An ophthalmically bioactive agent delivery system comprising a contact lens having dispersed therein as an oil-in-water microemulsion, an ophthalmically bioactive agent encapsulated in the oil phase, the oil phase comprising a material from which the agent VAN diffuse into and migrate through the contact lens into the post-lens tear film when the contact lens is placed on the eye and wherein the microemulsion is stabilized by the presence of a surfactant with sufficient packing at the oil-water interface to attenuate the rate of diffusion into and migration of agent through the contact lens.

Description of the Invention

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to methods and systems for the delivery of drugs to patients in need thereof.

2. Description of the Prior Art

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].

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 may lead to undesirable side effects. For example, beta-blockers such as Timolol that is used in the treatment of wide-angle glaucoma may have a deleterious effect on heart [TIMPOTIC.RTM. prescribing information, supplied by MERCK]. Furthermore, application of ophthalmic drugs as drops may result 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 minimizing or eliminating side effects.

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"; U.S. Pat. No. 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.

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. Opthalmol. 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. Opthalmol 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, U.S. Pat. No. 6,410,045, Drug delivery system for antiglaucomatous medication, Schultz; Clyde Lewis, Mint; Janet M; U.S. Pat. No. 4,484,922, Occular device, Rosenwald; Peter L., U.S. Pat. No. 5,723,131, Contact lens containing a leachable absorbed material, Schultz; Clyde L. Nunez; Ivan M.; Silor; David L.; Neil; Michele L.].

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., McIntosh, 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 hydrogels 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 drags 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; U.S. Pat. No. 4,668,506]. Direct entrapment of drug could increase loading but it does not increase the duration of release.

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 J L, 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]. These articles disclose that 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.

To substantially increase the duration of drug release, Chauhan et al suggested dispersing in contact lenses nanoparticles of ophthalmic bioactive agents nanoencapsulated in a material from which the ophthalmic drug 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. The particle size of the nanoparticles and the number thereof dispersed in the contact lens are such that the contact lens remains substantially transparent. [United States Published Patent Applications 20040241207 and 20040096477], Chauhan, Anuj; http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=- %2Fnetahtml%2FPTO%2Fsearch-bool.html&r=2&f=G&1=50&col=AND&d=PG01&s1=gulsen- &s2=chauhan&OS=gulsen+AND+chauhan&RS=gulsen+AND+chauhan-h2http://appft1.us- pto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%2Fnetahtml%2FPTO- %2Fsearch-bool.html&r=2&f=G&1=50&col=AND&d=PG01&s1=gulsen&s2=chauhan&OS=gu- lsen+AND+chauhan&RS=gulsen+AND+chauhan-h4Gulsen, Derya, "Ophthalmic drug delivery system", Gulsen D, Chauhan A--"Dispersion of microemulsion drops in HEMA hydrogel: 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., "Poly(vinyl 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. There are two main advantages of entrapment of drug in nanoparticles over soaking and direct entrapment of drug in a gel. First, if the solute is directly trapped in the gel, the release rates are controlled by diffusion through the gel. Contact lenses must be very thin (about 100 .mu.m thick) and only lightly crosslinked to ensure high oxygen permeability. Thus, if drugs are directly trapped in the lens during polymerization, they will be released in a short period of time. If the drugs are trapped inside the nanoparticles, and if the nanoparticles are designed to release drugs slowly, then a contact lens loaded with the drug containing particles can release drug for longer periods of time. Secondly, since the solubility of the hydrophobic drugs is much higher in oil, a significantly higher drug loading can be achieved by entrapping the drug in oil filled nanoparticles or nanocapsules, and subsequently, dispersing these particles in a hydrogel matrix.

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 surfactant, the polymeric surfactant being present in an amount sufficient to attenuate the rate of migration of the bioactive agent through the contact lens.

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.

SUMMARY OF THE INVENTION

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 as an oil-in-water microemulsion, an ophthalmically bioactive agent encapsulated in the oil phase of the microemulsion, the oil phase comprising an ophthalmically acceptable material from which the 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 microemulsion is stabilized by the presence of an ophthalmically acceptable surfactant with sufficient packing at the oil-water interface to attenuate the rate of diffusion into and migration of agent through the contact lens.

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.

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 fusion and migration of the ophthalmic drug during storage.

A fifth embodiment of the invention relates to a method of manufacturing a bioactive agent delivery system of claim 1 comprising providing a reactive mixture comprising at least one lens-forming component, the surfactant and the bioactive agent and polymerizing said monomer mixture.

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.

DETAILED DESCRIPTION OF THE INVENTION

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, which need not be described here.

Hydrophilic components are those which when mixed, at 25.degree. 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.

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, combinations thereof and the like.

The reaction mixtures may also comprise at least one hydrophobic component. Hydrophobic components are those which when mixed, at 25.degree. C. in a 1:1 ratio by volume with neutral, buffered water (pH about 7.0) form an immiscible mixture.

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.

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.

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.

The crux of the invention resides in the discovery that the rate of migration of bioactive agents, capable of diffusion through contact lenses and into the post-lens tear film when the contact lens is placed on the eye, is attenuated where the bioactive agent is an oil-in-water microemulsion and the ophthalmically bioactive agent is encapsulated in the oil phase of the microemulsion and the microemulsion is stabilized by the presence of a surfactant with sufficient packing at the oil-water interface The invention is exemplified herein using soft hydrogel lenses that comprise 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.sup.nd ed., Charles C. Thomas, Springfield, vol. 3, 1974].

Addition of the bioactive agent to the reaction mixture results in the formation of a microemulsion of the bioactive agent in the hydrogel matrix upon polymerization. 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. In 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, C. D., "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.

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 oil-in-water emulsion by the packing of the surfactant at the oil-water interface. An alternate possibility is that the surfactants present in the microemulsion form other types of structures inside the gel such as micelles, and these structures lead to a slow down in the release rates.

Suitable surfactants include any ophthalmically compatible surfactants capable of sufficient packing at the oil-water interface to attenuate migration therefrom of the active agent, but which does not deleteriously affect the optical transparency of the resulting contact lens. Exemplary of suitable surfactants are the Brij compounds; i.e., linear ethoxylated surfactant containing the same alkyl chain length (CIS) and increasing numbers of ethoxylate (EO) units (e.g., 10, 20, and 100).

Exemplary of bioactive agents that may be delivered according to the present invention are timolol and cyclosporine; 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. In the examples, the following materials were employed: HEMA monomer and ethylene glycol dimethacrylate (EGDMA); ethyl butyrate and benzoyl peroxide; timolol maleate, pluonic F127, Dulbecco's phosphate buffered saline (PBS), sodium caprylate, and sodium hydroxide pellets (99.998%); Darocur TPO and cyclosporine.

EXAMPLES

Example 1

The first step in synthesis of gels loaded with drug containing microemulsions requires synthesis of an oil-in-water microemulsion. Hydrophobic drugs such as cyclosporine, dexamethasone, or even the base form of timolol can be dissolved in the oil phase of the microemulsion. The microemulsions are then added to HEMA monomer and polymerized to form a HEMA gel laden with drug containing microemulsion drops.

Synthesis of Pluronic microemulsions: The microemulsions described below utilize ethyl butyrate as the oil phase, Pluronic F 127 as the surfactant, and sodium caprylate as the co-surfactant. In these studies, the base form of timolol is entrapped in the oil drops of the microemulsions. The fraction of drug in the oil phase and also the fraction of the oil phase in the microemulsions are varied to develop systems with different drug loadings. Four types of microemulsions are described below. They are referred to as meA, meB, meC, and meD.

To make meA, first dissolve 0.0831 g of timolol maleate salt in 6 ml of 0.77M NaOH solution. The pH of the resulting solution is above the pKa of timolol (pKa-9.2), and thus the base form of timolol separated out from the aqueous solution. After allowing the mixture to phase separate, pipette out 5 ml of the aqueous phase, and added 400 .mu.l of ethyl butyrate to extract the timolol base. After extraction, separate the upper oil phase (timolol base dissolved in ethyl butyrate) and the lower aqueous phase. The upper phase (timolol containing ethyl butyrate which is referred as T/E below) was used as the oil phase of the microemulsions MeA is water-in-oil (W/O) microemulsion stabilized by Pluronic F127 surfactant and sodium caprylate co-surfactant. To make the surfactant solution, dissolve 1.2 g of Pluronic F127 and 0.0163 g of sodium caprylate in 9 ml saline (0.85 wt % NaCl in DI water). In order to dissolve the surfactant in the aqueous solution, the mixture had to be stirred at about 600 rpm at room temperature for a period of about 5 hours. Add 0.1 ml T/E and 0.5 ml of 1.5M NaOH solution to 4.5 ml of the surfactant solution, and stirred the mixture at 600 rpm at room temperature. After about 3 hours, the solution turned clear, which indicated microemulsion formation.

MeB was made by the same procedures as meA, except that meB has a slightly higher content of oil phase than meA. To synthesize meB, 0.15 ml instead of 0.1 ml TIE was added to 4.5 ml of surfactant solution.

MeC was also made by similar procedures as meA. For preparing meC, pure timolol base was used as the oil phase instead of a mixture of timolol and ethyl butyrate. To synthesize meC, 0.1642 g of timolol maleate was added to 6 ml of 1.5 M NaOH solution to generate timolol base, and the mixture was allowed to phase separate. Then pipette out and discard 5 ml of the top aqueous phase, and the rest of the mixture was dried by blowing nitrogen for about 30 minutes. Separately dissolve 2.145 g of Pluronic F127 and 0.016 g of sodium caprylate in 8 ml saline (0.85 wt % NaCl in DI water) for use as the surfactant solution for meC. In order to dissolve the surfactant in the aqueous solution, the mixture had to be stirred at about 600 rpm at room temperature for a period of about 5 hours. Then add 1 ml of 2.31 M N aOH solution, 4 ml surfactant solution, and 0.383 g more Pluronic F127 to the "dried" timolol base, and stir the mixture at 600 rpm at room temperature for 3 hours.

MeD was also made by similar procedures as meA, except that it had a slightly higher content of timolol in T/E mixture, a slightly higher oil content in the microemulsion, as well as a higher total amount of surfactant added to the microemulsion. Specifically, 0.1222 g of timolol maleate was added to 6 ml of 0.77 M NaOH solution to generate timolol base, and the mixture was allowed to phase separate. Then pipette out and discard 5 ml of the top aqueous phase, and extracted timolol base with 230 .mu.l ethyl butyrate. Separately dissolve 1.64 g of Pluronic F127 in 9 ml saline (0.85 wt % NaCl in DI water) as the surfactant solution for meD. In order to dissolve the surfactant in the aqueous solution, the mixture had to be stirred at about 600 rpm at room temperature for a period of about 5 hours. Then add 0.1 ml TIE and 0.5 ml of 1.5 M NaOH solution to 4.5 ml of the surfactant solution, and stir the above solution at 600 rpm at room temperature for 3 hours.

The compositions of the four types of microemusions described above are summarized in Table 1 (see Original Patent).

Claim 1 of 6 Claims

1. An ophthalmically bioactive agent delivery system comprising a contact lens having dispersed therein as an oil-in-water microemulsion, an ophthalmically bioactive agent encapsulated in the oil phase of the microemulsion, the oil phase comprising an ophthalmically acceptable material from which the 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 microemulsion is stabilized by the presence of an ophthalmically acceptable surfactant with sufficient packing at the oil-water interface to attenuate the rate of diffusion into and migration of agent through the contact lens.
 

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