WO2009032266A2

WO2009032266A2 - Dispersions of microparticles and microgels in hydrogels for drug delivery

Info

Publication number: WO2009032266A2
Application number: PCT/US2008/010352
Authority: WO
Inventors: Anuj Chauhan; Chi-Chung Li; Hyun-Jung Jung
Original assignee: University Of Florida
Priority date: 2007-09-04
Filing date: 2008-09-04
Publication date: 2009-03-12
Also published as: WO2009032266A3

Abstract

An ophthalmically bioactive agent delivery system comprising a contact lens having dispersed therein microparticles or microgels of a crosslinked polymer, the microparticles or microgels having entrapped therein an ophthalmically bioactive agent, the crosslinked polymer comprising an ophthalmically acceptable material from which the bioactive agent is capable of diffusion into and migration through the contact lens and into the post-lens tear film when the contact lens is placed on the eye and wherein the degree of polymerization and/or crosslinking is such that the rate of diffusion into and migration through the contact lens of the ophthalmically bioactive agent is attenuated,

Description

TITLE: DISPERSIONS OF MICROP ARTICLES AND MICROGELS IN HYDROGELS FOR DRUG DELIVERY

Inventors: Anuj CHAUHAN, Chi-Chung LI and Hyun-Jung JUNG

RELATED APPLICATION:

[0001] This application claims the benefit of U.S. Provisional Application No. 60/935,856 filed September 4, 2007, which is herein incorporated by reference in its entirety.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY

SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was made with Government support under Grant No. CBET

0426327, awarded by National Science Foundation. The Government has certain rights in this invention.

FIELD OF THE INVENTION

[0003] The present invention relates to methods and systems for the delivery of drugs to patients in need thereof. Specifically, the present invention relates to ophthalmically bioactive agent delivery system.

BACKGROUND OF THE INVENTION

[0004] Providing and maintaining adequate concentrations of bioactive agents, such as drugs, for example, in the pre-corneal tear film for extended periods of time is one of the major problems plaguing methods and systems for ocular drug delivery. When they are applied as eye drops, most drugs penetrate poorly through the cornea. Drainage of instilled drug with the tear fluid, and absorption through the conjunctiva leads to a short duration of action. The additional pre-corneal factors that contribute to the poor ocular bio-availability of many drugs when instilled in the eye as drops are tear turnover and drug binding to tear fluid proteins. In addition to the above factors, the rate of corneal uptake is high at early times, but it declines rapidly. This may lead to a transient period of overdose and associated risk of side effects followed by an extended period of sub-therapeutic levels before the administration of next dose. All the above factors indicate the need for an ocular drug delivery system that will be as convenient as a drop but will serve as a controlled release vehicle [Nagarsenker, M.S., Londhe, V.Y., Nadkarni, G.D., "Preparation and evaluation of liposomal formulations of tropicamide for ocular delivery", Int. J. of Pharm., 1990, 190: 63-71].

[0005] Topical delivery via eye drops that accounts for about 90% of all ophthalmic formulations is very inefficient and in some instances leads to serious side effects [Lang, J. C, "Ocular drug delivery conventional ocular formulations". Adv. Drug Delivery, 1995, 16: 39- 43]. Only about 5% of the drug applied as drops penetrate through the cornea and reaches the ocular tissue, while the rest is lost due to tear drainage [Bourlais, C.L., Acar, L., Zia H., Sado, P.A., Needham, T., Leverge, R., "Ophthalmic drug delivery systems", Progress in retinal and eye research, 1998, 17, 1 : 33-58]. The drug mixes with the fluid present in the tear film upon instillation and has a short residence time of about 2-5 minutes in the film. About 5% of the drug gets absorbed and the remaining flows through the upper and the lower canaliculi into the lacrimal sac. The drug containing tear fluid is carried from the lacrimal sac into the nasolacrimal duct, and eventually, the drug gets absorbed into the bloodstream. This absorption leads to drug wastage and more importantly, the presence of certain drugs in the bloodstream leads to undesirable side effects. For example, beta-blockers such as Timolol that is used in the treatment of wide-angle glaucoma have a deleterious effect on heart [TIMPOTIC prescribing information, supplied by MERCK]. Furthermore, application of ophthalmic drugs as drops results in a rapid variation in drug delivery rates to the cornea that limits the efficacy of therapeutic systems [Segal, M., "Patches, pumps and timed release", FDA Consumer magazine, October 1991]. Thus, there is a need for new ophthalmic drug delivery systems that increase the residence time of the drug in the eye, thereby reducing wastage and eliminating side effects.

[0006] There have been a number of attempts in the past to use contact lenses for ophthalmic drug delivery; however, all of these focused on soaking the lens in drug solution followed by insertion into the eye. In one of the studies, the authors focused on soaking the lens in eye-drop solutions for one hour followed by lens insertion in the eye [Hehl, E.M., Beck, R., Luthard K., Guthoff R., "Improved penetration of aminoglycosides and fluoroquinolones into the aqueous humour of patients by means of Acuvue contact lenses", European Journal of Clinical Pharmacology, 1999, 55 (4): 317-323]. Five different drugs were studied and it was concluded that the amount of drug released by the lenses are lower or of the same order of magnitude as the drug released by eye drops. This happened perhaps because the maximum drug concentration obtained in the lens matrix is limited to the equilibrium concentration. In another study researchers developed a contact lens with a hollow cavity by bonding together two separate pieces of lens material [Nakada, K., Sugiyama, A., "Process for producing controlled drug-release contact lens, and controlled drug-release contact lens thereby produced"; United States Patent: 6,027,745, May 29, 1998]. The compound lens is soaked in the drug solution. The lens imbibes the drug solution and slowly releases it upon insertion in the eye. The compound lens suffers from the same limitations as the drug-soaked lens because the concentration of the drug in the cavity is the same as the concentration of the drug in the drops and thus such a lens can supply the drug for a limited amount of time.

[0007] Furthermore, the presence of two separate sheets of lens material leads to smaller oxygen and carbon dioxide permeabilities that can cause an edema in the corneal tissue. The other studies and patents listed below suffer from the same limitations because they are also based on soaking of contact lenses or similar devices in drug-solutions followed by insertion into the eye [Hillman, J. S., "Management of acute glaucoma with Pilocarpine-soaked hydrophilic lens" Brit. J. Ophthal.58 (1974) p. 674-679, Ramer, R. and Gasset, A., "Ocular Penetration of Pilocarpine:" Ann.Ophthalmol.6, (1974) p. 1325-1327, Montague, R. and Wakins, R., "Pilocarpine dispensation for the soft hydrophilic contact lens" Brit J. Ophthal. 59, (1975) p. 455-458, Hillman, J.,Masters, J. and Broad, A. "Pilocarpine delivery by hydrophilic lens in the management of acute glaucoma" Trans. Ophthal. Soc.U. K. (1975) p. 79-84, Giambattista, B.,Virno, M., Pecori-Giraldi, Pellegrino, N. and Motolese, E. "Possibility of Isoproterenol Therapy with Soft Contact Lenses: Ocular Hypotension Without Systemic Effects" Ann. Ophthalmol 8 (1976) p. 819-829, Marmion, V. J. and Yardakul, S. "Pilocarpine administration by contact lens" Trans. Ophthal. Soc.U. K. 97, (1977) p. 162-3, United States Patent 6,410,045, Drug delivery system for antiglaucomatous medication, Schultz; Clyde Lewis, Mint; Janet M; United States Patent 4,484,922, Occular device,. Rosenwald; Peter L., United States Patent Patent 5,723,131, Contact lens containing a leachable absorbed material, Schultz; Clyde L. Nunez; Ivan M.; Silor; David L.; Neil; Michele L.].

[0008] A number of researchers have trapped proteins, cells and drugs in hydrogel matrices by polymerizing the monomers that comprise the hydrogel, in presence of the encapsulated species [Elisseeff, J., Mclntosh, W., Anseth, K., Riley, S., Ragan, P., Langer, R., "Photoencapsulation of chondrocytes in poly( ethylene oxide)-based semi-interpenetrating networks", Journal of Biomedical Materials Research, 2000, 51 (2): 164-171; Ward, J. H., Peppas, N. A., "Preparation of controlled release systems by free-radical UV polymerizations in the presence of a drug", Journal of Controlled Release, 2001, 71 (2): 183- 192; Scott, R. A., Peppas, N. A., "Highly crosslinked, PEG-containing copolymers for sustained solute delivery", Biomaterials, 1999, 20 (15): 1371-1380; Podual, K., Doyle F. J., Peppas N. A., "Preparation and dynamic response of cationic copolymer hydro gels containing glucose oxidase", Polymer, 2000, 41 (11): 3975-3983; Colombo, P., Bettini, R., Peppas, N.A., "Observation of swelling process and diffusion front position during swelling in hydroxypropyl methyl cellulose (HPMC) matrices containing a soluble drug", Journal of Controlled Release, 1999, 61 (1,2): 83-91; Ende, M.T.A., Peppas, N.A., "Transport of ionizable drugs and proteins in crosslinked poly(acrylic acid) and poly(acrylic acid-co-2- hydroxyethyl methacrylate) hydrogels. 2. Diffusion and release studies", Journal of Controlled Release, 1997, 48 (1): 47-56; US patent 4,668,506].

[0009] Although such direct loading of drug into the lenses can permit higher loadings of the drugs, it can result in an activity loss during polymerization. Furthermore, a majority of the drug can diffuse from the lenses into the packaging medium and the drug retained in the lens can diffuse from the lens rapidly after insertion into the eye. To address these issues Chauhan et al developed nanoparticle laden gels that can load substantial amount of drug to the gel which can then be released at a controlled rate from the nanoparticles. [Gulsen D, Chauhan A- "Dispersion of microemulsion drops in HEMA hydro gel: a potential ophthalmic drug delivery vehicle". Int J Pharm 292,95-117, 2005., Gulsen D, Chauhan A- "Ophthalmic drug delivery through contact lenses". Invest Ophth Vis Sci 45,2342-2347, 2004.] Also Graziacascone et al discloses a study on encapsulating lipophilic drugs inside nanoparticles, and entrapping the particles in hydrogels. [Graziacascone, M., Zhu, Z., Borselli, F., Lazzeri, L., "Polyvinyl alcohol) hydrogels as hydrophilic matrices for the release of lipophilic drugs loaded in PLGA nanoparticles", Journal of Material Science: Materials in Medicine, 2002, 13: 29-32]. They used PVA hydrogels as hydrophilic matrices for the release of lipophilic drugs loaded in PLGA particles. These systems are potentially useful but display the shortcoming of burst release due to the presence of the drug outside the particles. [0010] A number of researchers have focused on developing 'imprinted' contact lenses [Hiratani H, Alvarez-Lorenzo C- "The nature of backbone monomers determines the performance of imprinted soft contact lenses as timolol drug delivery systems" Biomaterials 25,1105-1113, 2004; Hiratani H, Fujiwara A, Tamiya Y, Mizutani Y, Alvarez-Lorenzo C- "Ocular release of timolol from molecularly imprinted soft contact lenses" Biomaterials 26,1293-1298, 2005; Hiratani H, Mizutani Y, Alvarez-Lorenzo C- "Controlling drug release from imprinted hydrogels by modifying the characteristics of the imprinted cavities" Macromol Biosci 5,728-733, 2005: Alverez-Lorenzo C, Hiratani H, Gomez-Amoza JL, Martinez-Pacheco R, Souto C, Concheiro A- "Soft contact lenses capable of sustained delivery of timolol" J Pharm Sci 91,2182-2192, 2002; Hiratani H, Alvarez-Lorenzo C- "Timolol uptake and release by imprinted soft contact lenses made of N,N-diethylacrylamide and methacrylic acid" J Control Release 83,223-230, 2002]. The imprinting leads to an increase in the partition coefficients and slower release of drugs, but the increase is not very substantial, and these lenses typically have an initial burst release.

[0011] In a copending patent application there is disclosed a bioactive agent delivery system comprising a substantially optically transparent contact lens having dispersed therein (1) an ophthalmically bioactive agent, the agent being capable of diffusion through the contact lens and into the post-lens tear film when the contact lens is placed on the eye and (2) associated with the bioactive agent, at least one ophthalmically compatible polymeric surfactant, the polymeric surfactant being capable of forming a microemulsion and being present in an amount sufficient to attenuate the rate of migration of the bioactive agent through the contact lens.

[0012] It is an object of the present invention to provide a novel bioactive agent delivery system, particularly adapted for delivering the agent to the eye. More particularly, the invention comprises trapping drug-loaded highly crosslinked EGDMA microparticles and microgels into contact lenses. A number of researchers have developed microgels and microparticles of various types and utilized these for drug delivery applications. [United States Patent 7,056,901 and European Patent WO03082316, "Microgel particles for the delivery of bioactive materials", Frechet; Jean M. J., Murthy; Niren; United States Patent 5,078,994, "Microgel drug delivery system", Nair; Mridula, Tan; Julia S.; United States Patent 7,160,557, "Matrices formed of polymer and hydrophobic compounds for use in drug delivery", Bernstein; Howard, Chickering; Donald, Khattak; Sarwat, Straub; Julie; United States Patent 5,811,124, "Microparticles with high drug loading Fernandez"; Julio M., Knudson; Mark B.; United States Patent 5731005, "Hydrogel-based microsphere drug delivery systems", Ottoboni; Thomas B., Jungherr; Lisa B., Yamamoto; Ronald K.; United States Patent Application 2004156906, "Thermosensitive and biodegradable microgel and a method for the preparation thereof Ding Jiandong, Zhu Wen, Wang Biaobing and Zhang Ying]. However none of these studies deal with entrapping microgels or microparticles in contact lenses for the extended release of ophthalmic drugs.

SUMMARY OF THE INVENTION

[0013] The above and other objects are achieved by the present invention, one embodiment of which relates to an ophthalmically bioactive agent delivery system comprising a contact lens having dispersed therein microparticles or microgels of a crosslinked polymer, said microparticles or microgels having entrapped therein an ophthalmically bioactive agent, said crosslinked polymer comprising an ophthalmically acceptable material from which said bioactive agent is capable of diffusion into and migration through said contact lens and into the post-lens tear film when said contact lens is placed on the eye and wherein the degree of polymerization and/or crosslinking is such that the rate of diffusion into and migration through said contact lens of said ophthalmically bioactive agent is attenuated. By "ophthalmically acceptable" is meant that a material has substantially no detrimental effect on the mammalian eye into which it is placed.

[0014] A second embodiment of the invention is a method of administering a bioactive agent to a patient in need thereof comprising placing on the eye the above described drug delivery system.

[0015] Third and fourth embodiments of the invention concern a kit and its use for the storage and delivery of ophthalmic drugs to the eye, the kit comprising: a) a first component containing at least one of the above described drug delivery systems, and b) a second component containing at least one storage container for the first component, the storage container additionally containing a material that substantially prevents the diffusion and migration of the ophthalmic drug during storage.

[0016] A fifth embodiment of the invention relates to a method of manufacturing a bioactive agent delivery system comprising providing a monomer mixture having a lens- forming monomer, the microparticles or microparticles loaded with the bioactive agent and polymerizing said monomer mixture.

[0017] Sixth and seventh embodiments of the invention concern articles of manufacture comprising packaging material and the above described drug delivery system or the above- described kit contained within the packaging material, wherein the packaging material comprises a label which indicates that the drug delivery system and kit can be used for ameliorating symptoms associated with pathologic conditions of the eye

[0018] There has thus been outlined, rather broadly, the more important features of the invention in order that the detailed description thereof that follows may be better understood, and in order that the present contribution to the art may be better appreciated. There are, of course, additional features of the invention that will be described further hereinafter.

[0019] In this respect, before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not limited in its application to the details of construction and to the arrangements of the components set forth in the following description or illustrated in the drawings. The invention is capable of other embodiments and of being practiced and carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein are for the purpose of description and should not be regarded as limiting.

[0020] As such, those skilled in the art will appreciate that the conception upon which this disclosure is based may readily be utilized as a basis for the designing of other structures, methods and systems for carrying out the several purposes of the present invention. It is important, therefore, that equivalent constructions insofar as they do not depart from the spirit and scope of the present invention, are included in the present invention.

[0021] For a better understanding of the invention, its operating advantages and the specific objects attained by its uses, reference should be had to the accompanying drawings and descriptive matter which illustrate preferred embodiments of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS AND THE FIGURES

[0022] Figure 1 illustrates Timolol base form release from PHEMA gel directly entrapped with Timolol base.

[0023] Figure 2(a) illustrates release from IX microparticle-laden gels loading gels (200 micron thick, EGDMA particles). The gel weighed 0.0476g.

[0024] Figure 2(b) illustrates release from 2X microparticle-laden gels loading gels (100 micron thick, EGDMA particles). The gel weighed 0.0246g. [0025] Figure 2(c) illustrates release from 4X microparticle-laden gels loading gels (100 and 200 micron thick, PGT particles). Gel weights are 0.0230 and 0.0504 g for the 100 and 200 μm thick gels.

[0026] Figure 2(d) illustrates release from 7X microparticle-laden gels loading gels (100 and 200 micron thick, PGT particles). Gel weights are 0.0239 and 0.0515 g for the 100 and 200 μm thick gels.

[0027] Figure 2(e) illustrates release from 4X microparticle-laden gels loading gels (100 and 200 micron thick, ETT particles). Gel weights are 0.0250 and 0.0556 g for the 100 and 200 μm thick gels.

[0028] Figure 2(f) illustrates release from 7X microparticle-laden gels loading gels (100 and 200 micron thick, ETT particles). Gel weights are 0.0269 and 0.0569 g for the 100 and 200 μm thick gels.

[0029] Figure 2(g) illustrates release from 2X microparticle-laden gels loading gels (100 and 200 micron thick, EGDMA particles). Gel weights are 0.0246 and 0.0573 g for the 100 and 200 μm thick gels.

[0030] Figure 3 (a) illustrates release from 4X Timolol loading gels (100 and 200 micron, PGT crosslinker) in 100 ppm solution (timolol/PBS). The gel weights are 0.0267 and 0.0537 g for the 100 and 200 micron thick gels.

[0031] Figure 3(b) illustrates uptake by 4X Timolol loading gels (100 and 200 micron, PGT crosslinker) in 1000 ppm solution (timolol/PBS). The gel weights are 0.0364 and 0.0535 g for the 100 and 200 micron thick gels. [0032] Figure 3(c) illustrates uptake by 4X Timolol loading gels (100 and 200 micron, PGT crosslinker) in 2500 ppm solution (timolol/PBS). The gel weights are 0.0311 and 0.0584 g for the 100 and 200 micron thick gels.

[0033] Figure 3(d) illustrates release of timolol into 3.5 ml PBS after packaging in 1 ml PBS for 1 month for 200 micron thick 2X(lower curve) and 4X (upper curve) EGDMA gels. Gel weights are 0.0597 and 0.0601 g for the 100 and 200 μm thick gels.

[0034] Figure 3(e) illustrates release of timolol into 3.5 ml PBS after packaging in 1 ml PBS for 1 month for 100 micron thick 4X EGDMA gels. The gel weighed 0.0263g.

[0035] Figure 4 illustrates Timolol release from microgelA-laden PHEMA gel. The top three curves correspond to incomplete mixing during extraction data and the bottom two correspond to perfect mixing. The numbers on the curves represent the fraction of loaded drug that was released during the initial extraction.

[0036] Figure 5 illustrates Timolol released from PHEMA lenses loaded with microgels B, C, and D. Extraction was conducted under perfect mixing conditions for each gel. The numbers on the curves represent the fraction of loaded drug that was released during the initial extraction.

DETAILED DESCRIPTION OF THE INVENTION

[0037] The present invention is predicated on the discovery that contact lenses, preferably, soft contact lenses can function as new vehicles for ophthalmic drug delivery to reduce drug loss, eliminate systemic side effects, and improve drug efficacy.

[0038] The contact lenses of the present invention are formed from reaction mixtures which comprise the reactive components, catalyst, other desired components, and optionally a solvent. The reaction mixtures may be cured using conventionally known conditions, known to those skilled in the art.

[0039] Hydrophilic components are those which when mixed, at 25°C in a 1 :1 ratio by volume with neutral, buffered water (pH about 7.0) forms a homogenous solution. Any of the hydrophilic monomers known to be useful to make hydrogels may be used.

[0040] In one embodiment the hydrophilic monomer comprises at least one of DMA,

HEMA, glycerol methacrylate, 2-hydroxyethyl methacrylamide, NVP, N-vinyl-N-methyl acrylamide, N-methyl-N-vinylacetamide, polyethyleneglycol monomethacrylate, methacrylic acid and acrylic acid, polymers and copolymers of any of the foregoing, mixtures thereof.

[0041] The reaction mixtures may also comprise at least one hydrophobic component.

Hydrophobic components are those which when mixed, at 25°C in a 1:1 ratio by volume with neutral, buffered water (pH about 7.0) form an immiscible mixture.

[0042] Examples of suitable hydrophobic components include silicone containing components, fluorine containing components, components comprising aliphatic hydrocarbon groups having at least 3 carbons, combinations thereof and the like.

[0043] The term component includes monomers, macromers and prepolymers. "Monomer" refers to lower molecular weight compounds that can be polymerized to higher molecular weight compounds, polymers, macromers, or prepolymers. The term "macromer" as used herein refers to a high molecular weight polymerizable compound. Prepolymers are partially polymerized monomers or monomers which are capable of further polymerization.

[0044] The invention is exemplified herein using soft hydrogel lenses that are made of poly

2- hydroxyethyl methacrylate p-(HEMA). However, it will be understood by those skilled in the art that the range of materials that may be employed as vehicles in the present invention is limited only by the selection of materials that may be employed in the manufacture of contact lenses and the nature of the particular ophthalmic drug to be incorporated therein. The term, "optically transparent" as used herein is intended to refer to a degree of transparency equivalent to that of p-HEMA or other material employed as a contact lens. The p-HEMA hydrogel matrix may be synthesized by any convenient method, e.g., bulk or solution free radical polymerization of HEMA monomers in presence of a cross linker such as ethylene glycol-di-methacrylate (EGDMA) [Mandell, R.B., "Contact Lens Practice: Hard and Flexible Lenses", 2^nd ed., Charles C. Thomas, Springfield, vol. 3, 1974]. [0045] Addition of the drug-laden highly crosslinked microparticles and/or microgels to the polymerizing medium and subsequent polymerization results in the formation of a dispersion of the microgels and/or microparticles in the hydrogel matrix. If contact lenses made of this material are placed on the eye, the drug molecules will diffuse from the particles, travel through the lens matrix, and enter the post-lens tear film (POLTF), i.e., the thin tear film trapped in between the cornea and the lens, hi the presence of the lens, drug molecules will have a much longer residence time in the post-lens tear film, compared to about 2-5 minutes in the case of topical application as drops [Bourlais, C. L., Acar, L., Zia H., Sado, P.A., Needham, T., Leverge, R., "Ophthalmic drug delivery systems ", Progress in retinal and eye research, 1998, 17, 1 : 33-58; Creech, J. L., Chauhan, A., Radke, C.J., "Dispersive mixing in the posterior tear film under a soft contact lens", I&EC Research, 2001, 40: 3015-3026; McNamara, N.A., Poise, K.A., Brand, R.D., Graham, A.D., Chan, J.S., McKenney, CD., "Tear mixing under a soft contact lens: Effects of lens diameter". Am. J. of Ophth., 1999, 127(6): 659-65]. The longer residence time will result in a higher drug flux through the cornea and reduce the drug inflow into the nasolacrimal sac, thus reducing drug absorption into the blood stream. In addition, due to the slow diffusion of the drug molecules through the particles, drug-laden contact lenses can provide continuous drug release for extended periods of time. [0046] Without wishing to be bound by any theory, the inventors believe that the mechanism of attenuation of migration of the active agent is a slowing of migration of the active agent from the microparticles and microgels by the degree of polymerization and/or crosslinking of the material in which the bioactive agent is entrapped.

[0047] Suitable crosslinked polymers include, e.g., poly(ethylene glycol dimethacrylate), ethoxylated (n) trimethylolpropane triacrylate (wherein n=3, 6, 9, 15 or 20; trimethylolpropane triacrylate, tris (2-hydroxy ethyl) isocyanurate triacrylate, 1,3 -butyl ene glycol dimethacrylate, diethylene glycol dimethacrylate, alkoxylated hexanediol diacrylate, ditrimethylolpropane tetraacrylate, dipentaerythritol pentaacrylate, ethoxylated pentaerythritol tetraacrylate, dipentaerythritol pentaacrylate or pentaacrylate ester.

[0048] Suitable crosslinking agents include, e.g., (bis-acrylylcystamine), piperazine di- acrylamide), triallyl citric triamide, ethylene diacrylate, N,N'-methylenebisacrylamide, N₅N'-

(1 ,2-dihydroxyethylene)bisacrylamide, N,N'-diallyltartardiamide, N,N'-cystamine- bisacrylamide, N,N'-propylenebisacrylamide, diacrylamide dimethylethef, piperazine diacrylamide, 1 ,2-diacrylamide ethyleneglycol, ethyl eneureabisacrylamide, ethylene diacrylate, or N,N'-bisacrylylcystamine.

[0049] Exemplary of bioactive agents that may be delivered according to the present invention is timolol; although it will be understood that the selection of any suitable bioactive agent for delivery to the eye is well within the skill of the art

Examples

Example 1: Synthesis of HEMA gels loaded with highly crosslinked micro-particles.

[0050] Highly crosslinked microparticles were prepared with three types of monomers: (i) ethylene glycol dimethacrylate (EGDMA); (ii) propoxylated glyceryl triacrylated (PGT); and

(iii) ethoxylated trimethylol propane triacrylate (ETT). [0051] The first step in the synthesis of gels loaded with highly crosslinked microparticles requires the synthesis of an emulsion of the monomer (EGDMA, PGT or ETT) in water. These monomers are hydrophobic, and so these form the oil phase in the emulsion. Hydrophobic drugs such as cyclosporine, dexamethasone, or the base form of timolol can be dissolved in the monomer drops. The drug containing drops are then polymerized to yield the drug loaded crosslinked EGDMA microparticles. Since these monomers contains multiple vinyl groups, the particles are highly crosslinked. Also drug (ex. Timolol base) is added to the emulsion particles to obtain 'templated or imprinted' particles, i.e., these particles have a high partitioning for the drug because of creation of pockets in the particles that recognize the drug molecules. The details of the process are as follows: 6 g of 1.04M NaOH (purged with nitrogen) were added to 120 mg of timolol maleate powder. At such a high pH, timolol maleate forms the base form of timolol that is relatively hydrophobic. To concentrate the base form, 5 ml of the upper water phase was pipetted out. To the remaining mixture, 1 g of monomer (EGDMA, PGT or ETT) and 7.5 mg of benzoyl peroxide were added, followed by addition of 5 g of water (purged with nitrogen) and 1.65 g of 2.08 M NaOH. Timolol base dissolved in the monomer (EGDMA, PGT or ETT) phase resulting in the formation of a drug-laden emulsion. The emulsion was next heated in an 80°C hot water bath and stirred at 1100 rpm for 6.5 hours. This resulted in polymerization of the emulsion drops to form drug- containing crosslinked (EGDMA, PGT or ETT) particles. The particles were then allowed to settle for a day, and the cross-linked phase was withdrawn and used as the concentrated particle suspension in the gel synthesis.

[0052] Next, the drug laden micro-particles (EGDMA, PGT or ETT) were loaded in p- HEMA hydrogels by adding the concentrated particle dispersion to the HEMA monomer mix followed by polymerization. Specifically, 1.35 ml of the HEMA monomer, 0.5 ml DI water, 5μl of ethylene glycol dimethacrylate (EGDMA), and 0.1 g of the concentrated particle suspension were mixed together in a glass tube. This solution was degassed by bubbling nitrogen for 15 minutes to reduce the amount of dissolved oxygen. Next, 3 mg of the photoinitiator, Darocur TPO, was added to the mixture, and the solution was stirred for 15 minutes. The mixture was then poured in between two glass plates separated by a 100 or 200 μm thick plastic spacer. The glass plates were then placed on a UV-light illuminator (UVB) for 40 minutes for gel curing. The gels prepared with the procedure described above are referred as IX gels. The amount of particle suspension was doubled and quadrupled to obtain 2X and 4X gels, respectively. For PGT, 7X gels were also prepared.

Example 2: Drug release from control (without crosslinked particles or microgels) pHEMA gel

[0053] Control pHEMA gels were prepared by following the same procedure as described above for preparing microparticle-laden gels except that the microparticle suspension was not added. Timolol was loaded into the gels by directly adding it to the polymerizing mixture. Subsequently the drug containing pHEMA gel was cut into circular pieces with 1.65 cm diameter and 0.2 mm thickness, dried out in the air overnight, and then weighed the next day before the drug release experiment. Next the gel was soaked in 3.5 PBS and dynamic drug concentration in PBS was measured to determine the amount of drug released from the gel. The drug release profiles for these control p-HEMA gels are shown in Fig. 1 (Timolol base form release from PHEMA gel directly entrapped with Timolol base). The data clearly shows that 200 μm thick pHEMA gels release drug for a short period of about 4 hours and so are not useful for extended delivery.

Example 3: Timolol release from p-HEMA lenses loaded with highly crosslinked EGDMA microparticles

[0054] All particle-laden lenses were cut into circular pieces with 1.65 cm diameter and 0.2 mm thickness, dried out in the air overnight, and then weighed the next day before the drug release experiment. The gel was then submerged in 200 ml PBS under minimal stirring (140 rpm) and at room temperature for 24 hours to extract the unreacted monomer. This step is referred to as the extraction or the initial soaking or the extraction step. At the end of the extraction step, PBS aliquots were collected and the concentration of timolol was measured to determine the fraction of drug that is released in the extraction step. Next the gels were withdrawn from the PBS used in the extraction step and soaked in fresh 3.5 PBS. During this stage the drug concentration was measured every 24 hours without replacing the PBS. The time-dependent concentrations of timolol in PBS were determined by measuring the absorbance as a function of time by UV- Vis spectrophotometer in the 261-309nm wavelength range. For some experiments, the timolol concentrations were also measured by a HPLC using a reverse phase Cl 8 column (Symmetry** Cl 8, Waters). The mobile phase used was 10% pH=2.5 phosphate buffer, 65% DI water, and 25% acetonitrile. The samples were measured with a flow rate of 1 ml/min of the mobile phase at 30 ⁰C, and detected at 280nm. [0055] Figures 2a-g show drug release profiles from microparticle-laden gels for several different types of particles (EGDMA, PGT or ETT), for several different crosslinker loadings (IX, 2X, 4X, 7X), and for two different thicknesses (100 and 200 microns). The weights of the gels used in the release studies were slightly different for different cases and are indicated in the figure captions. The data in Figs. 2 clearly show that there is an extended drug release from the gel which lasts for about 10-15 days. This release duration is substantially longer than the duration of release from the control pHEMA gels, and the duration of release is relatively independent of the gel thickness proving that the extended release is occurring due to drug trapped inside the particles. The amount of drug released is proportional to the particle loading and also to the gel thickness further proving that the drug is released from the particles. The amount released differered for different systems, with EGDMA releasing the least and PGT and ETT releasing about the same amounts. Example 4: Packaging of microparticle-laden gels

[0056] A typical contact lens first undergoes an extraction and is then stored in packaging solution for an extended period of time. Drug molecules could potentially diffuse out of the particles into the gel and/or packaging solution during storage. It was thus decided to package the gels in drug solutions to determine if drug molecules can be prevented from being released from the particles by packaging in solutions with adequate drug concentrations. These experiments were conducted with protocols same as the drug release experiments described in Example 2 except that drug solutions in PBS were used as the mediums rather than PBS. In these examples the amount of drug in the solution is plotted as a function of time in Figures 3 a-c. The initial drop in the drug amount is due to rapid drug uptake into the gel. The slow reduction later is due to drug partitioning into the microparticles. This data shows that at concentrations of 500 ppm or above, drug molecules can be prevented from diffusing out into the packaging solution. Instead, drug molecules may diffuse into the particles leading to further increase in the drug loading in the particles. [0057] Also, gels loaded with 2X and 4 X EGDMA suspensions were packaged in 1 ml PBS for 1 month to simulate shelf storage. Drug release tests were then conducted following the same protocols as described in Example 3. The drug release profiles from 200 micron thick 2X gels and 100 micron thick 4X gels are shown in Figures 3 d and 3e, respectively. Both of these systems show extended release of drug.

Example 5: Synthesis of HEMA gels loaded with highly crosslinked EGDMA microgels [0058] It is well known that free radical polymerization leads to formation of micron sized gels at short times, and these subsequently grow larger, and eventually depending on the water fraction, join to form one contiguous gel. If the polymerization is terminated at short times by quenching, one may obtain a dispersion of micro gels in the continuous phase which could be monomer and linear or weakly crosslinked polymer (bulk polymerization) or a mix of the monomer and linear or weakly crosslinked polymer in the solvent (solution polymerization). Below is described a process for the formation of EGDMA microgels, and the subsequent entrapment of these micro gels in HEMA gels to yield a HEMA gel that contains small but highly crosslinked EGDMA microgels. Since EGDMA monomer contains 2 vinyl groups, the micro gels of EGDMA become highly crosslinked. The degree of crosslinking can be reduced by incorporating some fraction of HEMA into the micro gels. [0059] To synthesize micro-gels of pure EGDMA, first, timolol base was generated by adding 6 g of 1.04M NaOH to 240 mg of timolol maleate. Next 11 ml of the upper water phase was pipetted out to increase the fraction of the timolol base in the mixture. From the remaining mixture, timolol base was extracted with 0.85 g of benzoyl peroxide/EGDMA mixture (2.9:97.1 ratio by weight). Next, the solution was heated at 80°C for 15 minutes, followed by quenching in a 0°C water bath. The solution at this stage is a dispersion of EGDMA microgels in monomelic EGDMA with some linear polymeric or weakly crosslinked chains. Next, 7.2 ml of un-purged DI water was added to the solution to completely stop the reaction. The solution with microgels was then stirred at 600 rpm for 12 minutes, vortexed for 30 seconds, and then left stationary on the counter over night. [0060] To incorporate the micro gels into the HEMA matrix, the same procedure as the one utilized to incorporate the EGDMA particles into the gel was followed. The only difference was that the microgel solution replaced the particle suspension. Specifically, 1.35 ml of the HEMA monomer, 5 μl of ethylene glycol dimethacrylate (EGDMA), and 1 g of the micro gel solution were mixed together in a glass tube. This solution was degassed by bubbling nitrogen for 15 minutes to reduce the amount of dissolved oxygen which can be a scavenger of both initiating and propagating species in radical polymerization. Next, 3 mg of the photoinitiator, Darocur TPO, was added to the mixture, and the solution was stirred for 15 minutes. The mixture was then poured in between two glass plates separated by a 100 or 200 μm thick plastic spacer. The glass plates were then placed on a UV-light illuminator (UVB) for 40 minutes for gel curing.

Example 6: Drug release experiments from microgel-laden lens

[0061] All particle-laden lenses were cut into circular pieces with 1.65 cm diameter and 0.2 mm thickness, dried out in the air overnight, and then weighed the next day before the drug release experiment. The gel was then submerged in 200 ml PBS under stirring (140 rpm) and at room temperature for 15-24 hours to extract the unreacted monomer. This step is referred to as the extraction or the initial soaking or the extraction step. At the end of the extraction step, PBS aliquots were collected and the concentration of timolol was measured to determine the fraction of drug that is released in the extraction step. Next the gels were withdrawn from the PBS used in the extraction step and used in the drug release studies. The drug release experiments reported below were performed by soaking the gel sample in 3.5 PBS, and measuring concentration every 24 hours without replacing the PBS. The time-dependent concentrations of timolol in PBS were determined by measuring the absorbance as a function, of time by UV- Vis spectrophotometer in the 261-309 nm wavelength range. The timolol concentrations were also measured by a HPLC using a reverse phase Cl 8 column. The mobile phase used was 10% pH=2.5 phosphate buffer, 65% DI water, and 25% acetonitrile. The samples were measured with a flow rate of 1 ml/min of the mobile phase at 30°C, and detected at 280nm.

[0062] The drug release results for hydrogel loaded with bulk polymerized EGDMA micro- gels A are shown in Fig. 4 (Timolol release from microgelA-laden PHEMA gel). The four curves correspond to four gels that were prepared identically but had different extent of mixing in the extraction stage. These systems also exhibit an initial burst because of incomplete drug removal during the extraction phase followed by a slow release for a period of about 10 days. The total drug release from these systems is about 20 μg in 10 days, and if the initial burst is excluded the released amount is about 1 μg/day. To study the effect of drug loading and polymerization time of microgel on timolol drug release by microgel-laden PHEMA lenses, we conducted drug release experiments on three systems, microgel B, C, and D, where timolol loadings are 17, 17, and 20 mg of timolol /g of dry gel, and the polymerization times are 17, 19.5, and 14.5 minutes, respectively. The results of PHEMA lenses loaded with these microgels are shown in Figure 5. The results show that for all three systems, the drug loss during extraction is about 78%. The total drug release from these systems are about 110, 50, and 30 μg in 10 days, and if the initial bursts are excluded, the release rates are about 2, 1, and 4.5 μg/day for microgel B, C, and D, respectively. The results suggest that the longer polymerization time applied for the synthesis of microgels, the slower the release of timolol out of these microgels. This makes sense because the larger the highly crosslinked domains, the longer it takes for drug to diffuse out of these domains. [0063] It is noted that the present invention is also applicable for the incorporation in hydrophobic lenses such as, for example, silicone, polydimethylsiloxane, TRIS, methyl methacrylate, tris(trimethylsiloxysilyl)propyl (meth)acrylate, triphenyldimethyl- disiloxanylmethyl (meth)acrylate, pentamethyl-disiloxanylmethyl (meth)acrylate, tert-butyl- tetramethyl- disiloxanylethyl (meth)acrylate, methyldi(trimethylsiloxy)silylpropyl-glyceryl (meth)acrylate; pentamethyldi-siloxanyl-methyl methacrylate; heptamethylcyclotetrasiloxy methyl methacrylate; heptamethylcyclotetrasiloxy-propyl methacrylate; (trimethylsilyl)- decamethyl-pentasiloxy-propyl methacrylate; and dodecamethyl pentasiloxypropyl methacrylate.

[0064] Unless otherwise stated, all percentages expressed herein are by weight. The entire disclosures and contents of each reference, patent and patent application referred to above are expressly incorporated herein by reference [0065] Having now described a few embodiments of the invention, it should be apparent to those skilled in the art that the foregoing is merely illustrative and not limiting, having been presented by way of example only. Numerous modifications and other embodiments are within the scope of one of ordinary skill in the art and are contemplated as falling within the scope of the invention and any equivalent thereto. It can be appreciated that variations to the present invention would be readily apparent to those skilled in the art, and the present invention is intended to include those alternatives. Further, since numerous modifications will readily occur to those skilled in the art, it is not desired to limit the invention to the exact construction and operation illustrated and described, and accordingly, all suitable modifications and equivalents may be resorted to, falling within the scope of the invention.

Claims

CLAIMSWHAT IS CLAIMED IS:

1. An ophthalmically bioactive agent delivery system comprising a contact lens having dispersed therein microparticles or microgels of a crosslinked polymer, said microparticles or microgels having entrapped therein an ophthalmically bioactive agent, said crosslinked polymer comprising an ophthalmically acceptable material from which said bioactive agent is capable of diffusion into and migration through said contact lens and into the post-lens tear film when said contact lens is placed on the eye and wherein the degree of polymerization and/or crosslinking is such that the rate of diffusion into and migration through said contact lens of said ophthalmically bioactive agent is attenuated.

2. The ophthalmically bioactive agent delivery system of claim 1 wherein said crosslinked polymer is poly(ethylene glycol dimethacrylate), ethoxylated (n) trimethylolpropane triacrylate (wherein n=3, 6, 9, 15 or 20; trimethylolpropane triacrylate, tris (2-hydroxy ethyl) isocyanurate triacrylate, 1,3-butylene glycol dimethacrylate, diethylene glycol dimethacrylate, alkoxylated hexanediol diacrylate, ditrimethylolpropane tetraacrylate, dipentaerythritol pentaacrylate, ethoxylated pentaerythritol tetraacrylate, dipentaerythritol pentaacrylate or pentaacrylate ester.

3. The ophthalmically bioactive agent delivery system of claim 2 wherein said polymer is crosslinked with (bis-acrylylcystamine), piperazine di-acrylamide), triallyl citric triamide, ethylene diacrylate, N,N'-methylenebisacrylamide, N,N'-(1,2- dihydroxyethylene)bisacrylamide, N,N'-diallyltartardiamide, NjN'-cystamine-bisacrylamide, N,N'-propylenebisacrylamide, diacrylamide dimethylether, piperazine diacrylamide, 1 ,2- diacrylamide ethyleneglycol, ethyleneureabisacrylamide, ethylene diacrylate, or N,N'- bisacrylylcystamine.

4. A bioactive agent delivery system of claim 1 wherein said contact lens comprises a polymer formed from a reaction mixture comprising at least one hydrophilic monomer.

5. A bioactive agent delivery system of claim 4 wherein said hydrophilic monomer is an unsaturated carboxylic acid; acrylic substituted alcohol; vinyl lactam or acrylamide.

6. A bioactive agent delivery system of claim 5 wherein said hydrophilic monomer is selected from the group consisting of methacrylic or acrylic acid, 2- hydroxyethylmethacrylate, 2-hydroxyethylacrylate, N-vinyl pyrrolidone, methacrylamide or N,N-dimethylacrylamide, and mixtures thereof.

7. A bioactive agent delivery system of claim 1 wherein said contact lens comprises at least one hydrophobic material.

8. A bioactive agent delivery system of claim 7 wherein said hydrophobic material is selected from the group consisting of silicone, polydimethylsiloxane, methyl methacrylate, tris(trimethylsiloxysilyl)propyl (meth)acrylate, monomethacryloxypropyl terminated mono-n- butyl terminated polydimethylsiloxane , mono-(3-methacryloxy-2-hydroxypropyloxy)propyl terminated, mono-butyl terminated polydimethylsiloxane , bis-3-methacryloxy-2- hydroxypropyloxypropyl polydimethylsiloxanes, 3-methacryloxy-2- hydroxypropyloxy)propylbis (trimethylsiloxy)methylsilane, triphenyldimethyl- disiloxanylmethyl (meth)acrylate, pentamethyl-disiloxanylmethyl (meth)acrylate, tert-butyl- tetramethyl- disiloxanylethyl (meth)acrylate, methyldi(trimethylsiloxy)silylpropyl-glyceryl (meth)acrylate; pentamethyldi-siloxanyl-methyl methacrylate; heptamethylcyclotetrasiloxy methyl methacrylate; heptamethylcyclotetrasiloxy-propyl methacrylate; (trimethylsilyl)- decamethyl-pentasiloxy-propyl methacrylate; and dodecamethyl pentasiloxypropyl methacrylate and mixtures thereof.

9. A method of manufacturing the ophthalmically bioactive agent delivery system of claim 1 comprising providing a polymerizable reaction mixture comprising at least one polymerizable contact lens forming component and said microparticles or microgels of a crosslinked polymer having entrapped therein said ophthalmically bioactive agent and polymerizing said monomer to form said contact lens.

10. The method of claim 9 including the step of forming said microparticles or microgels by polymerizing and crosslinking a microparticle or microgel forming monomer in the presence of said ophthalmically bioactive agent.

11. A method of administering an ophthalmically bioactive agent to an eye comprising contacting said eye with the ophthalmically bioactive agent delivery system of claim 1 for a time sufficient for at least a portion of said agent to diffuse into and migrate through said contact lens and enter the tear film of said eye.

12. A kit and its use for the storage and delivery of ophthalmic drugs to the eye, the kit comprising: a first component containing at least one of the above described drug delivery systems, and a second component containing at least one storage container for the first component, the storage container additionally containing a material that substantially prevents the diffusion and migration of the ophthalmic drug during storage.

13. An article of manufacture comprising the above described drug delivery system packaged in dry state with a label which indicates that the drug delivery system has to be hydrated 24 hours prior to insertion into the eyes.

14. An article of manufacture comprising packaging material and the above described drug delivery system or the above-described kit contained within the packaging material, wherein the packaging material comprises a label which indicates that the drug delivery system and kit can be used for ameliorating symptoms associated with pathologic conditions of the eye.