chemical coating applied to the surface. Alternatively, at least one drug receiving layer is applied to a separate layer previously applied to the surface, such as, but not limited to, a layer described herein for creating a coating layer that releases a drug from the coating in a specific direction.

[0197] In another aspect of the present invention, the printing formulation used to print the drug-receiving layer may include materials such as chemicals that allow for polymerization or hardening of the printed drug reservoir layer and, in certain cases, allow for tailoring the physical properties of the drug-receiving layer that affect the release of the drugs described herein, such as, but not limited to, porosity, drug diffusion rate, etc. Materials used to achieve these goals include, but are not limited to, adhesives, crosslinkers, or combinations thereof. The use of adhesives, crosslinkers, or combinations thereof to provide materials with the physical properties desired for the present invention is known in the art and is abundant in the literature, and adaptation to the present invention can be performed using experimentation or mathematical modeling.

[0198] In one preferred embodiment of the present invention, the drug receiving layer comprises a superabsorbent polymer, including, but not limited to, at least one polyvinylpyrrolidine homopolymer, at least one polyvinylpyrrolidone copolymer, at least one polyacrylamide homopolymer, at least one polyacrylamide copolymer, at least one polyacrylate homopolymer, at least one polyacrylate copolymer, at least one proteinaceous material, at least one carbohydrate, or a combination thereof.

[0199] The drug reservoirs may be applied to the surface or desired location using any suitable method or means described herein or known in the art, including, but not limited to, direct coating, droplet or microdroplet application, inkjet printing, dipping, impregnation, spin coating, drip coating, screen coating, silk screen coating, pad printing, or a combination thereof.

[0200] E. Drugs As previously mentioned, at least one drug reservoir layer of at least one coating of the present invention contains at least one drug provided therein such that the at least one drug can be released from the at least one coating. Generally, the selection of the drug provided in the coating layer is a matter of choice for one of skill in the art, and there is a vast body of both patent and non-patent literature available to those of skill in the art to identify drugs that are effective in treating or preventing a disease, disorder, or condition.

[0201] The drug may be provided in the coating in a sufficient amount such that, upon release from the coating, the drug is provided in a therapeutically effective amount to the route and location of administration of the medical device of the present invention in or on a subject. When considering the concentration of drug provided in the coating of the present invention so that an appropriate amount of drug is released from the coating of the present invention, the physical properties of the coating of the present invention discussed herein, such as, but not limited to, pore size and water content, may be taken into consideration.

[0202] As discussed herein, the medical devices of the present invention, similar to other drug delivery methods such as through injection or oral administration, are provided in or on a subject so that the drug is released at a specific location rather than systemically. This allows for the drug to be delivered to a specific location, preferably at a lower or more precise dose than can be obtained with other methods. The concentrated delivery of drug by the medical devices of the present invention will also reduce the incidence of drug side effects that are characteristic of more systemic routes of administration, as the systemic load of drug in the subject is significantly reduced compared to more systemic administration of the drug.

[0203] As discussed herein, the location of the drug delivery device can be determined by the nature of the medical device and the disease, disorder, or condition being prevented or treated. For example, implantable cardiac stents are provided in blood vessels as part of a typical medical procedure, and contact lenses are typically provided in the eye, although this need not be the case.

[0204] Drugs can be provided with or released from the coating layers of the present invention in various forms. In one aspect of the present invention, a drug is provided in or at least partially released from the coating layer as a single active ingredient without association with any other ingredients that may alter the activity or deliverability of the at least one drug. That is, the drug is provided or released in a free state, not associated with other chemicals, such as drug delivery chemicals described herein or known in the art.

[0205] Alternatively, the drug is provided in the coating layer or is at least partially released from the coating layer in at least one encapsulated form, at least one microencapsulated form, at least one nanoencapsulated form, at least one emulsion, at least one water-in-oil emulsion, at least one oil-in-water emulsion, or at least one liposome, or combinations thereof, as described herein or known in the art.

[0206] As described herein, the drug provided in the coating layer or released from the coating can be virtually any drug known in the art, including, but not limited to, small molecule drugs or biological drugs. A vast amount of literature exists on these types of drugs, both in patent and non-patent literature. A comprehensive list is beyond the scope of this document. Preferred classes of drugs are provided herein, including, but not limited to, at least one anti-inflammatory drug, at least one anti-allergic drug, at least one antibiotic drug, at least one drug for the treatment of glaucoma, at least one drug for the treatment of macular degeneration, at least one ophthalmic drug, at least one hydrophilic drug, at least one hydrophobic drug, at least one antiparasitic drug, at least one steroid drug, at least one drug for the treatment of dry eye, and at least one drug for the treatment of ocular discomfort, or combinations thereof.

[0207] In one preferred embodiment of the present invention, the drug is provided in the coating layer or released from the coating layer in at least one encapsulated form. Preferred encapsulating materials are discussed herein and known in the art, including, but not limited to, at least one biodegradable polycyanoacrylate, at least one biodegradable poly(alkyl cyanoacrylate), at least one biodegradable calcium phosphate, at least one legumin, at least one polysaccharide (amphiphilic copolymer) grafted with polyester, at least one poly(methylidene malonate), at least one gelatin, at least one poly(E-caprolactone), at least one sodium alginate, at least one agarose hydrogel, at least one PMMA, at least one biotinylated polyethylene glycol conjugated with lactobionic acid, at least one poly(vinyl alcohol) hydrogel, at least one biotinylated pullulan acetate, at least one diblock copolymer, and combinations thereof.

[0208] In another preferred embodiment of the present invention, the polycyanoacrylate is one disclosed herein or known in the art, including, but not limited to, at least one polybutylcyanoacrylate, at least one polyhexylcyanoacrylate, at least one polyethyl-cyanoacrylate, at least one polyisobutylcyanoacrylate, and combinations thereof.

[0209] In one preferred embodiment of the present invention, the drug is provided in the coating layer or released from the coating layer in nanoencapsulated form by at least one encapsulating material of nanoparticles, at least one oil-in-water emulsion, at least one water-in-oil emulsion, or at least one liposomal material, or a combination thereof. The nanoparticles, if present, can be any of those disclosed herein or described in the art, including, but not limited to, chitosan nanoparticles, human serum albumin nanoparticles; silica nanospheres, PEGylated core-shell nanoparticles, biodegradable PGGA (poly(D,L-lactide-co-glycolide) particles, PLA (polylactic acid), PGA, PLG (poly-(D,L-glycolide)) polymeric nanoparticles, biocompatible gliadin nanoparticles, low pH sensitive PEG-stabilized plasmid-lipid nanoparticles, tocopherol derivative-stabilized nanosized emulsion particles, PLA-PEG nanoparticles, nanoparticles composed of hydrophilic proteins bound to apolipoprotein E, biodegradable poly(benzylnacaproline) nanoparticles, biotinylated poly(ethylene glycol) conjugated with lactobionic acid, carboxymethyl dextran magnetic nanoparticles, and combinations thereof.

[0210] F. Printing One aspect of the present invention is that various components of at least one coating are preferably produced using at least one printing technique. The coating components include various layers, including but not limited to, at least one drug reservoir layer, at least one drug receiving layer, and at least one layer, and may not include all of the listed components. The same or different printing techniques can be used to produce various components. Similarly, one or more printing techniques can be used to produce a particular component. Printing of various components or layers preferably uses the printing formulation of the present invention, but this is not required. The printing formulation of the present invention is described in further detail herein.

[0211] A wide variety of printing techniques are applicable to applying the various layers of the coatings of the present invention. The choice of which printing technique to use is a matter of choice for those skilled in the art based on the particular size, shape, thickness, printing resolution, and other characteristics of the layer to be applied. Those skilled in the art will have available technical literature to match the desired properties of the printed layer with the characteristics, advantages, and limitations of the printing technique. Similarly, those skilled in the art will be able to match the printing formulation used to create the layers of the present invention with the particular printing technique and, similarly, the desired properties of the printed layer.

[0212] The properties of the printing formulation used to create the layer, such as, but not limited to, the viscosity and surface tension of the printing formulation. Also, the properties of the printing device in combination with the printing formulation are factors to consider, such as, but not limited to, when printing techniques, such as inkjet printing techniques, utilize printing structures that may require relatively stringent physical and chemical properties of the printing solution so that the printing formulation does not clog or damage or interfere with the printing device.

[0213] Additionally, if a portion of a layer is printed in a liquid or semi-solid form and then converted to a solid or semi-solid form, for example, but not limited to, by polymerization or partial polymerization, the properties of the printing liquid or semi-solid should be considered. As a preferred embodiment of the present invention, the compositions of Doshi et al., published U.S. Application No. 2008 / 0062381A1, published March 13, 2008, are applicable, particularly when a pigment is optionally present in such formulations and at least one drug is optionally provided in such formulations.

[0214] Preferred printing methods are digital in nature, such as those described by Doshi et al. (US 2008 / 0062381(A1)), which is incorporated herein by reference in its entirety, to enable relatively highly accurate methods and means for providing high-quality, well-defined printed products. Because the methods and associated devices are digital in nature, the printing process is adaptable to computer control and product design. Preferred digital printing methods and structures are discussed herein. As a non-limiting introduction to digital printing methods and devices, the following digital printing methods are preferred: inkjet printing, three-dimensional printing (3D printing), piezo printing, thermal printing, laser printing, and MEMS printing, where the printing head or related or associated structures are rotary or non-rotary. Generally, although not exclusively, the printing solution of the present invention replaces the ink solution of existing commercially available printing devices, specifically within the printing cartridge.

[0215] Similarly, preferred printing methods include pad printing, including but not limited to pad transfer printing, which are known in the art. Pad printing is less precise than digital printing, but is the preferred printing method for the present invention. Pad printing for printing an image of the iris of the eye onto a contact lens is known in the art (see, for example, U.S. Patent Nos. 5,414,477, 5,302,978, and 4,668,240).

[0216] Inkjet printing is known in the art and can take a variety of forms and associated structures, as discussed herein. Generally, inkjet printing refers to printing devices and methods that utilize high-precision printing methods and structures that allow for the production of high-quality, precise structures. Generally, available inkjet printing devices and structures can be utilized with minimal modification, where the ink solution normally present in an inkjet cartridge or reservoir is replaced with a solution containing a polymerizable monomer and an associated polymerization initiator, as needed. After being dispensed from the inkjet printing structure, the polymerizable monomer can be polymerized purposefully and at a rapid rate.

[0217] Three-dimensional printing is primarily, though not exclusively, based on inkjet printing technology. These methods and devices allow for the production of one-off or multiple copies of a structure or structures. Generally, a polymerizable solution is placed into a printing device, dispensed under computer control, and polymerized in repeated printing cycles or steps to generate the three-dimensional structure. Examples of available and preferred 3D printing devices and associated structures and cartridges include, but are not limited to, the following: 3D Systems (www.3dsystems.com / default.asp) (3-29-2011), ProJet™ 6000 Professional 3D Printer (http: / / printin3d.com / sites / printin3d.com / files / downloads / Projet_6000_brochure_USEN.pdf) (3-29-2011); Stratasys, Inc. (http: / / www.stratasys.com / ); Fortus 3D Production Systems - Fortus 900mc; Z Corporation (www.zcorp.com); Zprinter® 650 (http: / / www.zcorp.com / en / Products / 3D-Printers / ZPrinter-650 / spage.aspx) Vertical Resolution—90–100 microns (0.0035–0.004 inches) Smallest Feature—100 microns (0.004 inches); 3D Systems (http: / / www.3dsystems.com / default.asp); and Viper si2™ SLA System (http: / / www.3dsystems.com / products / datafiles / viper / datasheets / Viper_final_rev_0303.pdf).

[0218] Piezoprinting is a subtype of inkjet printing and is the preferred printing method of the present invention. Examples of available and preferred piezo printing devices and related structures and cartridges include, but are not limited to, MicroFab Technologies, Inc. (www.microfab.com) (3-29-2011); Jetlab® 4x1, 4x1-A (http: / / www.microfab.com / equipment / pdf / jetlab4xl xla.pdf) (3-29-2011); XY Accuracy / Repeatability - + / - 25 microns / + / - 5 microns (4xl-A); ONE Technologies (www.onelabs.com) (3-29-2011); Material Deposition Systems (www.onelabs.com / matdep00.htm) (3-29-2011), resolution on the order of 0.2 nanometers, Multi-Axis Printing Systems (www.onelabs.com / maxp00.htm) (3-29-2011); FujiFilm USA | Dimatix, Inc. (http: / / www.dimatix.com / index.asp) (3-29-2011); Dimatix Materials Printer DMP-5000 (http: / / www.dimatix.com / files / DMP-5000-Datasheet.pdf) (3-29-2011) XY Accuracy / Repeatability - + / - 5 microns / + / - 1 micron; Mimaki JF Series (http: / / www.mimakiusa.com) (4-1-2011) Model JF1610 or JF1631 (http: / / www.mimakiusa.com / IndustrialProduct.aspx?level=3&pid=3&cid=14) (4-1-2011), resolution up to 1200 dpi.

[0219] Thermal printing is a subtype of inkjet printing and is the preferred printing method of the present invention. Examples of thermal printing devices and related structures and cartridges include, but are not limited to: Hewlett Packard (www.hp.com) (4-1-2011); HP Designjet H45000 Printer Series http: / / www.hp.com / united-states / colorspan / djh45000-datasheet.pdf (4-1-2011).

[0220] Laser printing is a subtype of inkjet printing and is the preferred printing method of the present invention. Examples of laser printing devices and related structures and cartridges include, but are not limited to, the Xerox Phaser 6010 laser printer http: / / www.xerox.ca / office / printers / colour-printers / phaser-6010 / spec-enca.html or the HP Color LaserJet Enterprise CP4025 Printer series - HP Color LaserJet Enterprise CP4025dn Printer (CC490A). http: / / h10010.www1.hp.com / wwpc / us / en / sm / WF06b / 18972-18972-3328060-15077-236268-3965792-3965795-3974244.html, or those later developed.

[0221] Optionally, the printing device, such as but not limited to an inkjet printing device, may include a rotary printer head. These types of printing structures may allow for improved printing on curved surfaces. Preferably, a donut shape may be printed on the contact lens such that the visible light transmission of the optical center of the lens is not affected.

[0222] Another preferred printing method is MEMS printing, which is based on a technology that allows for the printing of integrated circuit substrates but is applicable to the fabrication of very small functional structures. Examples of functional structures created by MEMS printing include mechanical gears and other mechanical devices, lab-on-chip structures for performing chemical reactions and laboratory procedures, including diagnostic procedures.

[0223] Another preferred printing method is MEMS printing, which is based on a technology that allows for the printing of integrated circuit substrates but is applicable to the fabrication of very small functional structures. Examples of functional structures created by MEMS printing include mechanical gears and other mechanical devices, lab-on-chip structures for performing chemical reactions and laboratory procedures, including diagnostic procedures.

[0224] G. Printable Formulations For printing layers or structures of the present invention using printing techniques discussed herein and known in the art, particularly digital printing methods and techniques, printable formulations useful in the present invention can optionally contain one or more drugs, any single drug compound or composition, or any combination of drug compounds or compositions. The printable formulations can be provided in water, monomer, or solvent at a concentration of preferably from about 0% to greater than about 99.5%, or from about 0.001% to about 99.5%, preferably from about 0.005% to about 90%, or from about 1% to about 80%, more preferably from about 10% to about 60%, or from about 20% to about 40%. Optionally, to provide a digitally printed formulation with at least one drug, the printable formulation can also contain particles or microparticles, preferably at a concentration of from about 0% to about 15%, or from about 0.001% to about 10%, preferably from about 0.005% to about 4%, or from about 1% to about 3%. Examples of drugs include, but are not limited to, timolol, gentamicin, and nevanac. As discussed herein, properties and compositions comprising printable formulations and other components include printable formulations that are or become part of an article of manufacture of the present invention, such as a lens, such as a contact lens, and also include compositions comprising at least one printable formulation that can be used to make any article of manufacture of the present invention.

[0225] The printable formulation may contain water, a monomer, a polymer, or a suitable solvent to make the printable formulation suitable for producing a digital print. A suitable solvent is one that is compatible with producing a print, such as a digital print, on or within a surface, such as on or within a polymer. For example, suitable solvents for polymers used to produce lenses, such as contact lenses, include, but are not limited to, isopropanol, water, acetone, or methanol, either alone or in combination, and may contain a monomer. Suitable concentrations of solvents are from about 0% to greater than about 99.5%, or from about 0.1% to about 99.5%, preferably from about 1% to about 90%, or from about 10% to about 80%, more preferably from about 20% to about 70%, or from about 30% to about 60%. Different polymers, monomers, and printable formulations have different tolerances and reactivities to different solvents. Therefore, an appropriate match between the solvent and the polymer, monomer, and printable formulation may be considered. For hydrogel polymers, adjustment of the swelling ratio may be achieved by varying the concentration of solvent or crosslinker.

[0226] The printable formulation may also include a monomer, polymer, homopolymer, heteropolymer, or copolymer. In a preferred embodiment of this aspect of the invention, the printable formulation includes a monomer that can be polymerized to form a polymer using a polymerization method appropriate for a given monomer, mixture thereof, or polymer, or mixture thereof. The monomer may also be used to reduce the viscosity of the printable formulation. Alternatively, the printable formulation may include a polymer that increases the viscosity of the printable formulation. Alternatively, the printable formulation may include a polymer and a monomer. Suitable concentrations of the monomer are about 5% to greater than 99%, preferably about 25% to about 75%, and more preferably about 35% to about 60%. Suitable concentrations of the polymer are about 0% to about 50%, preferably about 5% to about 25%, and more preferably about 10% to about 20%. When the monomer and polymer are mixed, the total concentration of the monomer and polymer is about 10% to greater than 99%, preferably about 25% to about 75%, and more preferably about 35% to about 65%.

[0227] The viscosity of the solution containing the printable formulation may be as high as about 500 centipoise to about 5,000 centipoise, preferably about 1 to about 200 centipoise, or about 10 to about 80 centipoise, preferably about 20 to about 70 centipoise, or about 30 to about 60 centipoise, or about 1 to about 10 centipoise. Solutions with low viscosity tend to be "flowable" when dispensed, allowing different colors to merge and blend, resulting in images with a more natural appearance. Such blending can be improved using various methods, including sonication or vibration at appropriate durations and frequencies to promote proper blending. Solutions with too low a viscosity are too "flowable" and therefore may result in images with potentially undesirable characteristics, such as pooling of the printable formulation in the digitally encoded image or spreading of the printable formulation in unintended locations. Solutions with too high a viscosity may be easily dispensed using pad printing but are not suitable for other printing processes. Additionally, solutions with high viscosity may tend to "bead" on surfaces and may not blend with the surrounding environment, including droplets or beads surrounding the printing formulation. Agents such as thickeners or diluents (including suitable solvents) may be used to adjust the viscosity of the printable formulation.

[0228] Alternatively, a drug-receiving layer may be used that holds the inkjetted digital droplets in place until fixed. Another approach could be to use a printable formulation that uses derivatized oligomers that can stop fluidization by instantaneous curing. Both of these approaches are discussed herein.

[0229] A printable formulation containing at least one monomer may also include a polymerization initiator so that, when the printable formulation containing at least one type of monomer is dispensed, polymerization of the monomers in the printable formulation is initiated. The number, type, and amount of initiators are a matter of choice depending on the type of monomer in the printable formulation. Suitable initiators include, but are not limited to, UV initiators, which initiate polymerization via UV irradiation, and thermal initiators, which initiate polymerization via thermal energy.

[0230] The printable formulation may also include a dispersing agent to allow for a uniform composition of the formulation within the container, preferably provided at a suitable concentration, such as about 1% to about 10%.

[0231] The printable formulation may also include at least one antimicrobial or antiseptic agent to kill or reduce the number or growth of microbial agents, or to prevent microbial agents from growing. Preferred antimicrobial agents include antibacterial agents, antifungal agents, and disinfectants. Preferably, such antibacterial agents, antibacterial agents, antifungal agents, and disinfectants are provided at an appropriate concentration, such as about 0% to about 1%.

[0232] The printable formulation may also include at least one humectant, such as 1,3-dioxane-5,5-dimethanol (U.S. Pat. No. 5,389,132), at a suitable concentration. Preferably, the humectant concentration ranges from about 0% to about 2%.

[0233] The printable formulation may also include at least one antioxidant or low-corrosion agent, such as alkylated hydroquinone, at a suitable concentration, such as about 0.1% to about 1% (U.S. Pat. No. 4,793,264). The PF may also include a non-stick or anti-sticking agent, such as 2-methyl-1,3-propanediol, at a suitable concentration, such as about 0% to about 1%. The printable formulation may also include an evaporation retarder, such as diethyleneglycerol or ethylene glycol, at about 0% to about 2% (U.S. Pat. No. 5,389,132).

[0234] A preferred printable formulation may have the following composition: [Table 1]

[0235] H. Modulation of Drug Release As previously mentioned, the combination of layers and components of the coating of the present invention functions to modulate the release of at least one agent from the coating.

[0236] Various physical and chemical forces affect the modulation of drug release from the coatings of the present invention, including, but not limited to, the diffusion characteristics of at least one layer of the coating or the coating itself, the capillary action characteristics of at least one layer of the coating or the coating itself, the mass action characteristics of at least one layer of the coating or the coating itself, the drug concentration gradient in at least one layer of the coating or the coating itself, the drug solubility characteristics in at least one layer of the coating or the coating itself, temperature, the molecular weight of the drug, the size of the drug, the drug encapsulation structure, the thickness of at least one layer of the coating or the coating itself, the porosity of at least one layer of the coating or the coating itself, the pore size of at least one layer of the coating or the coating itself, the molecular exclusion size or characteristics of at least one layer of the coating or the coating itself, the water content of at least one layer of the coating or the coating itself, the drug concentration in at least one layer of the coating or the coating itself, the drug concentration gradient in at least one layer of the coating or the coating itself, and the packaging environment presented to the coatings of the present invention.

[0237] In one embodiment of the invention, at least one agent has a sustained release over time. In another embodiment of the invention, at least one agent has a pulsatile release over time. In yet another embodiment of the invention, two or more agents are released at once.

[0238] I. Contact lenses In one preferred embodiment of the present invention, the medical device on which the coating is made comprises a contact lens. Contact lenses containing a drug on or within the contact lens are known in the art. However, these contact lenses do not provide the structure of the present invention, such as at least one coating including at least one drug reservoir layer that can contain at least one drug, and at least one layer that can contain a structure, in which the release of at least one drug from at least one coating layer is regulated by at least one layer of the current coating, either alone or in combination.

[0239] The selection of the printing technique used to create the various layers of the coating of the present invention, including the coating layer as a whole, is a choice of one of skill in the art based on the state of the art and the teachings provided herein, as well as a consideration of the printing formulation to be used, as well as an evaluation of the various factors to consider when selecting a printing technique to produce a structure with desired chemical and physical properties.

[0240] Various materials for making contact lenses are known in the art and are useful in the present invention. Preferred materials include, but are not limited to, acrylic resins, silicones, polyvinyl alcohol, and combinations thereof. These materials are provided on the surface of the contact lens to be modified using the methods of the present invention.

[0241] There are various general types of contact lenses known in the art that are useful in the present invention. Preferred general types of contact lenses include, but are not limited to, hybrid lenses, hydrophilic lenses, and hydrophilic lenses. These types of contact lenses provide the contact lens surfaces that may be modified using the methods of the present invention.

[0242] In addition, there are other common types of contact lenses known in the art that are useful in the present invention. These lenses include, but are not limited to, spherical lenses, toric lenses, multifocal lenses, tinted lenses, corrective optical power lenses, and lenses without corrective optical power. These types of contact lenses provide contact lens surfaces that can be modified using the methods of the present invention.

[0243] There are various methods that can be used to make lenses useful in the present invention. Preferred methods for making contact lenses, at least in part or in combination, include, but are not limited to, lathing, casting, spin casting, and inkjet printing. These contact lenses provide the surface of the contact lens that is modified using the method of the present invention.

[0244] Once a contact lens is manufactured, various secondary or finishing operations may be utilized and are useful in the present invention. Preferred secondary or finishing operations include, but are not limited to, edging, polishing, tinting, hydration, extraction, and sterilization. These secondary or finishing operations may optionally be performed before or after the contact lens is modified by the methods of the present invention, or both.

[0245] In one aspect of the present invention, at least one drug in at least one coating layer can be provided on the surface of a contact lens. In another aspect of the present invention, at least one drug in at least one coating layer can be provided within a contact lens. In another aspect of the present invention, at least one drug can be provided on the inside of a contact lens in combination with at least one drug in at least one coating layer on the surface of the lens, without the structure of at least one coating layer. In yet another aspect of the present invention, at least one coating layer containing at least one drug can be provided both on the surface of the lens and on the inside of the lens.

[0246] In some cases, the agent provided in at least one coating may have optical properties that may interfere with the optical function of the contact lens, such as agents having color or opacity. Preferred agents for use in the present invention do not have such optical properties, but this need not be the case, as agents having such optical properties are useful in the present invention.

[0247] In another aspect of the invention, the one or more coatings may optionally have dispersed therein nanoparticles having a particle size of less than about 50 nm, nanoencapsulated ophthalmic agents that allow the ophthalmic agent to diffuse and migrate through the contact lens into the under-lens tear film or toward the eyelid when the contact lens is placed on the eye, the nanoparticles being dispersed within or on at least one surface of the contact lens in an amount such that the lens optionally remains substantially optically clear (see, e.g., U.S. Patent No. 7,638,137(B2) issued to Chauhan et al. on December 29, 2009).

[0248] In another aspect of the invention, the one or more coatings may optionally have dispersed therein nanoparticles having a particle size of less than about 50 nm, nanoencapsulated ophthalmic agents that allow the ophthalmic agent to diffuse and migrate away from the contact lens into the under-lens tear film or toward the eyelid when the contact lens is placed on the eye, nanoparticles dispersed within or on at least one surface of the contact lens in an amount such that the lens optionally remains substantially optically clear (see, e.g., U.S. Patent No. 7,638,137(B2) issued to Chauhan et al. on December 29, 2009).

[0249] In yet another aspect of the present invention, when at least one agent is provided with or without a drug delivery composition described herein, the at least one agent provided with or without the drug delivery composition is substantially optically transparent. However, this need not be the case. In one aspect of the present invention, when the at least one agent provided with or without the drug delivery composition is substantially optically transparent, or is not substantially optically transparent, the optical properties of the at least one agent or other structure of the at least one coating layer can be masked with a coloring, such as an opaque material or color pigmentation, as known in the art.

[0250] J. Packaging The articles of manufacture made by the methods of the present invention can be provided in a variety of forms and packaging formats and solutions, many of which are established packaging formats, while others are unique to the present invention.

[0251] The articles of manufacture made by the methods of the present invention may be provided packaged in a dry state, preferably in a dehydrated or lyophilized state, using methods known in the art. The articles of manufacture made by the methods of the present invention may also be provided packaged in a wet state, i.e., in a suitable solution and, where appropriate, in a hydrated state.

[0252] The packaging format can be any format required. For example, the manufactured article produced by the method of the present invention can be provided in a suitable and conventional packaging for the manufactured article, such as a vial, a box, or other container such as a plastic container, or in a vial. Vial and blister packaging are preferred, but not necessarily for, for example, contact lenses.

[0253] When present, the solution present in the packaging format, particularly in the wet packaging format, may contain at least one agent present in at least one coating layer, an agent different from that provided in the coating layer, or a combination thereof.

[0254] In one case, the concentration of the drug in the packaging solution is less than the concentration of the drug in the coating layer, in which case it is likely that the drug in the coating layer can migrate from the coating layer to the packaging layer and eventually reach a steady-state equilibrium, which is not the case here.

[0255] In other cases, the concentration of the drug in the packaging solution is equal to the drug in the coating layer, in which case the drug in the packaging solution is likely to be at steady state with the drug in the coating layer, but this need not be the case.

[0256] Alternatively, the concentration of drug in the packaging solution is higher than the concentration of drug in the coating layer, in which case the drug in the packaging solution will likely migrate into the coating layer and eventually reach a steady-state equilibrium, although this need not be the case.

[0257] In yet another instance, there may be a drug provided in the packaging layer that is not present in the coating layer, in which case it is likely, but not necessary, that the drug in the packaging solution will migrate to the contact lens and eventually reach a steady-state equilibrium.

[0258] III. How to Use Medicated Lenses - General The present invention includes methods of treating or preventing a disease, disorder, or condition, or pathology, comprising: a) providing a subject in need of treatment for the disease, disorder, or condition; and b) optionally providing an article of manufacture of the invention made using a method of the invention to the subject in a location suitable for treatment of the disease, disorder, or condition, wherein the article of manufacture releases one or more agents in an amount sufficient to treat or prevent the disease, disorder, or condition.

[0259] Additionally, U.S. Patent No. 9,931,296 and U.S. Patent No. 10,413,506 to Doshi all relate generally to methods of using medical devices containing pharmaceutical agents, particularly methods of using drug delivery contact lenses, and are incorporated herein by reference, particularly for purposes of methods of using medical devices containing pharmaceutical agents, particularly methods of using drug delivery contact lenses.

[0260] Described herein are the articles of manufacture, their components, and compositions of the present invention, as well as their desirable properties and selection criteria, how they are arranged and function together, and what criteria can be used to select and arrange them for a particular article of manufacture for a particular purpose. Additionally, described herein are the methods for manufacturing the articles of manufacture of the present invention, as well as the coating layers and various components of the coating layers, including, but not limited to, the drug reservoir layer and drug receptor layer, the printing formulations and printing techniques used to make them, and the physical properties of the drug release modulation, as well as the criteria for selecting them for manufacturing an article of manufacture for a particular purpose. Criteria for selecting the drug, including the purpose for which the drug will be used, its physical properties, its concentration, release characteristics, and its modulation, are also described herein.

[0261] The articles of manufacture and drugs of the invention, optionally made by the methods of the invention, tailored for the treatment or prevention of a particular disease, disorder, or condition are selected and provided for the article of manufacture, such that the release characteristics are evaluated based on the desired dose, regime, route of administration, and location of administration to provide the pharmacological properties of the drug. The drug is preferably selected to match the disease, disorder, or condition at stake, along with the location where the drug is to be released, based on criteria disclosed herein and provided by the state of the art.

[0262] Also provided is a subject in need of treatment or prevention of a disease, disorder, or condition. Then, using methods known in the art, based on where the article of manufacture of the present invention is placed (including, but not limited to, insertion onto a surface, insertion, or implantation, including surgery as needed), the article of manufacture is placed on or within the subject at a desired location so that the agent is released from the article of manufacture to treat or prevent the disease, disorder, or condition. If the agent is released over time, the article of manufacture can be, or alternatively is, removed from the subject. For articles of manufacture of the present invention placed in an easily accessible location on the subject, such as the skin or eye, removal is easily accomplished. For articles of manufacture of the present invention that are implanted or inserted into a subject, the removal process is more complicated and may require surgery. In some cases, removal of an article of manufacture of the present invention from a subject is undesirable due to discomfort or risks associated with removal. In such cases, the article of manufacture may remain in place.

[0263] IV. PACKAGED MEDICAL DEVICES COMPRISING DRUG DELIVERY CONTACT LENSES The present invention provides a packaged medical device comprising: a) at least one drug delivery contact lens comprising: 1) at least one coating disposed on at least one surface of the drug delivery contact lens; 2) at least one hydrophobic drug in at least one oil-in-water microemulsion, the at least one coating comprising the at least one hydrophobic drug, and further wherein the at least one coating is fabricated in whole or in part by additive printing; and b) at least one packaging solution comprising: 1) the at least one hydrophobic drug; 2) at least one hydrophobic drug; a) at least one packaging solution comprising a cyclodextrin, at least one oil-water microemulsion, or a combination thereof; and b) at least one packaging comprising: 1) at least one drug delivery contact lens; and 2) at least one packaging solution; d) the oil-water microemulsion of the drug delivery contact lens optionally comprises at least one cyclodextrin; and e) a packaged medical device, wherein the hydrophobic drug is stabilized in the drug delivery contact lens, the packaging solution, or a combination thereof.

[0264] The present invention can be practiced using materials and methods such as those disclosed herein or known in the state of the art or later developed.

[0265] A. Drug Delivery Contact Lenses In one aspect of the present invention, the drug delivery contact lenses comprise a) soft contact lenses, b) multifocal contact lenses, or c) combinations thereof.

[0266] B. Modulation of Drug Release One aspect of the present invention includes that the release of at least one hydrophobic drug from a drug delivery contact lens is controlled by the physical properties of the drug delivery lens, the chemical properties of the drug delivery lens, or a combination thereof.

[0267] Another aspect of the present invention includes the physical properties of the drug delivery lens including structures or conditions, or combinations thereof, provided by additive printing.

[0268] Further aspects of the invention include that the chemical properties of the drug delivery lens include a chemical compound, a chemical composition, an oil-water microemulsion, or short-range interactions, or a combination thereof.

[0269] An additional aspect of the present invention includes where the chemical properties of a drug delivery contact lens are modified by the addition of at least one cyclodextrin to alter the rate at which a drug is released from the drug delivery contact lens.

[0270] C. Coating One aspect of the present invention includes at least one coating comprising one or more layers.

[0271] D. Hydrophobic drugs One aspect of the present invention includes that the at least one hydrophobic agent is provided in a pharmaceutically effective amount.

[0272] Another aspect of the invention includes wherein the at least one hydrophobic agent comprises a prostaglandin, a prostaglandin derivative, latanoprost, bimatoprost, atropine, a cannabinoid capable of treating glaucoma, THC, or a combination thereof.

[0273] Endogenous and exogenous cannabinoids are useful in treating glaucoma and other ocular diseases, disorders, and conditions, such as those treatable through their neuroprotective effects. Intraocular pressure (IOP) can be altered through the endocannabinoid system (ECS), which is integrated throughout the eye. Two suitable endocannabinoids are 2-AG and AEA, whose precursor is arachidonic acid. These cannabinoids bind to cannabinoid receptor 1 (CB1), and compounds that bind to CB2 are also useful. Research has demonstrated the medicinal properties of cannabinoids in reducing IOP for the treatment of glaucoma. Among the exogenous compounds cited and introduced are delta-9-tetrahydrocannabinol (delta-9-THC), the phytocannabinoid delta-8-THC, and the CB1 agonist WIN55,212-2. Other endogenous and exogenous cannabinoids and THC are also effective in treating glaucoma and other ocular conditions and may have neuroprotective effects. See generally, Panahi Y, Manayi A, Nikan M, Vazirian M. The arguments for and against cannabinoid application in glaucomatous retinopathy. Biomed Pharmacother. 2017;86:620-627, https: / / eyewiki.aao.org / Cannabinoids_for_Glaucoma, and Cannabinoids for Glaucoma-EyeWiki (aao.org), and Passani et al. J Clin Med. 2020 Dec;9(12):3978. Cannabis extracts in crude, partially purified, or purified forms, and pure compounds, or mixtures thereof, are also useful for treating ocular diseases, disorders, and conditions.

[0274] A further aspect of the invention includes at least one hydrophobic drug being thermolabile in aqueous solution.

[0275] Additional aspects of the invention include those in which at least one hydrophobic drug undergoes hydrolytic degradation.

[0276] One aspect of the present invention includes the hydrophobic drug in the drug delivery contact lens, packaging solution, or combination thereof being steam sterilized and then heat stabilized, hydrolytically stabilized, or a combination thereof.

[0277] E. Oil-water microemulsions One aspect of the present invention involves at least one oil-water microemulsion comprising oil droplets in an aqueous medium to form a microemulsion.

[0278] F. Printing An aspect of the present invention includes that the additive printing includes inkjet printing.

[0279] Another aspect of the invention includes where additive printing includes digital printing, 3D printing, digital 3D printing, pad printing, or a combination thereof.

[0280] Further aspects of the invention include where additive printing includes additive printing, additive 3D printing, or a combination thereof.

[0281] G. Packaging Solution One aspect of the present invention includes the packaging solution comprising at least one hydrophobic drug in operative association with at least one cyclodextrin within at least one oil-water microemulsion, or a combination thereof.

[0282] H. Packaging One aspect of the present invention includes the at least one packaging comprising at least one blister pack.

[0283] Another aspect of the present invention includes the at least one packaging comprising at least one vial.

[0284] I. Additional Medications One aspect of the present invention includes at least one drug delivery contact lens, at least one packaging solution, or a combination thereof, further comprising at least one additional drug.

[0285] Another aspect of the present invention includes that at least one additional agent is provided in a pharmaceutically effective amount.

[0286] A further aspect of the present invention includes wherein the at least one additional agent further comprises at least one hydrophilic agent.

[0287] Additional embodiments of the present invention include wherein the at least one additional agent further comprises at least one hydrophobic agent.

[0288] One aspect of the invention includes wherein the at least one additional agent further comprises an antibiotic, an intraocular pressure reducing agent, a comfort enhancing agent, an anti-inflammatory agent, a penetration enhancer, an agent for macular degeneration, an agent for diabetic retinopathy, or a combination thereof.

[0289] Another embodiment of the present invention includes wherein the at least one additional agent further comprises dorzolamide, timolol, or a combination thereof.

[0290] Further embodiments of the present invention include those wherein the at least one additional agent further comprises timolol, Alphagan, Axopt, Cosopt, Lumigan, Travatan, Xalatan, Combigan, timolol hemihydrate, betaxolol, levobunolol, metipranolol, apraclonidine, brimonidine tartrate, brinzolamide, methazolamide, dorzolamide, acetazolamide, carbachol, travoprost, latanoprost, tafluprost, netarsudil, or a combination thereof.

[0291] Additional embodiments of the invention include those wherein the at least one additional agent further comprises sodium hyaluronate, hyaluronic acid, cyclosporine, polyethylene glycol 400, hypromellose, polyvinyl alcohol, carboxymethylcellulose, dextran 70, hydroxypropyl methylcellulose, anhydrous liquid lanolin, mineral oil, petrolatum, mannitol, thiomersal, carbomer, cetrimide, glycerin, polysorbate 80, povidine, or a combination thereof.

[0292] One aspect of the present invention includes wherein the at least one additional agent further comprises Padoforte, Lotemax, Flurometholone, Nebanac, Acular, Xybrom, or a combination thereof.

[0293] Another embodiment of the invention includes wherein the at least one additional agent further comprises flurbiprofen, acetazolamide, ethylenediaminetetraacetic acid, palmitoylcarnitine, sodium caprate, sodium dodecyl sulfate, sodium deoxycholate, polyoxyethylene-g-lauryl ether, 1-α-lysophosphatidylocholine, deoxycholate, taurodeoxycholate, glycocholate, benzalkonium chloride, or a combination thereof.

[0294] A further aspect of the present invention includes wherein the at least one additional agent further comprises Aflivelcet®.

[0295] Additional embodiments of the invention include those wherein the at least one additional agent further comprises dexamethasone, at least one steroid, pilocarpine nitrate, tropicamide, methylprednisolone, flurbiprofen, penicillin, ciprofloxacin, sulfacetamine sodium, indomethacin, hydrocortisone, indomethacin, ciprofloxacin hydrochloride, insulin, indomethacin, ketorolac tromethamine, or a combination thereof.

[0296] One aspect of the present invention includes wherein the at least one additional agent further comprises gentamicin, tobramycin, erythromycin, polytrim, cilproflizacin, viamox, xymer, or a combination thereof.

[0297] Another embodiment of the present invention includes wherein the at least one additional agent further comprises atropine.

[0298] V. Drug Delivery Contact Lenses The present invention includes a drug delivery contact lens comprising: a) at least one coating disposed on at least one surface of the drug delivery contact lens; b) at least one hydrophobic drug in at least one oil-water microemulsion; c) optionally at least one cyclodextrin; d) the at least one coating comprises at least one hydrophobic drug; and e) further, the at least one coating is fabricated in whole or in part by additive printing.

[0299] The present invention can be practiced using materials and methods such as those disclosed herein or known in the state of the art or later developed.

[0300] VI. Methods of Making Drug Delivery Contact Lenses The present invention includes a method of making a drug delivery contact lens, comprising: a) providing a contact lens; and b) printing at least one coating on the contact lens with an ink, wherein: 1) the ink comprises at least one hydrophobic drug, at least one oil-water microemulsion, or a combination thereof; 2) the ink optionally comprises at least one cyclodextrin; and 3) the printing comprises additive printing; and c) the coating, oil-water microemulsion, or combination thereof modulates the release of the at least one hydrophobic drug from the drug delivery contact lens, the at least one coating, or combination thereof.

[0301] The present invention can be practiced using materials and methods such as those disclosed herein or known in the state of the art or later developed.

[0302] In one aspect of the invention, the contact lens comprises a dry hydrogel, a silicone, or a silicone hydrogel.

[0303] VII. Ink The present invention comprises an ink for printing onto a contact lens, the ink comprising: a) at least one monomer; b) at least one crosslinking agent; c) at least one polymerization initiator; d) at least one hydrophobic agent; and e) at least one oil-water microemulsion; and f) the ink can be used to print onto a contact lens by additive printing.

[0304] The present invention can be practiced using materials and methods such as those disclosed herein or known in the state of the art or later developed.

[0305] One embodiment of the present invention includes an ink further comprising at least one cyclodextrin.

[0306] VIII. Methods of Treating or Presenting Ocular Diseases, Disorders, or Conditions Using Drug Delivery Contact Lenses The present invention includes a method of using a drug delivery contact lens, comprising: a) providing at least one drug delivery contact lens of the present invention comprising at least one hydrophobic drug; b) providing a subject in need of treatment or prevention, or a combination thereof, of at least one disease, disorder, or condition of the eye treatable or preventable by the at least one drug in the at least one drug delivery contact lens; c) operably engaging the at least one drug delivery contact lens with the subject's eye; and d) the subject is treated for, or prevented from having, the at least one disease, disorder, or condition of the eye treatable or preventable by the at least one drug in the at least one drug delivery contact lens, or a combination thereof.

[0307] The present invention can be practiced using materials and methods such as those disclosed herein or known in the state of the art or later developed.

[0308] Another aspect of the present invention includes where the ophthalmic disease, disorder, or condition is a) glaucoma, b) myopia, or c) a combination thereof.

[0309] The present invention includes a method for treating, preventing, or a combination thereof, at least one disease, disorder, or condition of the eye, comprising: a) providing at least one drug delivery contact lens of the present invention comprising at least one hydrophobic drug; b) providing a subject in need of treatment or prevention, or a combination thereof, of at least one disease, disorder, or condition of the eye treatable or preventable by the at least one drug in the at least one drug delivery contact lens; c) operably engaging the at least one drug delivery contact lens with the subject's eye; and d) the subject is treated for, or prevented from having, the at least one disease, disorder, or condition of the eye treatable or preventable by the at least one drug in the at least one drug delivery contact lens, or a combination thereof.

[0310] The present invention can be practiced using materials and methods such as those disclosed herein or known in the state of the art or later developed. [Example]

[0311] Example 1 Stabilization of Latanoprost Packaging Solution Ophthalmic medications have traditionally been administered via eye drop systems, which poses several challenges. First, eye drops have low bioavailability upon application. Eye drops typically have a residence time of approximately 5 minutes or less, resulting in an effective bioavailability of 1-5%. Second, eye drops often suffer from patient noncompliance, a problem that arises particularly from the inconvenience of administering eye drops more than twice daily. Finally, eye drops generally contain preservatives such as benzalkonium chloride, which can cause eye irritation and further exacerbate the second problem. Several approaches have been proposed to eliminate the use of eye drops, such as ophthalmic medication rings or implants such as Durista. Another approach is drug delivery via contact lenses. By layering ophthalmic drugs into a coating "ink" and then applying the coating to the surface of a contact lens via inkjet printing to create a single- or multi-layer structure, the lens becomes a convenient, non-invasive drug delivery system, replacing the need for constant eye drops or expensive and risky surgery. This final product can then be worn for up to 7 days, 30 days or more, and constantly releases the drug over that period. One such drug that can be incorporated into the coating is latanoprost, a prostaglandin analog used to treat glaucoma. The drug is first printed onto the dry lens surface in a single- or multi-layer 3D structure. After hydration, the printed wet lens is placed in a packaging solution containing latanoprost and sterilized by steam sterilization. One issue is the stability of latanoprost throughout the manufacturing process and the shelf life of the resulting product. The steam sterilization step catalyzes the degradation of latanoprost - aqueous solutions of latanoprost are susceptible to hydrolysis at the terminal ester at temperatures above 4°C. The mechanism of degradation is shown in Figure 1.

[0312] Latanoprost's primary degradation product, latanoprost free acid, cannot penetrate the cornea as easily as latanoprost and reduces the drug's IOP-lowering effect. Therefore, it is important to minimize latanoprost's exposure to water.

[0313] The typical contact lens manufacturing process described above features multiple steps in which latanoprost is exposed to water. Hydration of dry contact lenses and steam sterilization of latanoprost-coated contact lenses pose a risk of latanoprost degradation. Furthermore, contact lenses are equilibrated in an aqueous packaging solution after sterilization. This adds another step where latanoprost can degrade—if the drug diffuses from the coating into the aqueous solution and undergoes hydrolysis, the resulting product is not therapeutically active and leaves less drug available. This poses unique challenges for the manufacture of contact lenses containing latanoprost, as few viable methods exist for sterilizing final contact lenses other than steam sterilization. Furthermore, requiring storage of the final product below 5°C reduces commercial viability. For example, Xalatan, a brand name for latanoprost eye drops, requires storage at 2–5°C before opening. Alternative solutions are desirable to enable steam sterilization of drug-coated contact lenses and to allow for greater tolerance in post-manufacture storage conditions. Achieving both would enable the manufacture and stable storage of latanoprost-coated contact lenses, thereby introducing an alternative glaucoma treatment that is more convenient and easier to apply than eye drops and less risky than conventional surgery for medication insertion.

[0314] Additionally, it is desirable to control the drug release from the final product in order to maintain therapeutically effective latanoprost release in the eye at desired therapeutic levels.

[0315] The aforementioned problems in the manufacture of latanoprost-coated contact lenses may also apply to other drugs that are heat-labile and undergo hydrolysis in aqueous solutions. One of these drugs is atropine. Atropine can be decomposed according to the following scheme in Figure 2:

[0316] Atropine is used to slow the progression of myopia in children, but none of the hydrolysis products in Figure 2 are therapeutically active in slowing myopia progression. Therefore, as with latanoprost, it is of utmost importance to reduce atropine's exposure to water as much as possible.

[0317] To allow for steam sterilization of the final drug-coated contact lenses, 2-hydroxypropyl-β-cyclodextrin (cyclodextrin) can be added to various manufacturing steps in the manufacturing process as follows: 1. Addition of cyclodextrin to the aqueous or oily phase of latanoprost microemulsion 2. Adding cyclodextrin to the packaging solution

[0318] Sawatdee et al. (Sawatdee, S. (2013, February 23). Development of a stable latanoprost solution for use as Eye Drops. Thai Science. https: / / www.thaiscience.info / joumals / Article / CMJS / 10886517.pdf) propose that the hydrophobic portion of latanoprost, including the ester, can nestle inside the ring, forming an occlusive complex that protects the molecule from hydrolysis. This molecule has also been shown to be well tolerated in humans and is therefore a promising potential solution to the instability of latanoprost. One scheme for complex formation is shown below in Figure 3.

[0319] By adding 2-hydroxypropyl-β-cyclodextrin to the microemulsion, the packaging solution, or both, latanoprost can be complexed with cyclodextrin, and thus protected from hydrolysis.Optionally, cyclodextrin can also be added to the hydration solution to protect latanoprost from hydrolysis.The proposed mechanism for each addition will be further explained below, but the applicant does not intend to limit the present invention to any specific mechanism of action.

[0320] 1. The addition of cyclodextrin to latanoprost microemulsions provides a "safety net" component for latanoprost. Cyclodextrin can be added to either the oil phase, the water phase, or both phases. a. Cyclodextrin can be directly dissolved in latanoprost to form the complex shown in Figure 3. Oil can then be added to the cyclodextrin-latanoprost mixture. The oil can be any substance that is immiscible with water without a surfactant. More preferred oils are fatty acids, examples of which are included in Table 1. [Table 2] The cyclodextrin, latanoprost, and oil are mixed until a homogeneous solution called the "oil phase" is formed. The cyclodextrin-latanoprost complex dissolves in the oil, encapsulating the drug inside the oil. The addition of cyclodextrin to the oil increases the solubility of latanoprost in the oil phase. This prevents latanoprost from diffusing out of the oil phase and leaving the final product. An aqueous phase containing a surfactant is then added to the oil phase. The two phases are mixed until a homogeneous microemulsion is formed. This is shown in the following scheme in Figure 4. b. Cyclodextrin can also be added to the aqueous phase of the microemulsion.When the latanoprost from the cyclodextrin-latanoprost complex diffuses out of the oil droplets, the cyclodextrin in the aqueous phase can complex with the diffused latanoprost to prevent the hydrolysis of latanoprost caused by the water in the aqueous phase.Then, this latanoprost can return to the oil phase of the microemulsion. The microemulsion is then incorporated into a coating which is then inkjet printed onto the dry contact lens. 2. Cyclodextrin can be optionally added to the hydration solution. During hydration of a dry drug-coated contact lens, latanoprost can diffuse out of the lens into the hydration solution. If cyclodextrin is present in the hydration solution, it can complex with any diffused latanoprost, which will prevent latanoprost from decomposing. Then, latanoprost can return to the contact lens, improving the efficacy of the product. 3. Cyclodextrin can also be added to the packaging solution to function in the same manner as when added to the hydration solution. During the sterilization and equilibration steps of contact lens manufacturing, latanoprost can diffuse from the drug coating into the aqueous packaging solution, where it can be hydrolyzed and reduce its therapeutic efficacy. Storage temperatures above 5°C can exacerbate this effect by shifting the equilibrium constant toward the packaging solution and increasing the rate of hydrolytic degradation. When cyclodextrin is added to the packaging solution, latanoprost that diffuses from the contact lens into the packaging solution is complexed with the cyclodextrin, thereby protecting the latanoprost from degradation. Furthermore, the complexed latanoprost can return to the contact lens coating, increasing the therapeutic efficacy of the lens.

[0321] The addition of cyclodextrin to all three components (microemulsion, hydration solution, and packaging solution) increases the therapeutic efficacy and significantly extends the shelf life of contact lens drug products containing latanoprost.

[0322] The addition of cyclodextrin to the oil phase of a microemulsion can also be used to control drug release. The addition of cyclodextrin increases the solubility of latanoprost in oil, reducing its rate of diffusion from the microemulsion to the exterior of the lens. This slows the drug release rate to approach zero-order kinetics, potentially increasing the efficacy of the final product.

[0323] To protect latanoprost from degradation, microemulsions (with or without cyclodextrin) can also be added directly to the packaging solution. By introducing oil droplets suspended in water, latanoprost can theoretically be dissolved in the oily phase of the microemulsion-packaging solution. Once dissolved in oil, there is no water available to hydrolyze latanoprost, which is the primary mechanism of degradation. This is shown in Figure 5.

[0324] To test the effect of different formulations on the stability of latanoprost, different packaging solution formulations can be made. One formulation contained 2-hydroxypropyl-β-cyclodextrin, a cyclic oligosaccharide with a hydrophobic "ring" interior.

[0325] To prevent the degradation of atropine, as with latanoprost, 2-hydroxypropyl-β-cyclodextrin (cyclodextrin) can be used. Cyclodextrin can be added to the final atropine drug product as follows: 1. Addition of cyclodextrin to the oil or water phase of the microemulsion 2. Adding cyclodextrin to the packaging solution

[0326] Cyclodextrins function in the same manner for atropine and latanoprost, as per FIG.

[0327] Similar to latanoprost, when atropine and cyclodextrin are dissolved in the aqueous phase of a microemulsion or packaging solution, the cyclodextrin can act as a "safety net" for atropine. Optionally, cyclodextrin may also be incorporated into the hydration solution to protect atropine from hydrolysis. Like latanoprost, cyclodextrin can also be incorporated into the oily phase to increase the solubility of atropine. When incorporated into the final lens product, the cyclodextrin-microemulsion reduces the rate of diffusion from the lens.

[0328] Example: For latanoprost, both the additive-free approach and blank formulations were studied at both 5°C ± 3°C and 25°C ± 5°C for at least two months to document changes in assay values ​​and the appearance of any new peaks that may be related to latanoprost degradation. The following formulations of latanoprost packaging solution were tested: a blank control solution with no additives, a solution containing 10% microemulsion, and a solution containing 2-hydroxypropyl-β-cyclodextrin. The formulations are in Tables 2, 3, 4, and 5 below. [Table 3] [Table 4] [Table 5] [Table 6]

[0329] 100 g of cyclodextrin formulations were prepared by weighing all non-aqueous reagents on an analytical balance according to the % (w / w) in Table 4 and then mixing with water via magnetic stirring for 1 hour. 100 g of blank control formulations were prepared in the same manner by weighing all non-aqueous reagents and mixing them in water at the % (w / w) indicated in Table 1. 45 g of blank control formulation was then mixed with 5 g of microemulsion (Table 2) to produce 55 g of blank control formulation and 50 g of microemulsion formulation (Table 3). 2 mL of each solution was then dispensed into twenty 10 mL glass vials, capped, crimped, and steam sterilized via autoclave. A portion of each solution was kept in a 20 mL scintillation vial and remained unsterilized. The cyclodextrin formulations were prepared and sterilized, and the blank control formulation and microemulsion formulation were prepared and sterilized. Both sterilized and non-sterile solutions were tested at time 0 and at regular intervals for up to 3 months. All sterilized vials were kept crimped until tested upon opening.

[0330] At each testing interval, one previously opened vial and two newly opened vials were tested for all conditions, if applicable. Stability time points are shown in Table 6 below. [Table 7] *Only 2-hydroxypropyl-β-cyclodextrin packaging solution was tested on days 68 and 91.

[0331] The impurities 15-keto-Latanoprost and Latanoprost free acid were purchased and injected into HPLC to determine the retention time of each impurity and its relative retention time to Latanoprost. The HPLC method and impurities assayed are shown in Table 7 below. [Table 8] *Analyses performed before June 8, 2022 did not use 0.1% formic acid in the mobile phase. Results for the control formulation of latanoprost packaging solution containing no additives are in Table 8 below. [Table 9]

[0332] The assay data for the sterilized solutions at each temperature were converted to a percentage of the unsterilized assay, and the converted data are in Table 9. [Table 10]

[0333] At time 0, there was a 7.93% decrease in assay value from unsterilized to sterilized, indicating that this amount of latanoprost was degraded during the autoclave process. The assay value of the unsterilized sample remained constant at both temperatures, indicating that latanoprost was not degraded when not autoclaved. Furthermore, the assay value of the sterilized sample at 5°C remained constant within analytical variation. This indicated that latanoprost was not degraded at 5°C through the initial autoclave degradation. However, latanoprost showed a stable degradation trend at 25°C. Therefore, it can be concluded that latanoprost in an aqueous solution without any additives is not stable at 25°C.

[0334] The stability results for the 10% microemulsion packaging solution formulation are in Table 10 below. [Table 11]

[0335] The assay data for the sterilized solutions at each temperature were converted to a percentage of the unsterilized assay, and the converted data are in Table 11. [Table 12]

[0336] Similar to the blank control formulation, the 10% microemulsion formulation exhibits a significant decline in the latanoprost assay during the autoclave cycle. At time 0, there is a 13.50% decline in assay value from unsterilized to sterilized concentrations. Unsterilized samples in both conditions remain stable through two months. Similarly, after an initial decline, sterilized samples in both conditions remain stable through two months. In the 25°C test group, there is no decline in assay value measured two months after sterilization. Therefore, it can be concluded that the addition of microemulsion stabilizes latanoprost in aqueous solution at 25°C and that this addition is necessary for stabilization.

[0337] The stability results for the 2-hydroxypropyl-β-cyclodextrin packaging solution formulations are in Table 12 below.

[0338] Unsterilized samples stored at 25°C showed rapid degradation starting after one month (28 days). However, sterilized samples did not show the same degradation trend, so the unsterilized samples were excluded from the study and the observed results are considered outliers. The degradation was most likely due to contamination of the unsterilized samples.

[0339] The sterilized solution assay data for each month at each temperature was converted to a percentage of the unsterilized assay, and the converted data are presented in Table 13.

[0340] The 2-hydroxypropyl-β-cyclodextrin formulation, like the other two formulations, shows significant degradation during autoclaving. Sterilized samples at 5°C show stability through 3 months. Samples at 25°C showed an assay of 6.14%, indicating that with further optimization, 2-hydroxypropyl-β-cyclodextrin may be a viable additive to packaging formulations to stabilize latanoprost at 25°C. [Table 13] [Table 14]

[0341] The overall stability graphs at 5°C and 25°C are Figures 7 and 8, respectively.

[0342] At 5°C, none of the formulations, including the blank control formulation, showed degradation over at least two months. At 25°C, only the blank control formulation showed degradation over two months. This suggests that both 2-hydroxypropyl-β-cyclodextrin and the 10% microemulsion are effective and necessary for stabilizing latanoprost in aqueous solution.

[0343] The chromatogram of the final assay time point was evaluated for the presence of the oxidation impurity 15-ketolatanoprost and the hydrolysis impurity latanoprost free acid, see Table 14. [Table 15]

[0344] In contrast to the other two formulations, the microemulsion chromatogram showed no impurity peaks that could not be explained from the blank microemulsion chromatogram, suggesting that the addition of the microemulsion significantly reduced the hydrolysis rate.

[0345] 15-keto-latanoprost was not detected in any of the samples, suggesting that oxidation of latanoprost is not the primary cause of latanoprost instability in the steam-sterilized aqueous packaging solution.

[0346] In the blank control and the 2-hydroxypropyl-β-cyclodextrin formulation, formation of latanoprost free acid was observed.

[0347] Between 2-hydroxypropyl-β-cyclodextrin and microemulsion, microemulsion appears to be more effective at stabilizing latanoprost at 25°C. Latanoprost free acid, the major degradation product observed in the blank control formulation, was absent from any of the microemulsion formulation samples from time zero to 2 months. Furthermore, assay values ​​for the sterilized microemulsion samples showed no stability-based degradation trend. The assay value at 2 months showed a 2.21% increase from time zero, suggesting no degradation of latanoprost in the samples. In contrast, the 2-hydroxypropyl-β-cyclodextrin formulation showed a change of -7.86% from time zero at 2 months and -6.50% from time zero at 3 months. Additionally, the impurity latanoprost free acid was observed in the 2-hydroxypropyl-β-cyclodextrin sample from 1 month onward. The concentration of the impurity peak also increased over time, suggesting that the hydrolysis process continued over time (Table 13). This suggests that the additive 2-hydroxypropyl-β-cyclodextrin slows but does not completely stop the degradation of latanoprost. Both additives improved performance over the blank control formulation, showing a -22.15% decrease in assay value over 2 months and a corresponding increase in latanoprost free acid concentration (Table 13). Because the blank control formulation exhibited a stability-based degradation trend, it can be concluded that the addition of microemulsion or 2-hydroxypropyl-β-cyclodextrin can stabilize latanoprost in aqueous solution at temperatures above 5°C.

[0348] Example 2 Contact lenses coated with latanoprost packaged in a stabilized latanoprost packaging solution Drug-coated contact lenses were prepared, packaged and sterilized in a cyclodextrin packaging solution as detailed in Example 1. Drug-coated contact lenses were prepared with the following formulations:

[0349] formulation 1. Microemulsion formulations (for inks / coatings) 1.1.LAT-ME preparation 1.1.1. Latanoprost microemulsion was prepared in two parts: an aqueous phase and an oily phase. The aqueous phase was prepared by mixing Pluronic F127, water, and PEG400. This mixture was then sonicated for 10 minutes and mixed for 12 hours until clear. The oily phase was prepared by mixing latanoprost and Capmul MCM C-8-EP and sonicated for 10 minutes. The oily phase was mixed for 12-24 hours. The aqueous phase was added to the oily phase and mixed for 12-24 hours. The formulation is shown in Table 15 below. [Table 16]

[0350] 1.2 Preparation of cyclodextrin latanoprost-ME A cyclodextrin latanoprost microemulsion formulation can be prepared. This formulation is prepared by first mixing latanoprost and cyclodextrin, then mixing with Capmul MCM C-8-EP for about 12-24 hours to create an oily phase. Pluronic 127, water, and PEG 400 are simultaneously mixed for about 12-24 hours to create an aqueous phase. Once both solutions are completely formed (no undissolved particulates remain), the aqueous phase is added dropwise to the oily phase, and the two solutions are mixed for 12-24 hours or until a single solution is formed. The formulation is as shown in Table 16. [Table 17]

[0351] 2. Other ink additives 2.1. Preparation of Tween-HA 2.1.1. Additionally, Hylan A (hyaluronic acid, HA) has been shown to both increase latanoprost solubility in solution and increase latanoprost's ability to penetrate corneal tissue, thus increasing the drug's bioavailability. Hyaluronic acid is a polysaccharide molecule found naturally in the body. Hyaluronic acid retains water within its structure, making HA useful as a lubricant that retains moisture in the eye. It also reduces protein deposition in the eye. For these reasons, HA can be used in contact lens drug delivery systems as a comforting agent to ensure comfortable lens wear for one week. Tween-HA, a mixture of Tween-20 and HA, is included in the ink to incorporate HA into the lens. The formulation of Tween-HA is shown below in Table 17. [Table 18]

[0352] 2.1. Preparation of Masterbatch 2.1.1 Masterbatches form the basis of UV coatings and contain oligomers as well as various monomers capable of undergoing radical polymerization. The formulations are shown in Table 18. [Table 19]

[0353] 3. Ink Formulation 3.1. Preparation of LAT-ME-HA coating solution 3.1.1. Latanoprost-microemulsion-hyaluronic acid coating solution is prepared by mixing LAT-microemulsion with masterbatch. This mixture is then added to an automatic triturator with Tween-HA and triturated. The coating is then sonicated and then homogenized. 1-Ethoxy-2-propanol is used as a coating diluent and added until the desired printing viscosity of the coating solution is achieved. The formulation is shown in Table 19. [Table 20]

[0354] 1. Cyclodextrin-Latanoprost Microemulsion can also be used to prepare LAT-ME-HA coatings After preparing the LAT-ME-HA coating, a polymerization initiator is dissolved in the solution, which, when activated, generates free radicals during the inkjet printing process. Table 20 shows the formulation of the LAT-ME-HA-UV coating. [Table 21]

[0355] 4. Packaging Solution Formulation 4.1. Cyclodextrin-stabilized LAT PS 4.1.1. A latanoprost packaging solution stabilized with 2-hydroxypropyl-beta-cyclodextrin is prepared based on the desired concentration of latanoprost. The buffer salt, 2-hydroxypropyl-beta-cyclodextrin, and water are mixed until completely dissolved. The latanoprost is then mixed with the solution for approximately 4 hours until dissolved. Sodium hyaluronate is then added and mixed until completely dissolved. The solution is then filtered. The pH of the packaging solution is measured and, if necessary, adjusted to the desired range of 7.0 to 7.4. The formulation is in Table 21. [Table 22]

[0356] A LAT-ME-HA-UV coating solution was prepared, and a piezo printer head was used to dispense the coating solution, and a single layer of coating was printed onto dry contact lenses via an inkjet printing setup. The lenses were cured under UV light to polymerize the coating, thus forming drug-coated contact lenses. These drug-coated contact lenses were hydrated in 0.05% NaHCO3 solution and packaged in latanoprost packaging solution. The lenses and packaging solution were sterilized to form the final drug-coated contact lenses.

[0357] The performance of lenses made in accordance with the present invention was specifically characterized by weekly release profiles of a batch of combination drug contact lenses, as described in the Examples. Figures 9 and 10 show the daily and cumulative release of latanoprost from the contact lenses.

[0358] In an in vitro setting, latanoprost was shown to be released daily over a 7-day period from drug-coated contact lenses sterilized in a latanoprost packaging solution containing cyclodextrin.

[0359] All publications, including patent documents and scientific articles, mentioned in this application, as well as in the references and appendices, are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication was individually incorporated by reference.

[0360] All headings are for the convenience of the reader and should not be used to limit the meaning of the text that follows the heading, unless otherwise specified.

Claims

1. 1. A packaged medical device comprising: a) at least one drug delivery contact lens, 1) at least one coating disposed on at least one surface of the drug delivery contact lens; 2) comprising at least one hydrophobic drug in at least one oil-water microemulsion; the at least one coating comprises the at least one hydrophobic agent; and at least one drug delivery contact lens, wherein the at least one coating is produced wholly or partially by additive printing; b) at least one packaging solution, 1) the at least one hydrophobic drug; 2) at least one packaging solution comprising at least one cyclodextrin, at least one oil-water microemulsion, or a combination thereof; c) at least one packaging, 1) the at least one drug delivery contact lens; and 2) at least one packaging containing said at least one packaging solution; d) the oil-water microemulsion in the drug delivery contact lens optionally comprises at least one cyclodextrin; e) A packaged medical device further comprising: a hydrophobic drug stabilized in the drug delivery contact lens, the packaging solution, or a combination thereof.

2. The drug delivery contact lens comprises: a) soft contact lenses, b) multifocal contact lenses, or c) The packaged medical device of claim 1, comprising a combination thereof.

3. 10. The packaged medical device of claim 1, wherein the release of the at least one hydrophobic drug from the drug delivery contact lens is regulated by physical properties of the drug delivery lens, chemical properties of the drug delivery lens, or a combination thereof.

4. 4. The packaged medical device of claim 3, wherein the physical characteristics of the drug delivery lens include structures or conditions, or combinations thereof, provided by the additive printing.

5. 4. The packaged medical device of claim 3, wherein the chemical properties of the drug delivery lens include a chemical compound, a chemical composition, an oil-water microemulsion, or a short-range interaction, or a combination thereof.

6. 4. The packaged medical device of claim 3, wherein the chemical properties of the drug delivery contact lens are modified by the addition of at least one cyclodextrin to alter the rate at which the drug is released from the drug delivery contact lens.

7. 10. The packaged medical device of claim 1, wherein the at least one coating comprises one or more layers.

8. 10. The packaged medical device of claim 1, wherein the at least one hydrophobic agent is provided in a pharmaceutically effective amount.

9. 10. The packaged medical device of claim 1, wherein the at least one hydrophobic agent comprises a prostaglandin, a prostaglandin derivative, latanoprost, bimatoprost, atropine, a cannabinoid capable of treating glaucoma, THC, or a combination thereof.

10. 10. The packaged medical device of claim 1, wherein the at least one hydrophobic drug is thermolabile.

11. 10. The packaged medical device of claim 1, wherein said at least one hydrophobic drug is subject to hydrolytic degradation.

12. 10. The packaged medical device of claim 1, wherein the hydrophobic drug in the drug delivery contact lens, the packaging solution, or a combination thereof is steam sterilized and then heat stabilized, hydrolytically stabilized, or a combination thereof.

13. 10. The packaged medical device of claim 1, wherein the at least one oil-water microemulsion comprises oil droplets in an aqueous medium to form a microemulsion.

14. 10. The packaged medical device of claim 1, wherein the additive printing comprises inkjet printing.

15. 10. The packaged medical device of claim 1, wherein the additive printing comprises digital printing, 3D printing, digital 3D printing, pad printing, or a combination thereof.

16. 10. The packaged medical device of claim 1, wherein the additive printing comprises additive printing, additive 3D printing, or a combination thereof.

17. 10. The packaged medical device of claim 1, wherein the packaging solution comprises the at least one hydrophobic drug operatively associated with the at least one cyclodextrin within the at least one oil-water microemulsion, or a combination thereof.

18. The packaged medical device of claim 1 , wherein the at least one packaging comprises at least one blister pack.

19. The packaged medical device of claim 1 , wherein the at least one packaging comprises at least one vial.

20. 10. The packaged medical device of claim 1, wherein the at least one drug delivery contact lens, the at least one packaging solution, or a combination thereof further comprises at least one additional drug.

21. 21. The packaged medical device of claim 20, wherein the at least one additional agent is provided in a pharmaceutically effective amount.

22. 21. The packaged medical device of claim 20, wherein the at least one additional agent further comprises at least one hydrophilic agent.

23. 21. The packaged medical device of claim 20, wherein the at least one additional agent further comprises at least one hydrophobic agent.

24. 21. The packaged medical device of claim 20, wherein the at least one additional medication further comprises an antibiotic, an intraocular pressure reducing agent, a comfort enhancing agent, an anti-inflammatory agent, a penetration enhancer, an agent for macular degeneration, a diabetic retinopathy, or a combination thereof.

25. 21. The packaged medical device of claim 20, wherein the at least one additional agent further comprises dorzolamide, timolol, or a combination thereof.

26. 21. The packaged medical device of claim 20, wherein the at least one additional agent further comprises timolol, Alphagan, Axopt, Cosopt, Lumigan, Travatan, Xalatan, Combigan, timolol hemihydrate, betaxolol, levobunolol, metipranolol, apraclonidine, brimonidine tartrate, brinzolamide, methazolamide, dorzolamide, acetazolamide, carbachol, travoprost, latanoprost, tafluprost, netarsudil, or a combination thereof.

27. 21. The packaged medical device of claim 20, wherein the at least one additional agent further comprises sodium hyaluronate, hyaluronic acid, cyclosporine, polyethylene glycol 400, hypromellose, polyvinyl alcohol, carboxymethylcellulose, dextran 70, hydroxypropyl methylcellulose, anhydrous liquid lanolin, mineral oil, petrolatum, mannitol, thiomersal, carbomer, cetrimide, glycerin, polysorbate 80, povidine, or a combination thereof.

28. 21. The packaged medical device of claim 20, wherein the at least one additional agent further comprises Padoforte, Lotemax, Flurometholone, Nevanac, Acular, Xybrom, or a combination thereof.

29. 21. The packaged medical device of claim 20, wherein the at least one additional agent further comprises flurbiprofen, acetazolamide, ethylenediaminetetraacetic acid, palmitoylcarnitine, sodium caprate, sodium dodecyl sulfate, sodium deoxycholate, polyoxyethylene-g-lauryl ether, 1-α-lysophosphatidylcholine, deoxycholate, taurodeoxycholate, glycocholate, benzalkonium chloride, or a combination thereof.

30. 21. The packaged medical device of claim 20, wherein the at least one additional agent further comprises Aflibercet®.

31. 21. The packaged medical device of claim 20, wherein the at least one additional agent further comprises dexamethasone, at least one steroid, pilocarpine nitrate, tropicamide, methylprednisolone, flurbiprofen, penicillin, ciprofloxacin, sulfacetamine sodium, indomethacin, hydrocortisone, indomethacin, ciprofloxacin hydrochloride, insulin, indomethacin, ketorolac tromethamine, or a combination thereof.

32. 21. The packaged medical device of claim 20, wherein the at least one additional agent further comprises gentamicin, tobramycin, erythromycin, polytrim, cilproflizacin, viamox, xymer, or a combination thereof.

33. 21. The packaged medical device of claim 20, wherein the at least one additional agent further comprises atropine.

34. 1. A drug delivery contact lens comprising: a) at least one coating disposed on at least one surface of the drug delivery contact lens; b) at least one hydrophobic drug in at least one oil-water microemulsion; c) optionally comprising at least one cyclodextrin; d) said at least one coating comprises said at least one hydrophobic agent; e) A drug delivery contact lens further wherein said at least one coating is made wholly or partially by additive printing.

35. 1. A method of making a drug delivery contact lens, comprising: a) providing a contact lens; b) printing at least one coating onto said contact lens with ink, a. the ink comprises at least one hydrophobic agent, at least one oil-water microemulation, or a combination thereof; b. the ink optionally comprises at least one cyclodextrin; c. the printing includes printing with ink, including additive printing; c) the coating, oil-water microemulation, or a combination thereof, modulates the release of the at least one hydrophobic drug from the drug delivery contact lens, the at least one coating, or a combination thereof.

36. 36. The method of making a drug delivery contact lens of claim 35, wherein the contact lens comprises a dry hydrogel, a silicone, or a silicone hydrogel.

37. 1. An ink for printing on a contact lens, comprising: a) at least one monomer; b) at least one cross-linking agent; and c) at least one polymerization initiator; and d) at least one hydrophobic drug; and e) at least one oil-water microemulsion; f) An ink, wherein said ink can be used to print onto contact lenses by additive printing.

38. 38. The ink of claim 37, further comprising at least one cyclodextrin.

39. 1. A method of using a drug delivery contact lens, comprising: a) providing at least one drug delivery contact lens according to claim 1; b) providing a subject in need of treatment or prevention, or a combination thereof, of at least one ocular disease, disorder, or condition, or a combination thereof, treatable or preventable by at least one drug in said at least one drug delivery contact lens; c) operatively engaging the at least one drug delivery contact lens with the eye of the subject; d) The subject is being treated for, or prevented from having, at least one disease, disorder, or condition of the eye, or a combination thereof, that is treatable or preventable by at least one drug in the at least one drug delivery contact lens, or a combination thereof.

40. the ocular disease, disorder, or condition is a) glaucoma, b) myopia, or c) a combination thereof.

41. 1. A method of using a drug delivery contact lens, comprising: a) providing at least one drug delivery contact lens according to claim 34; b) providing a subject in need of treatment or prevention, or a combination thereof, of at least one ocular disease, disorder, or condition, or a combination thereof, treatable or preventable by at least one drug in said at least one drug delivery contact lens; c) operatively engaging the at least one drug delivery contact lens with the eye of the subject; d) The subject is being treated for, or prevented from having, at least one disease, disorder, or condition of the eye, or a combination thereof, that is treatable or preventable by at least one drug in the at least one drug delivery contact lens, or a combination thereof.

42. 1. A method for treating, preventing, or a combination thereof, at least one disease, disorder, or condition of the eye, comprising: a) providing at least one drug delivery contact lens according to claim 1; b) providing a subject in need of treatment or prevention, or a combination thereof, of at least one ocular disease, disorder, or condition, or a combination thereof, treatable or preventable by at least one drug in said at least one drug delivery contact lens; c) operatively engaging the at least one drug delivery contact lens with the eye of the subject; d) A method of treating, a method of preventing, or a combination thereof, wherein the subject is treated for, or prevented from having, the at least one disease, disorder, or condition of the eye, or a combination thereof, that is treatable or preventable by at least one drug in the at least one drug delivery contact lens.

43. 1. A method for treating, preventing, or a combination thereof, at least one disease, disorder, or condition of the eye, comprising: a) providing at least one drug delivery contact lens according to claim 34; b) providing a subject in need of treatment or prevention, or a combination thereof, of at least one ocular disease, disorder, or condition, or a combination thereof, treatable or preventable by at least one drug in said at least one drug delivery contact lens; c) operatively engaging the at least one drug delivery contact lens with the eye of the subject; d) A method of treating, a method of preventing, or a combination thereof, wherein the subject is treated for, or prevented from having, the at least one disease, disorder, or condition of the eye, or a combination thereof, that is treatable or preventable by at least one drug in the at least one drug delivery contact lens.

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