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(12) United States Patent (10) Patent No.: US 8,361,492 B2 Tauber et al. (45) Date of Patent: *Jan. 29, 2013

(54) DRUG DELIVERY SYSTEMAND METHODS (56) References Cited OF USE U.S. PATENT DOCUMENTS (75) Inventors: Shachar Tauber, Ozark, MO (US); 2003/0017208 A1* 1/2003 Ignatious et al...... 424/486 Randall Fuerst, Orangevale, CA (US); 2003/01931 18 A1 10/2003 Bango et al. 2003/0215624 A1 1 1/2003 Layman et al. Keela Davis, Springfield, MO (US); Lyle 2003/0232287 A1 12/2003 Bango Bowman, Pleasanton, CA (US); Gary 2004/0018226 A1 1/2004 Winek et al. Wnek, Cleveland, OH (US); Joseph J. 2005, OO67287 A1 3/2005 Fuerst et al. Bango, Jr., New Haven, CT (US) 2006/0085063 A1* 4/2006 Shastri et al...... 623, 141 2006/0171991 A1 8/2006 Bango 2006/0246113 A1 11/2006 Griffith et al. (73) Assignee: Ocugenics, LLC, Orangevale, CA (US) 2008.0002149 A1 1/2008 Fritsch et al. 2009/0217849 A1 9, 2009 Eastin et al. (*) Notice: Subject to any disclaimer, the term of this 2009, 0238858 A1 9, 2009 Kohnet al. patent is extended or adjusted under 35 OTHER PUBLICATIONS U.S.C. 154(b) by 493 days. Office Action issued in related U.S. Appl. No. 12/416,802, dated Sep. This patent is Subject to a terminal dis 17, 2010, 11 pages. claimer. International Search Report and Written Opinion issued in PCT/ US2010/029126, dated Jan. 14, 2011, 11 pages. Kenawy, E.R. et al. “Controlled Release of from (21) Appl. No.: 12/490,972 electrospun poly(vinyl ) nanofibers' Materials Science & Engineering A 459, pp. 390-396, 2007. (22) Filed: Jun. 24, 2009 Huang, Z.M., et al. A review on polymer nanofibers by electrospin ning and their applications in nanocomposites. Composites Science (65) Prior Publication Data & Terchnology 63, pp. 2223-2253, 2003. US 2009/O269392 A1 Oct. 29, 2009 * cited by examiner Related U.S. Application Data Primary Examiner — Frederick Krass Assistant Examiner — Dennis J Parad (63) Continuation-in-part of application No. 12/416,802, (74) Attorney, Agent, or Firm — Lathrop & Gage LLP filed on Apr. 1, 2009, now Pat. No. 8,083,347. (57) ABSTRACT (60) Provisional application No. 61/125,985, filed on Apr. Electrospun fibers are utilized to improve the mechanical 29, 2008. characteristics of a contact lens reducing the weight and mechanical strength of the polymers from which the lenses (51) Int. C. are typically formed. Electrospun fibers are also utilized as a A6DF 3/00 (2006.01) drug delivery system, both through direct use in the eye and A6 IK9/00 (2006.01) by inclusion of the fibers in a contact lens. The fibers are U.S. Cl...... 424/443; 424/429 loaded with therapeutic drugs by a variety of methods and (52) processed by coating and cross-linking the fibers. (58) Field of Classification Search ...... 424/429 See application file for complete search history. 25 Claims, 8 Drawing Sheets U.S. Patent Jan. 29, 2013 Sheet 1 of 8 US 8,361,492 B2

FIGURE 1

U.S. Patent Jan. 29, 2013 Sheet 2 of 8 US 8,361,492 B2

FIGURE 2

U.S. Patent Jan. 29, 2013 Sheet 3 of 8 US 8,361,492 B2

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U.S. Patent Jan. 29, 2013 Sheet 4 of 8 US 8,361,492 B2

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O O d 600’0 O ZOO’O(= u/8) uoheulueouOO US 8,361,492 B2 1. 2 DRUG DELIVERY SYSTEMAND METHODS fiber materials. The thinner cross-section lens provides OF USE increased oxygen permeability while maintaining mechani cal strength. CROSS-REFERENCE TO RELATED APPLICATIONS BRIEF DESCRIPTION OF THE DRAWINGS This is a continuation-in-part application which claims FIG. 1 is a scanning electron micrograph of a mat of fibers priority of U.S. Non-provisional patent application Ser. No. formed by electrospinning poly(vinyl) alcohol. 12/416,802 filed on Apr. 1, 2009, now issued as Pat. No. FIG. 2 is a scanning electron micrograph of a mat of fibers 8,083,347, which claims priority of U.S. Provisional Patent 10 formed by electrospinning poly(vinyl) alcohol and crosslinked by Submersion in methanol. Application No. 61/125,985 filed on Apr. 29, 2008, which FIG. 3 is a scanning electron micrograph of a mat of fibers applications are incorporated herein by reference. formed by electrospinning poly(vinyl) alcohol, crosslinked BACKGROUND by Submersion in methanol, coated with an aqueous solution 15 of poly(vinyl) alcohol, and then crosslinked a second time. FIG. 4 is a graph of the concentration of a therapeutic drug Field of the Invention released by a fiber mat soak-loaded with the therapeutic drug after deposition. Electrospun polymer fibers provide a material with a vari FIG. 5 is a graph of the concentration of a therapeutic drug ety of favorable characteristics that may be tailored to fit released by a fiber mat fabricated from a precursor solution various applications. The fibers in the electrospun materials containing the therapeutic drug and coated with poly(vinyl) provide Superior mechanical strength with reduced weight alcohol. and Volume. They also have high Surface area and porosity FIG. 5A is a graph of the first 60 minutes of the time period which may be altered as desired during fabrication. shown in FIG. 5. It is therefore desirable to provide a drug delivery system 25 FIG. 6 is a graph of the concentration of a therapeutic drug utilizing electrospun polymer fibers. The drug delivery sys released by a fiber mat fabricated from a precursor solution tem may utilize the fibers for insertion directly into the eye containing the therapeutic drug coated with poly(vinyl) alco maintaining the concentration of the drug in the eye at an hol, and crosslinked with methanol. efficacious level throughout the period of drug delivery. FIG. 6A is a graph of the first 60 minutes of the time period The system may also utilize an improved contact lens 30 shown in FIG. 6. incorporating electrospun fibers with desired characteristics, and a system and method for delivering ophthalmic drugs DETAILED DESCRIPTION from the improved contact lens to an eye over an extended period of time while maintaining the concentration of the Electrospun Fiber Mat Fabrication 35 The electrospun fiber mat used in the present invention is drug in the eye at an efficacious level throughout the period of fabricated by polymerizing electrospun fibers and loading a drug delivery. therapeutic drug in the fibermat using a variety of techniques, It is also desirable to provide a system and method for which are described below with examples. preloading drugs in the delivery system in a manner that The electrospinning process typically comprises an appa allows the delivery system to be stored for an extended period 40 ratus including one or more electrically-conducting liquid of time. dispenser, such as a stainless Steel needle, disposed adjacent to a collector. The liquid dispenser is held at a high electric SUMMARY OF THE INVENTION potential, or voltage, with respect to the collector. The electric potential may be either alternating current (AC) or direct The drug delivery system described herein utilizes both 45 current (DC), or a DC biased AC voltage. Alternatively, a “raw' electrospun fibers and an improved contact lens as the substrate for receiving the electrospun fibers may be inserted means of drug delivery. The fibers and the improved contact between the conducting dispenser and the collector Such that lens provide a drug delivery system comprising a drug-releas the fibers will be deposited on the substrate as they are pro ing scaffold formed from a mat of electrospun fibers and pelled from the liquid dispenser by the electric field toward methods for incorporating various therapeutic drugs into the 50 the collector. mat. The fiber mat may be utilized directly in the eye for A Solution Source, or well, containing a solution of the delivery of drugs, or incorporated into an improved contact polymer and various other components which may include a lens. polymer precursor (monomer) is attached to the electrically The therapeutic drugs may be loaded into the drug delivery conducting liquid dispenser by a fluid conducting element system by soaking the electrospun mats in a solution contain 55 such as a short tube. The polymer solution is propelled ing the drug, or by providing the drugs in the Solution feeding through the dispenser at a predetermined rate, either by grav the electrospinning process thus incorporating the drug into ity or by mechanical means such as a pump. As the Solution is the fibers in the electrospun mat. Various processes for treat dispensed through the electrically-conducting dispenser, the ing the electrospun mats after loading with therapeutic drugs high electric potential between the dispenser and the collector are also described for improving the drug delivery character 60 leads to the formation of uniform fibers which are deposited istics, such as coating the mats in a polymer and cross-linking on the collector. The fibers may be micro-fibers or nano-fibers the electrospun fibers. depending on the parameters of the electrospinning process. The improved contact lens described herein also comprises As the fibers are deposited on the collector they overlap to a contact lens that incorporates electrospun fibers to provide form a mat, as further described below. desirable physical characteristics. The improved contact lens 65 Polymer solutions for use in the fiber mat fabrication dis may be fabricated with a thinner cross-section due to the closed herein include, but are not limited to, aqueous solu increased mechanical strength and rigidity of the electrospun tions having between 5 and 15 percent polymer by weight. US 8,361,492 B2 3 4 Various additives may be added to the precursor solution to 3. Add 7.0 ml of the PVA/Vigamox solution to 2 syringes lower surface tension, or to otherwise alter the characteristics for a total of 14.0 ml of solution. of the solution or the electrospun fibers as desired. For 4. Electrospin the PVA/Vigamox solution from both example, surfactants, such as Triton X-100, poloxomer 407 or needles simultaneously at the following parameters: other suitable surfactant, may be added to the precursor solu 5 Dispense rate: 1.8 ml/hr tion to lower the surface tension of the solution. 18 gauge blunt end needles Polymers for use in the electrospinning process include, Voltage: 30 kV but are not limited to the following: poly(2-hyroxyethyl Travel distance: 4 in methacrylate) (pHEMA), poly(acrylic acid) (PAA), poly Total time: 2.5 hours (methacrylic acid), poly(Vinyl pyrolidone) (PVP), poly(N- 10 5. After electrospinning, the resulting mat is cut into vinyl pyrolidone) (PVP), Polyvinyl alcohol (PVA), poly approximately 3.0 mg Squares. (methyl methacylate) (PMMA), poly(glyceral methacrylate) 6. If crosslinking is desired, soak the squares in methanol (PGMA), Silicone Hydrogels, Fluorocarbon hydrogels, poly for 7 hours and allow to air dry in ambient conditions acrylamide (PAM), Silicone and 3-methacryloxy-2 hydrox overnight. ypropyloxy)propylbis(trimethylsiloxy)methylsilane. Other 15 7. Coat the squares in the remaining PVA polymer solution polymers may be utilized if soluble in a solvent such as water, created in step 1 above. Before coating the squares, the methanol, ethanol, hexane, acetonitrile, or tetrahydrofuran to PVA polymer solution is heated in a round bottom flask allow the electrospinning process. If the fibers are to be uti with attached condenser for 2 hours. lized in a contact lens as described below, the fibers are 8. After coating the squares in the polymer Solution, allow preferably formed from a polymer that is the same as the them to air dry in ambient conditions overnight. polymer to be used in the remainder of the contact lens, or a 9. If a second cross-link is desired soak the squares in polymer that has a similar index of refraction, to reduce methanol for 7 hours and then allow them to air dry in negative optical characteristics of the improved contact lens. ambient conditions overnight. Additional polymer precursor solutions are described below. When measuring drug release profiles the following pro As the fibers are deposited on the collector they form a mat 25 cedure was utilized: of overlaying fibers. In some methods of depositing the fibers, 1. Each sample mat was placed into 0.5 ml ISO 18369 the collectoris translated in one or more linear dimensions, or Saline solution in cuvettes. in a rotational or orbital manner, perpendicular to the direc 2. Absorbance measurements were taken at 1, 5, 10, 20, 60, tion of fiber deposition to increase the area over which the 1440, and 2880 minutes by removing the sample mat fibers are deposited and to improve the consistency of the 30 with tweezers and measuring the absorbance at 336 mm. fiber mat. Sample mats were immediately placed back in the After a desired period of deposition, a fibermat of a certain sample cuvette after measurement. thickness will be formed, and can be removed from the elec 3. Measurements were normalized by mass of the sample trospinning apparatus and prepared for further processing. mat prior to dip-coating. After deposition, the fibermat may be processed in several 35 Polymer Materials for Electrospun Fibers ways to improve the characteristics of the fibermat. The fiber Suitable hydrophobic comonomers (a) for use in electro mat may be coated with a polymer by exposing the mat to an spun fibers include, without this list being exhaustive, Solution of polymer precursor. As described below, coating C-C salkyl and C-C scycloalkyl acrylates and methacry the fibermat alters the characteristics of the fibermat, includ lates, C-C salkylacrylamides and -methacrylamides, acry ing the release of drugs incorporated in the fiber mat. After 40 lonitrile, methacrylonitrile, vinyl C-C salkanoates, any chemical processing, the mats may be further processed C-C salkenes, C-Chaloalkenes, styrene, lower alkyl Sty by cutting into sections or grinding into particles. rene, lower alkyl vinyl ethers, C-C perfluoroalkyl acrylates The fiber mats may also be processed by exposing them to and methacrylates or correspondingly partly fluorinated acry a crosslinking agent such as ethylene glycol dimethacrylate lates and methacrylates, C-C perfluoroalkyl-ethyl-thiocar (EGDMA), tetraetheylene glycol dimethacrylate 45 bonylaminoethyl acrylates and methacrylates, acryloxy- and (TEGDMA), divinyl benzene (DVB), divinylacrylamide methacryloxy-alkylsiloxanes, N-vinylcarbazole and (DVACR), or any tri-allyl crosslinking agent. Methanol may C-C alkyl esters of maleic acid, fumaric acid, itaconic acid, be added to PVA to crosslink the polymer. The crosslinking mesaconic acid and the like. Preferred comonomers are, for process increases the mechanical stability of the fiber mat by example, acrylonitrile, C-C alkyl esters of vinylically unsat linking adjacent fibers as they intersect randomly in the fiber 50 urated carboxylic acids having 3 to 5 carbon atoms, or vinyl mat. esters of carboxylic acids having up to 5 carbon atoms. An example process for creating an electrospun fibermatis Examples of Suitable hydrophobic comonomers (a) as follows. include methyl acrylate, ethyl acrylate, propyl acrylate, iso 1. Combine the following materials, mix, place over heat propyl acrylate, isobutyl acrylate (IBA), isooctyl acrylate and stir inside round-bottom flask with attached con 55 (OA), isodecyl acrylate (DA), cyclohexyl acrylate, 2-ethyl denser for 6.5 hours. hexyl acrylate (EHA), methyl methacrylate, ethyl methacry 10 wt % PPVA+2 wt % Triton X-100+DI water late, propyl methacrylate, butyl acrylate, vinyl acetate, vinyl 11.363 g Polyvinyl alcohol (Sigma-Aldrich 99% hydro propionate, vinyl butyrate, vinyl Valerate, styrene, chloro lyzed) prene, vinyl chloride, vinylidene chloride, acrylonitrile, 2.277 g Triton X-100 (Aldrich) 60 1-butene, butadiene, methacrylonitrile, vinyl toluene, vinyl 27.539 g Ultra highpurified water added to TritonX-100 ethyl ether, perfluorohexylethylthiocarbonylaminoethyl (Elgan) methacrylate, isobornyl methacrylate, trifluoroethyl meth 72.459 g Ultra high purified water added to PVA (Elgan) acrylate, hexafluoroisopropyl methacrylate, hexafluorobutyl This is the PVA polymer mixture. Without allowing the (meth)acrylate (HFBMA and HFBA), tris-trimethylsilyloxy polymer mixture to cool performing the following steps. 65 silyl-propyl methacrylate (TRIS), 3-methacryloxypropyl 2. Add 2,000 ml of Vigamox to 14.141 g of the PVA pentamethyldisiloxane and bis(methacryloxypropyl) tetram polymer mixture and vortex stir for 1 minute. ethyldisiloxane. Preferred examples of hydrophobic US 8,361,492 B2 5 6 comonomers (a) are methyl methacrylate, IBA, HFBA, alkanols, for example ethanol or methanol, and furthermore HFBMA, OA, EHA, DA, TRIS and acrylonitrile. Suitable carboxylic acid amides, such as dimethylformamide, dipolar hydrophilic comonomers (a) include, without this list being aprotic solvents, such as dimethyl sulfoxide or methyl ethyl conclusive, hydroxyl-substituted lower alkyl acrylates and ketone, ketones, for example acteone or cyclohexanone, methacrylates, acrylamide, methacrylamide, lower alky hydrocarbons, for example toluene, ethers, for example THF, lacrylamides and -methacrylamides, ethoxylated acry-lates dimethoxyethane or dioxane, and halogenated hydrocarbons, and methacrylates, hydroxyl-substituted lower alkylacryla for example trichloroethane, and also mixtures of suitable mides and -methacrylamides, hydroxyl-substituted lower solvents, for example mixtures of water with an alcohol, for alkyl vinyl ethers, sodium vinylsulfonate, sodium Styrene example a water/ethanol or a water/methanol mixture. Sulfonate, 2-acrylamido-2-methylpropanesulfonic acid, 10 If appropriate, a polymer network can be intensified by N-vinylpyrrole, N-vinyl-2-pyrrolidone, 2-vinyloxazoline, addition of a so-called crosslinking agent, for example a 2-vinyl-4,4'-dialkyloxazolin-5-one, 2- and 4-vinylpyridine, polyunsaturated comonomer (b). The invention furthermore vinylically unsaturated carboxylic acids having a total of 3 to relates to a polymer comprising the polymerization product 5 carbon atoms, amino-lower alkyl (where the term “amino” of a macromer according to the invention with, ifappropriate, also includes quaternary annononium), mono-lower alky 15 at least one vinylic comonomer (a) and with at least one lamino-lower alkyl and di-lower alkylamino-lower alkyl comonomer (b). Examples of typical comonomers (b) are, for acrylates and methacrylates, allyl alcohol and the like. Pre example, allyl(meth)acrylate, lower alkylene glycol di(meth) ferred comonomers are, for example, N-vinyl-2-pyrrolidone, acrylate, poly lower alkylene glycol di(meth)acrylate, lower acrylamide, methacrylamide, hydroxyl-substituted lower alkylene di(meth)acrylate, divinyl ether, divinyl sulfone, di alkyl acrylates and methacrylates, hydroxyl-substituted or trivinylbenzene, trimethylolpropane tri(meth)acrylate, lower alkylacrylamides and -methacrylamides and vinyli pentaerythritol tetra(meth)acrylate, bisphenol A di(meth) cally unsaturated carboxylic acids having a total of 3 to 5 acrylate, methylenebis(meth)acrylamide, triallyl phthalate or carbonatoms. Examples of suitable hydrophilic comonomers diallyl phthalate (a) include hydroxyethyl methacrylate (HEMA), hydroxy ethyl acrylate, hydroxypropyl acrylate, trimethylammonium 25 EXAMPLES 2-hydroxy-ypropyl methacrylate hydrochloride (Blemer R MQA, for example from Nippon Oil), dimethylaminoethyl methacrylate (DMAEMA), dimethylaminoethyl methacry lamide, acrylamide, methacrylamide, N,N-dimethylacryla mide (DMA), allyl alcohol, vinylpyridine, glycerol meth 30 Monomer? Cat Crosslinker % % % % % % acrylate, N-(1.I-dimethyl-3-oxobutyl)acrylamide, N-vinyl MMA 25.5 24.2 2-pyrrolidone (NVP), acrylic acid, methacrylic acid and the GMA 68 like. Preferred hydrophilic comonomers (a) are 2-hydroxy HEMA 93.25 ethyl methacrylate, dimethylaminoethyl methacrylate, trim NVP VP 35 ethylammonium-2-hydroxypropyl methacrylate hydrochlo MAA ride, N,N-dimethylacrylamide and N-vinyl-2-pyrrolidone. TEDGMA 5 The polymers according to the invention are built up in a EDGMA 1 1 1 1 IPP .2 .2 known manner from the corresponding monomers (the term AIBN monomers here also including a macromer according to the PWA Fibers 7.25 invention) by a polymerization reaction with which the expert 40 PHEMA Fibers 8.75 is familiar. Usually, a mixture of the abovementioned mono PVP Fibers 5 mers is heated, with the addition of an agent which forms free radicals. Such an agent which forms free radicals is, for *IPPIsopropyl percarbonate example, aZoisobutyronitrile (AIBN), potassium peroxodis *AIBN azoisobutyronitrile ulfate, dibenzoyl peroxide, hydrogen peroxide or sodium per 45 In each example above, electrospun fibers are made by carbonate. If the compounds mentioned are heated, for dissolving 15% of the polymer in methanol and electrospin example, free radicals are then formed, by homolysis, and can ning the fibers as described previously. The weight of elec then, for example, initiate a polymerization. trospun fiber is placed in a button mold, monomer composi A polymerization reaction can be carried out using a pho tion from the table added, vacuum pulled on the solution, toinitiator. Photopolymerization is the term used in this case. 50 button mold top added, and polymerized at 60°C. in an oven For photopolymerization, a photoinitiator which can initiate for 24 hours followed by curing at 80° C. for 4 hours. The free radical polymerization and/or crosslinking by the use of button removed and lens machined from the buttons by mea light is suitably added. Examples of this are familiar to the Suring hydration parameters on the polymerized materials. expert, and specifically, Suitable photoinitiators are benzoin Drug Delivery System Utilizing Electrospun Fibers methyl ether, I-hydroxycyclohexyl phenyl ketone and 55 The electrospun fibers may be loaded with a therapeutic Darocur and Irgacur types, preferably Darocur 11738(R) and drug and utilized as a drug delivery system. The fibers can be Darocur 29590(R). Reactive photoinitiators which can be used as inserts in the eye, either separately or as a mat. The incorporated, for example, into a macromer or can be used as insert can be placed in the cul-de-sac of the eye in the form of a special comonomer (a) are also Suitable. Examples of these dry fibers or a mat of dry fibers. This dry mat placed in the eye are to be found in EP 632 329. The photopolymerization can 60 will hydrate thereby releasing the therapeutic drug as the mat then be triggered offby actinic radiation, for example light, in hydrates. The fibers can also be inserted under the conjunctiva particular UV light of a suitable wavelength. The spectral or Sclera and will slowly erode away releasing the therapeutic requirements can be controlled accordingly, if appropriate, by drug, provided the fiber is not a crosslinked polymeric mate addition of suitable photosensitizers. Polymerization can be rial. carried out in the presence or absence of a solvent. Suitable 65 The fiber mats may be stored dry, as noted above, which solvents are in principle all solvents which dissolve the mono will minimize the loss of the therapeutic drug during storage. mers used, for example water, alcohols, such as lower This will require that residual impurities such as monomers US 8,361,492 B2 7 8 be kept to a minimum and that hydration time will be short. change the diffusion characteristics, by cross-linking the The fiber mats may also be stored in water or another solvent, fibers and by coating the fibers with a polymer or other coat which will remove impurities from the fibermats. The storage ing. Solution must also contain a sufficient concentration of the After the mats are created by electrospinning and Subjected therapeutic drug to prevent the drug from dissolving from the to drug-loading processing, if necessary, the mats may be fibers while in storage. coated with a polymer such as PVA by submersion in an This drug delivery system provides for the release of oph aqueous solution of the polymer coating. They may also be thalmic drugs from the fiber mat to an eye over an extended crosslinked before and after the PVA coating. period of time, thus improving the efficacy of the drug by An example of forming a fiber mat for drug delivery from maintaining atherapeutic concentration of the drug in the eye 10 electrospun fibers loaded with a therapeutic drug comprises for a long period of time. Known methods of delivering drugs the following steps. Dissolve 15% PVA in 5% moxifloxacin to an eye typically result in initially high concentrations of to methanol and electrospin into nanofibers. Place spun fibers drugs that quickly drop to levels which are too low for optimal in methanol containing 0.6% moxifloxacin for 2 hours and efficacy. The electrospun fibers in the drug delivery system then dry the electrospun fibers. Form the spun fibers into a may be loaded with appropriate drugs via several methods 15 matt and store until use as an insert to place dry in the lower described below. cul-de-sac of the eye. In a first method of loading the drug delivery system with A wide variety of therapeutic drugs may be spun into the appropriate drugs, the drugs are mixed with the polymer fibers, so long as the drug is soluble in a solvent with the Solution in the liquid well that feeds the electrospinning pro polymer Solution. Examples of various types of drugs that cess. The concentration of the drug in the polymer Solution may be spun into fibers include the following and any deriva will vary depending on the drug used and the rate and amount tives of the therapeutically-active agents which may include, to dispensed from the fibers when in use in the eye, and will but not be limited to: analogs, salts, esters, amines, amides, need to be determined experimentally or otherwise for each alcohols and acids derived from an agent of the invention and drug and polymer combination. Typically ranges of drug may be used in place of an agent itself. concentration in the polymer Solution may range from 0.1% 25 Examples of the antibacterial antibiotics include, but are to 20% of the polymer solution. The drugs are dispensed with not limited to: aminoglycosides (e.g., amikacin, apramycin, the polymer Solution through the electrically-conducting liq arbekacin, bambermycins, butirosin, dibekacin, dihydros uid dispenser, and incorporated directly into the fibers created treptomycin, fortimicin(s), gentamicin, isepamicin, kanamy by the electrospinning process. cin, micronomicin, neomycin, neomycin undecylenate, Polymer solutions for use in the drug delivery system 30 netilmicin, paromomycin, ribostamycin, Sisomicin, spectino include, but are not limited to, aqueous solutions having mycin, Streptomycin, tobramycin, trospectomycin), between 5 and 15 percent polymer by weight, similar to the amphenicols (e.g., azidamfenicol, chloramphenicol, florfeni base polymer solution utilized in the creation of the improved col, thiamphenicol), ansamycins (e.g., rifamide, rifampin, contact lens, with the addition of the therapeutic drug to be rifamycin SV, rifapentine, rifaximin), beta.-lactams (e.g., car dispensed from the contact lens. The concentration of the 35 bacephems (e.g., loracarbef), carbapenems (e.g., biapenem, drug in the contact lens and the rate of release in the eye are imipenem, meropenem, panipenem), cephalosporins (e.g., adjusted by altering the concentration of the drug in the poly cefaclor, cefadroxil, cefamandole, cefatrizine, cefazedone, mer Solution. More than onetherapeutic drug may be added to cefazolin, cefcapene pivoxil, cefclidin, cefdinir, cefditoren, the polymer Solution to provide an improved contact lens that cefepime, cefetamet, cefixime, cefinenoxime, cefodizime, delivers a “cocktail of drugs to the eye which may be tailored 40 cefonicid, cefoperaZone, ceforanide, cefotaxime, cefotiam, as necessary for the patient. cefoZopran, cefpimizole, cefpiramide, cefpirome, cefpo As an example offiber mat formation, without limiting the doXime proxetil, cefprozil, cefroxadine, cefsulodin, ceftazi range of parameters, mats for use with the drug delivery dime, cefteram, ceftezole, ceftibuten, ceftizoxime, ceftriax system described herein may be created by electrospinning one, cefuroxime, cefuZonam, cephacetrile Sodium, PVA onto a flat rotating collector for 4 hours at a dispense rate 45 cephalexin, cephaloglycin, cephaloridine, cephalosporin, of 1.8 ml per hour from an 18 gauge stainless steel needle cephalothin, cephapirin Sodium, cephradine, pivoefalexin), situated 4 inches from the collector, and held at 30 kV DC cephamycins (e.g., cefbuperaZone, cefinetazole, cefininox, from the collector. Varying the electrospinning time, the dis cefotetan, cefoxitin), monobactams (e.g., aztreonam, caru pense rate, the needle gauge, the separation between dis monam, tigemonam), oxacephems, flomoxef, moxalactam), penser and collector, and the dispenser potential are within 50 penicillins (e.g., amdinocillin, amdinocillin pivoxil, amox the scope of the drug delivery system described herein, and icillin, amplicillin, apalcillin, aspoxicillin, azidocillin, aZlocil the above described set of parameters is not limiting of the lin, bacampicillin, benzylpenicillinic acid, benzylpenicillin drug delivery system. Sodium, carbenicillin, carindacillin, clometocillin, cloxacil In a second method of loading the drug delivery matrix, the lin, cyclacillin, dicloxacillin, epicillin, fenbenicillin, floxacil PVA mat is created, and then the mat is soaked in a solution 55 lin, hetacillin, lenampicillin, metampicillin, methicillin containing the therapeutic drug. In this method, the therapeu Sodium, mezlocillin, nafcillin Sodium, oxacillin, penamecil tic drug must be a water soluble drug. The amount of drug lin, penethamate hydriodide, penicilling benethamine, peni loaded into the fiber mat is dependent, among other param cilling benzathine, penicilling benzhydrylamine, penicilling eters, on the soak time, the rate of uptake of the fibers, the fiber calcium, penicilling hydrabamine, penicilling potassium, diameter, and the concentration of drug in the Soak solution. 60 penicilling procaine, penicillinn, penicillino, penicillin V, The rate of drug delivery from the fiber mats after place penicillin V benzathine, penicillin V hydrabamine, penimepi ment in the eye is dependent, among other parameters, on the cycline, phenethicillin potassium, piperacillin, pivampicillin, fiber diameter, the drug solubility in water, the amount offiber propicillin, quinacillin, Sulbenicillin, Sultamicillin, talampi in the mat (or lens), the amount of drug loaded in the fiber, and cillin, temocillin, ticarcillin), other (e.g., ritipenem), lincosa other parameters. The rate of drug delivery may also be con 65 mides (e.g., clindamycin, lincomycin), macrollides (e.g., trolled by changing the polymer composition from hydro azithromycin, carbomycin, clarithromycin, dirithromycin, philic to hydrophobic, by treating the surface of the fibers to erythromycin, erythromycin acistrate, erythromycineStolate, US 8,361,492 B2 10 erythromycin glucoheptonate, erythromycin lactobionate, Zole, itraconazole, Saperconazole, terconazole) others (e.g., erythromycin propionate, erythromycin Stearate, josamycin, acrisorcin, amorolfine, biphenamine, bromosalicylchloranil leucomycins, midecamycins, miokamycin, oleandomycin, ide, buclosamide, calcium propionate, chlorphenesin, ciclo primycin, rokitamycin, rosaramicin, roXithromycin, spira pirox, cloxyquin, coparaffinate, diamthazole dihydrochlo mycin, troleandomycin), polypeptides (e.g., amphomycin, ride, exalamide, flucytosine, halethazole, hexetidine, bacitracin, capreomycin, colistin, enduracidin, enviomycin, loflucarban, nifuratel, potassium iodide, propionic acid, fusafungine, gramicidin s, gramicidin(s), mikamycin, poly pyrithione, Salicylanilide, Sodium propionate, Sulbentine, myxin, pristinamycin, ristocetin, teicoplanin, thiostrepton, tenonitroZole, triacetin, ujothion, undecylenic acid, Zinc pro tuberactinomycin, tyrocidine, tyrothricin, Vancomycin, vio pionate). mycin, Virginiamycin, Zinc bacitracin), tetracyclines (e.g., 10 Examples of the antineoplastic agents include, but are not apicycline, chlortetracycline, clomocycline, demeclocycline, limited to: antineoplastic antibiotics and analogs (e.g., aclaci doxycycline, guamecycline, lymecycline, meclocycline, nomycins, actinomycin fsub.1, anthramycin, aZaserine, bleo methacycline, minocycline, oxytetracycline, penimepicy mycins, cactinomycin, carubicin, carzinophilin, chromomy cline, pipacycline, rollitetracycline, Sancycline, tetracycline), cins, dactinomycin, daunorubicin, 6-diazo-5-oxo-L- and others (e.g., cycloserine, mupirocin, tuberin). 15 norleucine, doxorubicin, epirubicin, idarubicin, menogaril. Examples of the synthetic antibacterials include, but are mitomycins, mycophenolic acid, nogalamycin, olivomy not limited to: 2,4-diaminopyrimidines (e.g., brodimoprim, cines, peplomycin, pirarubicin, plicamycin, porfiromycin, tetroxoprim, trimethoprim), nitrofurans (e.g., furaltadone, puromycin, streptonigrin, Streptozocin, tubercidin, Zinosta furazolium chloride, nifuradene, nifuratel, nifurfoline, tin, Zorubicin), antimetabolites exemplified by folic acid ana nifurpirinol, nifurprazine, nifurtoinol, nitrofurantoin), quino logs (e.g., denopterin, edatrexate, methotrexate, piritrexim, lones and analogs (e.g., cinoxacin, ciprofloxacin, clinafloxa pteropterin, TomudeXR, trimetrexate), purine analogs (e.g., cin, difloxacin, enoxacin, fleroxacin, flumequine, grepafloxa cladribine, fludarabine, 6-mercaptopurine, thiamiprine, cin, lomefloxacin, miloxacin, nadifloxacin, nalidixic acid, thioguanine), pyrimidine analogs (e.g., ancitabine, azaciti norfloxacin, ofloxacin, oxolinic acid, paZufloxacin, pefloxa dine, 6-azauridine, carmofur, cytarabine, doxifluridine, cin, pipemidic acid, piromidic acid, roSoxacin, rufloxacin, 25 emitefur, enocitabine, floxuridine, fluorouracil, gemcitabine, sparfloxacin, temafloxacin, to Sufloxacin, trovafloxacin), Sul tagafur). fonamides (e.g., acetyl Sulfamethoxypyrazine, benzylsulfa Examples of the steroidal anti-inflammatory agents mide, chloramine-b, chloramine-t, dichloramine t, n. Sup.2- include, but are not limited to: 21-acetoxypregnenolone, formylsulfisomidine, n. Sup.4-beta.-d- alclometaSone, algestone, amcinonide, beclomethasone, glucosylsulfanilamide, mafenide, 4'-(methylsulfamoyl) 30 betamethasone, budesonide, chloroprednisone, clobetasol, Sulfanilanilide, noprylsulfamide, phthalylsulfacetamide, clobetasone, clocortolone, cloprednol, corticosterone, corti phthalylsulfathiazole, salazosulfadimidine, succinylsul sone, cortivazol, deflazacort, desonide, desoximetasone, dex fathiazole, Sulfabenzamide, Sulfacetamide, Sulfachlorpy amethasone, diflorasone, diflucortolone, difluprednate, enox ridazine, Sulfachrysoidine, Sulfacytine, Sulfadiazine, Sulfadi olone, fluazacort, flucloronide, flumethasone, flunisolide, cramide, Sulfadimethoxine, Sulfadoxine, Sulfaethidole, 35 fluocinolone acetonide, fluocinonide, fluocortin butyl, fluo Sulfaguanidine, Sulfaguanol, Sulfalene, Sulfaloxic acid, Sul cortolone, fluorometholone, fluperolone acetate, flupred famerazine, Sulfameter, Sulfamethazine, Sulfamethizole, Sul nidene acetate, fluprednisolone, flurandrenolide, fluticasone famethomidine, Sulfamethoxazole, Sulfamethoxypyridazine, propionate, formocortal, halcinonide, halobetasol propi Sulfametrole, Sulfamidocchrysoidine, Sulfamoxole, Sulfanil onate, halometaSone, halopredone acetate, hydrocortamate, amide, 4-sulfanilamidosalicylic acid, n. Sup.4-Sulfanilylsulfa 40 hydrocortisone, loteprednol etabonate, maZipredone, nilamide, Sulfanily lurea, n-sulfanilyl-3,4-Xylamide, Sulfanit medrysone, meprednisone, methylprednisolone, mometa ran, Sulfaperine, Sulfaphenazole, Sulfaproxyline, Sone furoate, paramethasone, prednicarbate, prednisolone, Sulfapyrazine, Sulfapyridine, Sulfasomizole, Sulfasymazine, prednisolone 25-diethylamino-acetate, prednisolone sodium Sulfathiazole, Sulfathiourea, Sulfatolamide, Sulfisomidine, phosphate, prednisone, prednival, prednylidene, rimexolone, Sulfisoxazole) sulfones (e.g., acedapsone, acediasulfone, 45 tiXocortol, triamcinolone, triamcinolone acetonide, triamci acetosulfone sodium, dapsone, diathymosulfone, glucosul nolone benetonide, and triamcinolone hexacetonide. fone sodium, Solasulfone, Succisulfone, Sulfanilic acid, p-sul Examples of the non-steroidal anti-inflammatory agents fanilylbenzylamine, Sulfoxone sodium, thiazolsulfone), and include, but are not limited to: aminoarylcarboxylic acid others (e.g., clofoctol, hexedine, methenamine, methenamine derivatives (e.g., enfenamic acid, , flufenamic anhydromethylene-citrate, methenamine hippurate, meth 50 acid, isonixin, , , niflumic enamine mandelate, methenamine Sulfosalicylate, nitroXo acid, talniflumate, terofenamate, ), arylacetic line, taurolidine, Xibomol). acid derivatives (e.g., , , aldlofenac, Examples of the antifungal antibiotics include, but are not , amtolimetin guacil, , cinmetacin, clopi limited to: polyenes (e.g., amphotericin b, candicidin, den rac, sodium, , , , nostatin, filipin, fungichromin, hachimycin, hamycin, lucen 55 , glucametacin, ibufenac, indomethacin, isofeZolac, Somycin, mepartricin, natamycin, nystatin, pecilocin, peri isoxepac, , metiazinic acid, , oxameta mycin), others (e.g., azaserine, griseofulvin, oligomycins, cine, piraZolac, , , tiaramide, , neomycin undecylenate, pyrrolnitrin, siccanin, tubercidin, tropesin, ), arylbutyric acid derivatives (e.g., viridin). bumadizon, butibufen, , xenbucin), arylcarboxylic Examples of the synthetic antifungals include, but are not 60 acids (e.g., clidanac, , tinoridine), arylpropionic limited to: allylamines (e.g., butenafine, naftifine, terbin acid derivatives (e.g., , , bermo afine), imidazoles (e.g., bifonazole, butoconazole, chlordan profen, bucloxic acid, , , , toin, chlormiidazole, clotrimazole, econazole, enilconazole, , , , , ketoprofen, fenticonazole, flutrimazole, isoconazole, ketoconazole, lano , , , piketoprolen, , conazole, miconazole, omoconazole, oxiconazole nitrate, 65 , protizinic acid, , , Sertaconazole, Sulconazole, tioconazole), thiocarbamates Ximoprofen, ), pyrazoles (e.g., difenamizole, epi (e.g., tolciclate, tolindate, tolnaftate), triazoles (e.g., flucona rizole), (e.g., apaZone, benzpiperylon, fepra US 8,361,492 B2 11 12 Zone, , , , phenylb thinner cross-section of the lens provides increased oxygen utaZone, pipebuZone, , ramifenaZone, permeability while maintaining mechanical strength. , thiazolinobutaZone), derivatives Fibers loaded with therapeutic drugs as described above (e.g., acetaminosalol, , benorylate, bromosaligenin, may be used to manufacture the improved contact lens. When calcium acetylsalicylate, , etersalate, fendosal, gen forming a contact lens using fibers that have been loaded with tisic acid, glycol salicylate, , lysine ace a therapeutic drug, the polymerization conditions and other tylsalicylate, mesalamine, morpholine salicylate, 1-naphthyl processing steps must be controlled to prevent degradation of salicylate, olsalazine, parsalmide, phenyl acetylsalicylate, the therapeutic drug. phenyl salicylate, Salacetamide, o-acetic acid, An example of forming a contact lens from electrospun salicylsulfuric acid, , Sulfasalazine), thiazinecar 10 fibers loaded with a therapeutic drug comprises the following boxamides (e.g., , , , lomoxi steps. Dissolve 15% polyacrylic acid and 5% tobramycin in cam, , ), E-acetamidocaproic acid, S-ad methanol and electrospin polyacrylic acid fibers containing enosylmethionine, 3-amino-4-hydroxybutyric acid, the antibiotic. Place these fibers in a button mold and add amixetrine, , , alpha.-bisabolol, buco 15 acrylic acid monomer, 1% EDGMA and 0.25% AIBN. Heat lome, , ditazol, emorfaZone, fepradinol, guaia at 550 C. for 24 hours and cure at 850 C. for 2 hours. Remove Zulene, , , , paranyline, from the mold and machine into a contact lens. Extract the perisoxal, produaZone, , , and residual monomers form the lens by placing in physiological Zileuton. saline containing 0.3% tobramycin for 24 hours. Remove Examples of anti-allergic agents include, but are not lim from extract solution, replace with fresh 0.3% tobramycin ited to: tranilast, ketotifen fumarate, pheniramine, diphenhy physiological Saline, autoclave at 1230 C and store until use. dramine hydrochloride, Sodium cromoglicate, bepotastine, The electrospun fiber mats may be incorporated into a epinastine HCl, olopatadine hydrochloride, levocombstine contact lens using other methods of contact lens fabrication. HCl, and bepotastine besilate. The previous examples of contact lens fabrication are illus Examples of glaucoma-treating agents include, but are not 25 trative of current contact lens fabrication techniques and limited to: pilocarpine hydrochloride, carbocal, latanoprost, methods of incorporating the fibermat into those methods of travoprost, bimatoprost, betaxolol, levobunalol, timolol, iga fabrication. They are not intended to be limiting of the present nipidine, brinzolamide, brimonidine and isopropylunopros invention. tOne. The desired concentration of therapeutic drug in the target Examples of antiviral agents include, but are not limited to: 30 tissue determines the amount of drug to be loaded in the idoxuridine, acyclovir, and trifluorouridine. improved contact lens. The target tissue concentration can be Examples of anti-mycotic agents include, but are not lim increased by adding additional fibers to the contact lens or by ited to: pimaricin, fluconazole, miconazole, amphotericin B, increasing the concentration of the therapeutic drug in the flucytosine, and itraconazole. solution from which the fibers are spun. Formation of the Improved Contact Lens 35 FIG. 1 is a scanning electron micrograph of a fiber mat Once the fiber mats have been produced, they are incorpo created by electrospinning poly(vinyl alcohol). The fibers are rated into a contact lens as it is manufactured. Acceptable deposited randomly throughout the mat in various orienta contact lens polymers for use in the improved contact lens, tions. include, but are not limited to polyHEMA, polyHEMA/MA, FIG. 2 is a scanning electron micrograph of a fiber mat polyHEMA/NVP/MMA, polyHEMA/MMA, polyHEMA/ 40 created by electrospinning poly(Vinyl alcohol) and crosslink GMA, polyHEMA/PC, polyVA, polyHEMA/PVP/MA, ing the resulting mat using methanol as a crosslinking agent. polyHEMA/PVA/MA, poly MA/PVP, and polyHEMA/PVP/ As can be seen in the figure, the fibers are linked at the MMA, Poly GMA/MMA, polyHEMA/ACR, polyAA/ intersection of overlapping fibers. HEMA, polyMMA/AA, polysilicone hydrogel, polyfluoro FIG. 3 is a scanning electron micrograph of a fiber mat carbon hydrogel, and collagen. The lens polymer is 45 created by electrospinning poly(Vinyl alcohol) and crosslink preferably a homo or co-polymer of the monomer used to ing the resulting mat using methanol as a crosslinking agent. form the fiber mat. The mat has then been coated with PVA and crosslinked a In one method of fabricating the improved contact lens, the second time. lens is formed individually by curing a monomer composition The fiber mats are tested for drug release properties by in a mold to polymerize the composition and create the con 50 cutting the mats into Small pieces and placing a piece into tact lens. The electrospun fibermats is cut into appropriately aqueous solution. The concentration of the drug in the solu sized sections or ground into appropriately-sized particles, tion is then measured over time. Since there is no mechanism and incorporated into the contact lens by inserting the mat in the solution for the removal of the drug, the concentration section into the mold with the monomer composition prior to of the drug will increase over time to its maximum value. If polymerization. The fibers are then polymerized with the 55 the concentration remains constant, it indicates that the fiber monomer composition and is incorporated into the improved mat is no longer releasing the drug. contact lens. In a second method of fabricating an improved FIG. 4 is a graph of the concentration of a therapeutic drug contact lens, the fibers may be polymerized into a button or released by a fiber mat soak-loaded with the therapeutic drug rod of polymer material by inserting the fibers into the appro after deposition. The concentration of the drug released by the priate mold and curing with monomers. The button or rod is 60 Soak-loaded mat reached its maximum concentration within 5 then processed by cutting or polishing to produce the final minutes of the start of the drug release test. This indicates that improved contact lens. the soak-loaded fibermat quickly releases all of the drug that The improved contact lens has Superior physical charac was loaded into the mat. teristics as a result of the addition of the electrospun fibers FIG. 5 is a graph of the concentration of a therapeutic drug into the lens. The improved contact lens may be fabricated 65 released by a fiber mat fabricated from a precursor solution with a thinner cross-section due to the increased mechanical containing the therapeutic drug and coated with poly(vinyl strength and rigidity of the electrospun fiber materials. The alcohol). This figure shows that the concentration reaches its US 8,361,492 B2 13 14 maximum value in the first hour, and thus that the fiber mat (isopropyl acrylate), poly(isobutyl acrylate), poly(isooctyl releases all the therapeutic drug within that time period. acrylate), poly(isodecyl acrylate), poly(cyclohexyl acrylate), FIG. 5A provides detail of the increasing concentration for poly(2-ethylhexyl acrylate), poly(ethyl methacrylate), poly the first hour of the test. It can be seen that the concentration (propyl methacrylate), poly(butyl acrylate), poly(vinyl increases over time, approaching its maximum value toward 5 acetate), polyvinyl propionate), poly(vinyl butyrate), poly the end of the first hour. (vinyl Valerate), poly(chloroprene), poly(vinyl chloride), FIG. 6 is a graph of the concentration of a therapeutic drug poly(vinylidene chloride), polymers of 1-butene, polybutadi released by a fiber mat fabricated from a polymer solution ene, poly(vinyl toluene), poly(Vinyl ethyl ether), polymers of containing the therapeutic drug.coated with poly(vinyl alco perfluorohexylethylthiocarbonylaminoethyl methacrylate, hol), and crosslinked with methanol. This figure shows an 10 poly(isobomyl methacrylate), polymers of trifluoroethyl increasing concentration throughout the time period of the methacrylate, polymers of hexafluoroisopropyl methacry test, revealing that the fiber mat in this test has continued to late, polymers of hexafluorobutyl acrylate, polymers of release the drug throughout the test period. The final maxi hexafluorobutyl methacrylate, polymers of tris-trimethylsily mum concentration is in the same range as for the mats shown loxy-silyl-propyl methacrylate, polymers of 3-methacrylox in FIG. 5, however the drug was released over a much longer 15 ypropylpentamethyldisiloxane, polymers of bis(methacry period of time. loxypropyl) tetramethyldisiloxane, polymers of hydroxyl FIG. 6A shows the detail of the initial 60 minutes of the Substituted lower alkyl acrylates and methacrylates, polymers test. This period of data indicates that the concentration ini of lower alkylacrylamides and -methacrylamides, polymers tially quickly jumps and then begins a more steady increase of ethoxylated acrylates and methacrylates, polymers of over time, indicating that the fiber mat initially releases the hydroxyl-substituted lower alkylacrylamides and -methacry drug quickly and then slows its rate of release over time. lamides, polymers of hydroxyl-substituted lower alkyl vinyl What is claimed is: ethers, poly(sodium vinylsulfonate), poly(sodium Styrene 1. A drug delivery system comprising: Sulfonate), polymers of 2-acrylamido-2-methylpropane a contact lens comprising electrospun fibers incorporated sulfonic acid, poly(N-vinylpyrrole), poly(N-vinyl-2-pyrroli into a polymer lens; 25 done), polymers of 2-vinyloxazoline, polymers of 2-vinyl-4, wherein the electrospun fibers are prepared by electro 4'-dialkyloxazolin-5-one, poly(2-vinylpyridine), poly(4- spinning a polymer Solution into a mat of fibers, vinylpyridine), polymers of vinylically unsaturated applying a cross-linking treatment to the mat offibers, carboxylic acids having a total of 3 to 5 carbon atoms, poly and applying a polymer coating to the mat of fibers; mers of amino-lower alkyl (where the term “amino” also and 30 includes quaternary ammonium), polymers of mono-lower at least one therapeutic drug; alkylamino-lower alkyl and di-lower alkylamino-lower alkyl wherein the at least one therapeutic drug is incorporated acrylates and methacrylates, poly(allyl alcohol), poly into the mat of fibers. methacrylamide, polymers of hydroxyl-substituted lower 2. The drug delivery system of claim 1 wherein the at least alkyl acrylates and methacrylates, hydroxyethyl methacry one therapeutic drug is incorporated into the mat of fibers by 35 late, poly(hydroxyethyl acrylate), poly(hydroxypropyl acry soaking the mat of fibers in a solution containing the at least late), poly(dimethylaminoethyl methacrylamide), poly(yi one therapeutic drug. nylpyridine), poly(glycerol methacrylate), polymers of N-(1, 3. The drug delivery system of claim 1 wherein the at least 1 dimethyl-3-oxobutyl)acrylamide, poly one therapeutic drug is incorporated into the mat of fibers by (dimethylaminoethyl methacrylate), polymers of spinning the mat of fibers from a solution containing the at 40 trimethylammonium-2-hydroxypropyl methacrylate hydro least one therapeutic drug. chloride, poly(N,N-dimethylacrylamide) and mixtures 4. The drug delivery system of claim3 wherein the solution thereof. contains at least one polymer selected from the group con 5. The drug delivery system of claim3 wherein the solution sisting of poly(2-hydroxyethylmethacrylate), poly(acrylic contains between 5 and 15 percent polymer by weight. acid), poly(methacrylic acid), poly(vinyl pyrrolidone), poly 45 6. The drug delivery system of claim 5 wherein the con (N-vinyl pyrrolidone), poly(vinyl alcohol), poly(methyl centration of the at least one therapeutic drug in the Solution methacrylate), poly(glycerol methacrylate), silicone hydro is between 0.01% and 20%. gels, fluorocarbon hydrogels, polyacrylamide, polymers of 7. The drug delivery system of claim 3 wherein the mat of silicone, polymers of (3-methacryloxy-2-hydroxypropyloxy) fibers is soaked in a cross-linking agent. propyl-bis(trimethylsiloxy)methylsilane, polymers of 50 8. The drug delivery system of claim 7 wherein the mat of C3-C18alkyl and C3-C18cycloalkyl acrylates and methacry fibers is coated with a polymer coating. lates, polymers of C3-C18alkylacrylamides and -methacry 9. The drug delivery system of claim 8 wherein the mat of lamides, polyacrylonitrile, polymethacrylonitrile, polymers fibers is soaked in a cross-linking agent after application of of vinyl C1-C18alkanoates, polymers of C2-C18alkenes, the polymer coating. polymers of C2-C18haloalkenes, polystyrene, poly-lower 55 10. The drug delivery system of claim 1 wherein the mat of alkylstyrene, polymers of lower alkyl vinyl ethers, polymers fibers is incorporated into the contact lens by inserting the mat of C2-C10perfluoroalkyl acrylates and methacrylates or cor of fibers into abutton or rod mold in which the contact lens is respondingly partly fluorinated acrylates and methacrylates, formed and polymerizing the contact lens around the mat of polymers of C3-C12perfluoroalkyl-ethyl-thiocarbonylami fibers. noethyl acrylates and methacrylates, polymers of acryloxy 60 11. The drug delivery system of claim 10 wherein the mat and methacryloxy-alkylsiloxanes, poly(N-vinylcarbazole), of fibers is ground into particles before being placed into the polymers of C1-C12alkyl esters of maleic acid, poly(fumaric mold. acid), poly(itaconic acid), poly(mesaconic acid), polymers of 12. The drug delivery system of claim 1 wherein the at least C1-C4alkyl esters of vinylically unsaturated carboxylic acids one therapeutic drug is selected from the group consisting of having 3 to 5 carbon atoms, polymers of vinyl esters of 65 antibacterial antibiotic drugs, synthetic antibacterial drugs, carboxylic acids having up to 5 carbon atoms, poly(methyl antifungal antibiotic drugs, synthetic antifungal drugs, anti acrylate), poly(ethyl acrylate), poly(propyl acrylate), poly neoplastic agents, steroidal anti-inflammatory agents, non US 8,361,492 B2 15 16 steroidal anti-inflammatory agents, anti-allergic agents, glau logs, cinoxacin, ciprofloxacin, clinafloxacin, difloxacin, coma-treating agents, antiviral agents and anti-mycotic enoxacin, fleroxacin, flumequine, grepafloxacin, lomefloxa agents. cin, miloxacin, nadifloxacin, nalidixic acid, norfloxacin, 13. The drug delivery system of claim 12 wherein the ofloxacin, oxolinic acid, paZufloxacin, pefloxacin, pipemidic antibacterial antibiotic drugs are selected from the group acid, piromidic acid, roSoxacin, rufloxacin, sparfloxacin, consisting of aminoglycosides, amikacin, apramycin, arbeka temafloxacin, toSufloxacin, trovafloxacin, Sulfonamides, cin, bambermycins, butirosin, dibekacin, dihydrostreptomy acetyl Sulfamethoxypyrazine, benzylsulfamide, chloramine cin, fortimicins, gentamicin, isepamicin, kanamycin, micro b, chloramine-t, dichloramine t, n. Sup.2-formylsulfisomi nomicin, neomycin, neomycin undecylenate, netilmicin dine, n. Sup.4-beta.-d-glucosylsulfanilainide, mafenide, 4'- paromomycin, ribostamycin, Sisomicin, spectinomycin, 10 (methylsulfamoyl)sulfanilanilide, noprylsulfamide, streptomycin, tobramycin, trospectomycin, amphenicols, phthalylsulfacetamide, phthalylsulfathiazole, Salazosulfadi aZidamfenicol, chloramphenicol, florfenicol, thiamphenicol, midine, Succinylsulfathiazole, Sulfabenzamide, Sulfaceta ansamycins, rifamide, rifampin, rifamycin SV, rifapentine, mide, Sulfachlorpyridazine, Sulfachrysoidine, Sulfacytine, rifaximin, beta.-lactams, carbacephems, loracarbef, carbap Sulfadiazine, Sulfadicramide, Sulfadimethoxine, Sulfadoxine, enems, biapenem, imipenem, meropenem, panipenem, 15 Sulfaethidole, Sulfaguanidine, Sulfaguanol, Sulfalene, Sulfa cephalosporins, cefaclor, cefadroxil, cefamandole, cefatriz loxic acid, Sulfamerazine, Sulfameter, Sulfamethazine, Sul ine, cefazedone, cefazolin, cefcapene pivoxil, cefclidin, cef famethizole, Sulfamethomidine, Sulfamethoxazole, Sul dinir, cefditoren, cefepime, cefetamet, cefixime, cef famethoxypyridazine, Sulfametrole, Sulfamidocchrysoidine, menoxime, cefodizime, cefonicid, cefoperaZone, ceforanide, Sulfamoxole, Sulfanilamide, 4-sulfanilamidosalicylic acid, cefotaxime, cefotiam, cefoZopran, cefpimizole, ce?piramide, n. Sup.4-Sulfanilylsulfanilamide, Sulfanily lurea, n-sulfanillyl cefpirome, cefpodoxime proxetil, cefprozil, cefroxadine, cef 3,4-Xylamide, Sulfanitran, Sulfaperine, Sulfaphenazole, Sul Sulodin, ceftazidime, cefteram, ceftezole, ceftibuten, cefti faproxyline, Sulfapyrazine, Sulfapyridine, Sulfasomizole, Sul Zoxime, ceftriaxone, cefuroxime, cefuZonam, cephacetrile fasymazine, Sulfathiazole, Sulfathiourea, Sulfatolamide, Sodium, cephalexin, cephaloglycin, cephaloridine, cepha Sulfisomidine, Sulfisoxazole, Sulfones, acedapsone, acedia losporin, cephalothin, cephapirin Sodium, cephradine, pivoe 25 Sulfone, acetosulfone sodium, dapsone, diathymosulfone, falexin, cephamycins, cefbuperaZone, cefimetazole, cefini glucosulfone sodium, Solasulfone, Succisulfone, Sulfanilic nox, cefotetan, cefoxitin, monobactams, aztreonam, acid, p-sulfanilylbenzylamine, Sulfoxone sodium, thiazolsul carumonam, tigemonam, oxacephems, flomoxef, moxalac fone, clofoctol, hexedine, methenamine, methenamine anhy tam, penicillins, amdinocillin, amdinocillin pivoxil, amox dromethylene-citrate, methenamine hippurate, methenamine icillin, ampicillin, apalcillinaspoxicillin, azidocillin, aZlocil 30 mandelate, methenamine Sulfosalicylate, nitroxoline, tauro lin, bacampicillin, benzylpenicillinic acid, benzylpenicillin lidine, and Xibornol. sodium, carbenicillin, carindacillin, clometocillin, cloxacil 15. The drug delivery system of claim 12 wherein the lin, cyclacillin, dicloxacillin, epicillin, fenbenicillin, floxacil antifungal antibiotic drugs are selected from the group con lin, hetacillin, lenampicillin, metampicillin, methicillin sisting of polyenes, amphotericin b, candicidin, dennostatin, Sodium, mezlocillin, nafcillin Sodium, oxacillin, penamecil 35 filipin, fungichromin, hachimycin, hamycin, lucensomycin, lin, penethamate hydriodide, penicilling benethamine, peni mepartricin, natamycin, nystatin, pecilocin, perimycin, aza cilling benzathine, penicilling benzhydrylamine, penicilling serine, griseofulvin, oligomycins, neomycin undecylenate, calcium, penicilling hydrabamine, penicilling potassium, pyrrolnitrin, siccanin, tubercidin, and viridin. penicilling procaine, penicillinn, penicillino, penicillin V, 16. The drug delivery system of claim 12 wherein the penicillin V benzathine, penicillin V hydrabamine, penimepi 40 synthetic antifungal drugs are selected from the group con cycline, phenethicillin potassium, piperacillin, pivampicillin, sisting of allylamines, butenafine, naftifine, terbinafine, imi propicillin, quinacillin, Sulbenicillin, Sultamicillin, talampi dazoles, bifonazole, butoconazole, chlordantoin, chlormiida cillin, temocillin, ticarcillin, ritipenem, lincosamides, clinda Zole, clotrimazole, econazole, enilconazole, fenticonazole, mycin, lincomycin, macrollides, azithromycin, carbomycin, flutrimazole, isoconazole, ketoconazole, lanoconazole, clarithromycin, dirithromycin, erythromycin, erythromycin 45 miconazole, omoconazole, oxiconazole nitrate, Sertacona acistrate, erythromycin estolate, erythromycin glucohepto Zole, Sulconazole, tioconazole, thiocarbamates, tolciclate, nate, erythromycin lactobionate, erythromycin propionate, tolindate, tolnaftate, triazoles, fluconazole, itraconazole, erythromycin Stearate, josamycin, leucomycins, midecamy Saperconazole, terconazole, acrisorcin, amorolfine, biphe cins, miokamycin, oleandomycin, primycin, rokitamycin, namine, bromosalicylchloranilide, buclosamide, calcium rosaramicin, roXithromycin, spiramycin, troleandomycin, 50 propionate, chlorphenesin, ciclopiroX, cloxyquin, coparaffi polypeptides, amphomycin, bacitracin, capreomycin, colis nate, diamthazole dihydrochloride, exalamide, flucytosine, tin, enduracidin, enviomycin, fusafungine, gramicidin S, halethazole, hexetidine, loflucarban, nifuratel, potassium gramicidins, mikamycin, polymyxin, pristinamycin, ristoce iodide, propionic acid, pyrithione, salicylanilide, Sodium pro tin, teicoplanin, thiostrepton, tuberactinomycin, tyrocidine, pionate, Sulbentine, tenonitrozole, triacetin, ujothion, unde tyrothricin, Vancomycin, viomycin, Virginiamycin, Zinc baci 55 cylenic acid, and Zinc propionate. tracin, tetracyclines, apicycline, chlortetracycline, clomocy 17. The drug delivery system of claim 12 wherein the cline, demeclocycline, doxycycline, guamecycline, lymecy antineoplastic agents are selected from the group consisting cline, meclocycline, methacycline, minocycline, of antineoplastic antibiotics, aclacinomycins, actinomycin oxytetracycline, penimepicycline, pipacycline, rollitetracy fSub.1, anthramycin, azaserine, bleomycins, cactinomycin, cline, sancycline, tetracycline, cycloserine, mupirocin, and 60 carubicin, carzinophilin, chromomycins, dactinomycin, tuberin. daunorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, 14. The drug delivery system of claim 12 wherein the epirubicin, idarubicin, menogaril, mitomycins, mycophe synthetic antibacterial drugs are selected from the group con nolic acid, nogalamycin, olivomycines, peplomycin, piraru sisting of 2,4-diaminopyrimidines, brodimoprim, tetroX bicin, plicamycin, porfiromycin, puromycin, Streptonigrin, oprim, trimethoprim, nitrofurans, furaltadone, furazolium 65 streptozocin, tubercidin, Zinostatin, Zorubicin, antimetabo chloride, nifuradene, nifuratel, nifurfoline, nifurpirinol, lites, folic acid analogs, denopterin, edatrexate, methotrexate, nifurprazine, nifurtoinol, nitrofurantoin, quinolones and ana piritrexim, pteropterin, Tomudex.RTM., trimetrexate, purine US 8,361,492 B2 17 18 analogs, cladribine, fludarabine, 6-mercaptopurine, thiami piketoprolen, pirprofen, pranoprofen, protizinic acid, Supro prine, thioguanine, pyrimidine analogs, ancitabine, azaciti fen, tiaprofenic acid, Ximoprofen, Zaltoprofen, pyrazoles, dine, 6-azauridine, carmofur, cytarabine, doxifluridine, difenamizole, , pyrazolones, apaZone, benzpipery emitefur, enocitabine, floxuridine, fluorouracil, gemcitabine, lon, , mofebutaZone, moraZone, oxyphenbutaZone, and tagafur. , pipebuZone, propyphenaZone, ramifena 18. The drug delivery system of claim 12 wherein the Zone, SuxibuZone, thiazolinobutaZone, salicylic acid deriva steroidal anti-inflammatory agents are selected from the tives, acetaminoSalol, aspirin, benorylate, bromosaligenin, group consisting of 21-acetoxypregnenolone, alclometaSone, calcium acetylsalicylate, diflunisal, etersalate, fendosal, gen algestone, amcinonide, beclomethasone, betamethasone, tisic acid, glycol salicylate, imidazole salicylate, lysine ace 10 tylsalicylate, mesalamine, morpholine salicylate, 1-naphthyl budesonide, chloroprednisone, clobetasol, clobetaSone, clo salicylate, olSalazine, parsalmide, phenyl acetylsalicylate, cortolone, cloprednol, corticosterone, cortisone, cortivaZol. phenyl salicylate, Salacetamide, Salicylamide o-acetic acid, deflazacort, desonide, desoximetaSone, dexamethasone, salicylsulfuric acid, Salsalate, Sulfasalazine, thiazinecarboxa diflorasone, diflucortolone, difluprednate, enoXolone, fluaza mides, ampiroXicam, droxicam, isoxicam, lomoxicam, cort, flucloronide, flumethasone, flunisolide, fluocinolone 15 piroXicam, tenoxicam, E-acetamidocaproic acid, S-adenosyl acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluo rometholone, fluperolone acetate, fluprednidene acetate, flu methionine, 3-amino-4-hydroxybutyric acid, amixetrine, prednisolone, flurandrenolide, fluticasone propionate, for bendazac, benzydamine, bucolome, difenpiramide, ditaZol. mocortal, halcinonide, halobetasol propionate, emorfaZone, fepradinol, guaiaZulene, nabumetone, nime halometaSone, halopredone acetate, hydrocortamate, hydro Sulide, oxaceprol, paranyline, perisoxal, produaZone, Super cortisone, loteprednol etabonate, maZipredone, medrysone, oxide dismutase, tenidap, and Zileuton. meprednisone, methylprednisolone, mometaSone furoate, 20. The drug delivery system of claim 12 wherein the paramethasone, prednicarbate, prednisolone, prednisolone anti-allergic agents are selected from the group consisting of 25-diethylamino-acetate, prednisolone sodium phosphate, tranilast, ketotifen fumarate, pheniramine, diphenhydramine prednisone, prednival, prednylidene, rimexolone, tiXocortol, hydrochloride, sodium cromoglicate, bepotastine, epinastine triamcinolone, triamcinolone acetonide, triamcinolone bene 25 HCl, olopatadine hydrochloride, levocombstine HCl, and tonide, and triamcinolone hexacetonide. bepotastine besilate. 19. The drug delivery system of claim 12 wherein the 21. The drug delivery system of claim 12 wherein the non-steroidal anti-inflammatory agents are selected from the glaucoma-Treating agents are selected from the group con group consisting of aminoarylcarboxylic acid derivatives, sisting of pilocarpine hydrochloride, carbocal, latanoprost, enfenamic acid, etofenamate, , isonixin, 30 travoprost, bimatoprost, betaxolol, levobunalol, timolol, iga meclofenamic acid, mefenamic acid, , talniflu nipidine, brinzolamide, brimonidine and isopropylunopros mate, terofenamate, tolfenamic acid, arylacetic, acid deriva tOne. tives, aceclofenac, acemetacin, , amfenac, amtol 22. The drug delivery system of claim 12 wherein the metin guacil, bufexamac, cinmetacin, clopirac, diclofenac antiviral agents are selected from the group consisting of Sodium, etodolac, felbinac, fenclozic acid, fentiazac, gluca 35 idoxuridine, acyclovir, and trifluorouridine. metacin, ibufenac, indomethacin, isofeZolac, isoxepac, lona 23. The drug delivery system of claim 12 wherein the Zolac, metiazinic acid, mofeZolac, oxametacine, piraZolac, anti-mycotic agents are selected from the group consisting of proglumetacin, Sulindac, tiaramide, tolmetin, tropesin, Zome pimaricin, fluconazole, miconazole, amphotericin B, flucy pirac, arylbutyric acid derivatives, bumadizon, butibufen, tosine, and itraconazole. fenbufen, Xenbucin, arylcarboxylic acids, clidanac, ketoro 40 24. The drug delivery system of claim 3 wherein the solu lac, tinoridine, arylpropionic acid derivatives, alminoprofen, tion contains the polymer polyvinyl alcohol. benoxaprofen, bermoprofen, bucloxic acid, carprofen, feno 25. The drug delivery system of claim 1 wherein the at least profen, flunoxaprofen, flurbiprofen, ibuprofen, ibuproxam, one therapeutic drug is a steroidal anti-inflammatory agent. indoprofen, ketoprofen, loxoprofen, naproxen, oxaprozin, k k k k k