Transport of Topical Anesthetics in Vitamin E Loaded Silicone

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Transport of Topical Anesthetics in Vitamin E Loaded Silicone Hydrogel Contact Lenses Cheng-Chun Peng, Michael T. Burke, and Anuj Chauhan* Department of Chemical Engineering, University of Florida, Gainesville, Florida 32611, United States S Supporting Information *

ABSTRACT: Transport of surface active anesthetic drugs through silicone hydrogel contact lenses containing nanosized vitamin E aggregates is explored for achieving extended anesthetics delivery. Commercial silicone hydrogel contact lenses release most ophthalmic drugs including local anesthetics for only a few hours, which is not adequate. Here we focus on creating dispersion of highly hydrophobic vitamin E aggregates in the lenses as barriers for drug diffusion for increasing the release durations. This approach has been shown previously to be successful in extending the release durations for some common hydrophilic ophthalmic drugs. The topical anesthetic drugs considered here (lidocaine, bupivacaine, and tetracaine) are hydrophilic at physiologic pH due to the charge, and so these cannot partition into the vitamin E barriers. However, these surface active drug molecules adsorb on the surface of the vitamin E barriers and diffuse along the surface, leading to only a small decrease in the effective diffusivity compared to non-surface-active hydrophilic drugs. The drug adsorption can be described by the Langmuir isotherm, and measurements of surface coverage of the drugs on the vitamin E provide an estimate of the available surface area of vitamin E, which can then be utilized to estimate the size of the aggregates. A diffusion controlled transport model that includes surface diffusion along the vitamin E aggregates and diffusion in the gel fit the transport data well. In conclusion, the vitamin E loaded silicone contact lens can provide continuous anesthetics release for about 1−7 days, depending on the method of drug loading in the lenses, and thus could be very useful for postoperative pain control after corneal surgery such as the photorefractive keratectomy (PRK) procedure for vision correction.

1. INTRODUCTION Excimer laser vision correction has been widely used since the first procedure was approved by FDA in 1995, and now more than 1 million procedures are performed annually in the United States.1 The excimer refractive surgery techniques correct several low to moderate refraction errors including myopia, hyperopia, and astigmatism. Currently laser in situ keratomileusis (LASIK) is the most common laser based procedure, followed by photorefractive keratectomy (PRK).2−4 LASIK is the procedure of choice for most patients in the civilian community mainly because of the significantly less postoperative discomfort, faster visual recovery, and maintenance of an intact Bowman’s membrane.5,6 However, the risk of several serious potential complications associated with LASIK, including corneal flap loss, tear or striae, and keratectasia, limits its applications.6−10 For subjects with thin corneas, anterior basement membrane dystrophy, and dry eyes,11,12 PRK remains the preferred procedure. PRK is also the preferred procedure for subjects with active lifestyles such as those in the military or involved in contact sports because any trauma after LASIK could lead to flap dislocation.13 In the United States military healthcare system, PRK is the preferred refractive surgical procedure, while LASIK has not been approved.14 © 2011 American Chemical Society

Patients who undergo PRK surgery generally receive a bandage contact lens (BCL) postoperatively. Several studies have shown that the BCL protects the de-epithelialized cornea, leads to a faster re-epithelialization, and reduces pain.13−17 Lenses are generally worn for 4−5 days after surgery, though typically the corneal re-epithelializes in 2−4 days with BCL.13,14 Contact lenses with higher oxygen permeability are preferred because they avoid hypoxia, which may lengthen postoperative healing time.13,18 After PRK surgery, the BCL wear is accompanied by instillation of several drugs including antibiotics, anti-inflammatory, and oral and topical anesthetics. For example, the patient might need to apply one drop every 2 h of topical nonpreserved 0.5% tetracaine hydrochloride for 72 h after surgery to control the pain after PRK.11 Reports indicate that pain starts ∼3 h after PRK, reaches its maximum at about 7 h, and usually is over about 24 h following surgery.19,20 The frequent dosage requirements interfere with the patients daily activities and can lead to the potential risk of drug overdose. Additionally, the presence of contact lens on the surface of the cornea, along with the rapid clearance of the instilled drugs, Received: September 14, 2011 Revised: November 30, 2011 Published: December 7, 2011 1478

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limits the fraction of the drugs that will reach the corneal epithelium. Since a BCL is commonly placed on the eye postoperatively, a contact lens that can serve effectively as a BCL while also delivering the needed ophthalmic drugs could be an ideal combination for use in the PRK surgery. Ophthalmic drug delivery through contact lenses has drawn many researchers’ attention because of the significant increase of drug residence time and bioavailability compared to eye drops.21−23 However, the rapid release in a few hours for most ophthalmic drugs of interest is the bottleneck in use of contact lenses for extended drug delivery.24 To increase drug release durations, several contact lens systems have been developed, including nanoparticle-laden lenses,25−29 biomimetic and imprinted contact lenses,30−36 and contact lens with layered structure.37 While these approaches are effective at extending the drug release duration from contact lenses, most studies cited above focused on conventional hydrophilic hydrogel materials, which are not suitable for use as BCL due to insufficient oxygen permeability. Several of the more research publications have focused on using silicone hydrogel contact for extended ophthalmic drug delivery.38,39 Silicone hydrogel contact lenses can be used for continuous extended wear for several weeks due to its high oxygen permeability, and these lenses have also shown to be effective as BCLs.13−15 The release duration of ophthalmic drugs from silicone hydrogels is typically much shorter than the wear duration of the lenses.24,40 We have shown that the release durations of some ophthalmic drugs can be increased by incorporation of vitamin E into these lenses by as much as 2 orders of magnitude.40−42 Vitamin E creates nanosized aggregates in the lenses which serve as diffusion barriers, especially for hydrophilic drugs, and thus increases the release duration. The inclusion of vitamin E in contact lenses has a minimal impact on key contact lens properties, including oxygen permeability and ion permeability to ensure the safety of extended wear.40 The optical properties, such as visual clarity, transparency for both visible and UV light, and refractive index, of these vitamin E loaded lens have been also examined and shown to be suitable for extended wear.40−42 The aim of this study is to investigate the potential of using vitamin E loaded contact lenses for the dual purpose of serving as a BCL after PRK surgery, while also delivering drugs for pain management. Commercial silicone hydrogel contact lenses O2OPTIX (Lotrafilcon B) from Ciba Vision Corp. are used in this study. The molecular structures of the three topical anesthetic drugs explored in this study, including lidocaine, bupivacaine, and tetracaine, are shown in Figure 1. The pKa values are 7.9, 8.1, and 8.4 for lidocaine, bupivacaine, and tetracaine, respectively, and thus these three drugs are present in ionized forms at physiological pH. In addition to focusing on the practical application of the commercial silicone lenses for delivery of anesthetics, we also further explore the transport mechanisms of these anesthetic drugs in the vitamin E loaded silicone hydrogels system by examining the interaction between drug molecules and the vitamin E aggregates.

Figure 1. Molecular structures of the anesthetic drugs. For preparation of silicone hydrogels that are similar in structure to the commercial contact lenses, ethylene glycol dimethacrylate (EGDMA, 98%), N,N-dimethylacrylamide (DMA, 99%), and 1-vinyl-2 pyrrolidone (NVP, 99+%) were purchased from Sigma-Aldrich Chemicals (Milwaukee, WI). The macromer acryloxy(polyethyleneoxy)propyl ether-terminated poly(dimethylsiloxane) (DBE-U12, 95+%, MW 1200− 1800) was purchased from Gelest Inc. (Morrisville, PA). 3-Methacryloxypropyltris(trimethylsiloxy)silane (TRIS) was supplied by Silar Laboratories (Scotia, NY), and 2,4,6-trimethylbenzoyldiphenylphosphine oxide (Darocur TPO) was kindly provided by Ciba Specialty Chemicals (Tarrytown, NY). All chemicals in this study were reagent grade and used as supplied without further purification. 2.2. Vitamin E Loading into Lenses. Vitamin E was loaded into contact lenses by soaking a lens in 3 mL of a vitamin E−ethanol solution for 24 h. After the loading step, the lenses were withdrawn and blotted to remove excess solution on the surface. The lenses were then dried in air overnight and weighed to determine the gain in weight due to vitamin E loading. 2.3. Drug Loading into Lenses. Two approaches were utilized for loading drugs into vitamin E loaded lenses: sequential and simultaneous. In the sequential approach, the lenses were first loaded with vitamin E and then loaded with drug by soaking the lenses in 3 mL of drug−PBS solutions for at least 7 days. The initial drug concentrations were 5.0, 2.5, and 1.0 mg/mL for lidocaine, bupivacaine, and tetracaine, respectively. At the end of the loading stage the lenses were taken out, and excess drug solution was blotted from the surface. The lenses were then air-dried and subsequently used in the release experiments. Drugs were loaded into control lenses, i.e., lenses without vitamin E by the same methods as described above. In the simultaneous approach, the drugs were added to the vitamin E−ethanol solution. The vitamin E−ethanol solutions were prepared at concentrations of 0.05, 0.10, and 0.15 g vitamin E/g ethanol, and the drugs were then dissolved in the solution. The concentration of the drugs in the solution was kept fixed irrespective of the vitamin E loading at 10, 10, and 1 mg/mL of ethanol solution for lidocaine, bupivacaine, and tetracaine, respectively. The lenses were soaked in 3 mL of drug−vitamin E−ethanol solution for 24 h to load vitamin E and drug simultaneously. At the end of the loading stage, the lenses were taken, blotted to remove the excess solution from the surface, and subsequently used for the release experiments. Drugs were also loaded into control lenses by soaking in 3 mL of drug ethanol solutions at concentration of 10, 10, and 1 mg/mL of ethanol for lidocaine, bupivacaine, and tetracaine, respectively. 2.4. Drug Release Experiments. The drug release experiments were carried out by soaking the drug-impregnated lenses in 2 mL of

2. MATERIALS AND METHODS 2.1. Materials. Commercial silicone hydrogel contact lenses O2OPTIX (Lotrafilcon B, diopter-6.50) from Ciba Vision Corp. (Duluth, GA) are used in this study. Lidocaine hydrochloride, bupivacaine hydrochloride, tetracaine hydrochloride, ethanol (>99.5%), and Dulbecco’s phosphate buffered saline (PBS) were purchased from SigmaAldrich Chemicals (St. Louis, MO), and vitamin E (D-α-tocopherol, Covitol F1370) was a kind gift from Cognis Corp. (Kankakee, IL). 1479

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Figure 2. Lidocaine release in PBS by O2OPTIX with various vitamin E loading. Drug was loaded by soaking the lenses in a 3 mL of 5 mg/mL lidocaine hydrochloride/PBS solution. fresh PBS. Since all these three anesthetic drugs have high solubility in water and the volume of aqueous medium is much larger than that of the hydrated contact lens, the drug release can be viewed as drug transport under perfect sink conditions. The amount of the residual drug in the lenses at equilibrium is negligible, and the initial drug loading is equal to the total amount of drug released from the lenses. The dynamic drug concentration in aqueous solution was determined by measuring the absorbance spectrum with a UV−vis spectrophotometer (Thermospectronic Genesys 10 UV). Although vitamin E has negligible aqueous solubility, it may be released in small quantities, and so its release was also monitored. The absorbance spectrum was measured in the range 231−291 nm for lidocaine and bupivacaine and 195−255 nm for tetracaine. The absorbance spectra of drugs is sufficiently different from that of vitamin E within these wavelength range so the spectra from the release medium could be deconvoluted to obtain both drug and vitamin E concentrations.43 Also, measurements of the entire spectra allowed an initial assessment of the stability of the drugs during processing and release. 2.5. Silicone Hydrogel Preparation. Most of the studies reported here were conducted with commercial contact lenses. However, some studies focusing on transport mechanisms required preparation of gels with variable thicknesses, and thus silicone hydrogels with composition similar to commercial contact lenses were prepared in lab. The synthesized silicone hydrogels were transparent and clear and exhibited drug release profiles similar to the commercial lenses. Other relevant properties such as modulus, ion and oxygen permeability, protein binding, etc., are not reported for the lab-prepared silicone hydrogels because these gels are only utilized to investigate transport mechanisms and are not proposed as replacements for commercial contact lenses. To prepare silicone hydrogels, hydrophilic monomers with high ion permeability are copolymerized along with the hydrophobic silicone monomer with high oxygen permeability, and a macromer is needed in the monomer mixture to ensure solubilization of all monomers. In this study, TRIS was used as the hydrophobic monomer, DMA was the hydrophilic monomers, and DBE-U12 was selected as the macromer. Highly hydrophilic NVP monomer was also added to increase the water content of the silicone hydrogel, and EGDMA was introduced in the monomer mixture for controlled cross-linking. To prepare the polymerizing mixture, 2.4 mL of a mixture that comprised 0.8 mL of TRIS, 0.8 mL of macromer, and 0.8 mL of DMA was combined with 0.12 mL of NVP and 0.1 mL of EGDMA and mixed by vortexing for 1 min. The mixture was then purged with bubbling nitrogen for 15 min to reduce the dissolved oxygen. To each monomer mixture, 12 mg of photoinitiator Darocur TPO was added with stirring for 5 min, and the final mixture was immediately injected into a mold which was composed of two 5 mm thick glass plates. The plates were separated by a plastic spacer of various thicknesses. The mold was then placed on ultraviolet transilluminator UVB-10 (UltraLum Inc.), and the gel mixture was cured by irradiating with UVB light (305 nm) for 50 min. The synthesized hydrogel was cut into circular pieces (about 1.65 cm diameter) with a cork borer for subsequent experiments. Prior to

conducting further tests, the prepared hydrogel was soaked in ethanol for 3 h and then dried at ambient temperature overnight to remove the unreacted monomer. 2.6. Determination of Critical Micelle Concentration (CMC) of Lidocaine. The surface tension isotherm of lidocaine was measured at room temperature by creating a pendant drop of lidocaine/PBS solution. The drop shape was digitally imaged and then fitted to the Young−Laplace equation by using the drop shape analysis system DSA100 (KRÜ SS) to calculate the surface tension. The concentration of lidocaine solution was varied from 0.01 to 360 mg/mL.

3. RESULTS AND DISCUSSION 3.1. Vitamin E Loading in Contact Lenses. The soaking of the commercial lenses in ethanol leads to substantial swelling. When the lenses are soaked in the vitamin E−ethanol solutions, the mass of vitamin E absorbed by the lenses is approximately equal to the product of the vitamin E concentration in the solution and the volume of ethanol absorbed by the lens. The mass of vitamin E loaded into a lens is thus directly proportional to the concentration of vitamin E loading in the ethanol−vitamin E solution.40 The concentrations of the vitamin E in the loading solution in this study were 0.05, 0.10, and 0.15 g vitamin E/g ethanol, which led to an average loading of 0.18, 0.37, and 0.55 g vitamin E/g pure lens, respectively. Drying or soaking the vitamin E−ethanol loaded lenses in water leads to extraction of ethanol from the lenses. The concentration of vitamin E then exceeds the solubility limit, leading to phase separation and formation of vitamin E aggregates. The vitamin E loaded lenses are uniformly transparent, suggesting that the sizes of the aggregates are smaller than the wavelength of the visible light of 400 nm. 3.2. Dynamics of Drug Release from Contact Lenses. 3.2.1. Release of Drug Loaded by Soaking in Drug− PBS Solution. The results of lidocaine release by O2OPTIX with various vitamin E loadings are shown in Figure 2. The release duration, defined as the time for 90% release, is only 1.8 h for the O2OPTIX lenses without vitamin E, which is inadequate for extended drug delivery. The drug release duration increases to 6.2 and 10.8 h on incorporation of 0.37 and 0.55 g vitamin E/g pure lens in the lenses, respectively. In addition to increasing the release duration, vitamin E incorporation also increases the total mass of drug released by the lenses. Vitamin E is highly hydrophobic, and so its incorporation into lenses does not increase the mass of drug absorbed for several hydrophilic drug such as timolol, dexamethasone phosphate, and fluconazole.40 The pH of the lidocaine/PBS solutions ranges from 6.0 to 7.4 based on the drug concentration in this study, which is lower than the pKa of lidocaine. Thus, the majority of lidocaine is present in the hydrophilic ionized form, 1480

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vitamin E incorporation on release of tetracaine are slightly different as shown in Figure 5. Again, higher vitamin E loading

which is highly unlikely to partition into the vitamin E aggregates. The increase of drug loading could perhaps be due to interaction between vitamin E and lidocaine through surface adsorption of lidocaine on the interface between vitamin E and the gel matrix, and we will further examine this assumption later. The hypothesis of interaction between lidocaine and vitamin E was further supported by release of vitamin E at very slow rates (less than 1% of the vitamin loading inside the lens) into the aqueous reservoir during the drug release experiment, as shown in Figure 3. Since vitamin E is typically not released

Figure 3. Vitamin E release from O2OPTIX from lenses driven by lidocaine release in PBS.

from lenses due to its hydrophobicity,40 it is reasonable to assume that the release of lidocaine enhanced the solubility of vitamin E in PBS. It is noted that the total vitamin E release accounts for less than 1% of the loaded amounts, and thus its slow elusion will not impact the drug transport in the lenses. Also, slow release of vitamin E into the tear film could be beneficial as vitamin E is an antioxidant that has shown potential benefits in prevention of several ophthalmic diseases including glaucoma and cataract.44−49 Figure 4 shows that the effect of vitamin E on bupivacaine release by O2OPTIX lenses is similar to that for lidocaine.

Figure 5. (a) Short time and (b) long time tetracaine release in PBS by O2OPTIX with various vitamin E loadings. Drug was loaded by soaking the lenses in a 3 mL of 1 mg/mL tetracaine hydrochloride/ PBS solution.

in the lens resulted in longer drug release durations. Control O2OPTIX without vitamin E released 90% of its initial drug loading in 2.4 h, while lenses with 0.37 and 0.55 g vitamin E/g pure lens released the loaded tetracaine in 13.9 and 22.6 h, respectively. However, unlike lidocaine and bupivacaine, the total drug uptake did not appear to significantly increase as the vitamin E loading amount increased. This is possibly due to the higher light sensitivity of tetracaine compared to lidocaine and bupivacaine, which leads to drug degradation during release experiment as evident in Figure 5b. The spectrum of the solution also shifted significantly over time, suggesting drug degradation (data not shown). Even though vitamin E loading extends the release duration of the anesthetic drugs, the effect is not as significant as those on other ophthalmic drugs. For example, with 0.37 g vitamin E/g pure lens loading, the drug release time for lidocaine increased from 1.8 to 6.2 h, which is a 3.5-fold increase. With similar amount of vitamin E loading, the lens can release the hydrophilic drug timolol for 28 h, a 40-fold increase compared to pure lens;40 it can also release the hydrophobic drug dexamethasone for 150 h, which is a 15-fold increase compared to pure lens.41 For hydrophilic drugs, such as timolol, the vitamin E loading inside the lens acts as diffusion barriers for drug transport due to the negligible affinity between drug and vitamin E aggregates, while for hydrophobic drugs, such as dexamethasone, the drug can freely partition into and diffuse through the highly viscous vitamin E aggregates. The fact that vitamin E incorporation increases the drug uptake even though the drug molecules are charged strongly suggests that the anesthetics explored here act as a surfactant-like molecule in this system, and thus their

Figure 4. Bupivacaine release in PBS by O2OPTIX with various vitamin E loading. Drug was loaded by soaking the lenses in a 3 mL of 2.5 mg/mL bupivacaine hydrochloride/PBS solution.

Control O2OPTIX lenses without vitamin E released 90% of the drug in 3.2 h, while lenses with 0.36 and 0.55 g vitamin E/g pure lens released the drug in 10.2 and 20.7 h, respectively. The mass of drug loaded into the lenses was also enhanced with vitamin E, while a slow release of vitamin E was also detected during bupivacaine release (data not shown). The effects of 1481

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vitamin E, which is similar to the case of sequential drug loading (data not shown). Also, tetracaine degraded likely due to exposure to light (Figure 6c). The increase in release duration through the simultaneous loading approach is very encouraging for extended drug delivery. The mechanisms that contribute to this effect are discussed later, but it is clear that the significant differences in the release behavior for the two approaches must be occurring due to differences in drug distribution inside the lenses. Contact lenses are typically stored in PBS solutions for extended periods prior to insertion in the eye, and it is thus useful to explore whether the extended release behavior for the simultaneous approach is preserved after packing for extended periods. To explore the packaging effect on the lidocaine release by contact lenses, the drug was dissolved at 10 mg/mL in a solution of 0.1 g/mL of vitamin E in ethanol. The drug was loaded in the O2OPTIX lenses by soaking the lenses in 3 mL of the drug−vitamin E− ethanol solution for 24 h. The drug loaded lenses were subsequently removed and soaked in 3 mL of 10 mg/mL drug− PBS solution for 1 or 7 days and then subjected to the drug release measurements by soaking in 2 mL of PBS. As shown in Figure 7, the lenses that were loaded with the drug through the

transport is different than both hydrophobic and hydrophilic drugs explored earlier. 3.2.2. Release of Drugs Loaded by Soaking in Drug−Ethanol Solution. The drug release results from lenses in which the drug was loaded through soaking in drug/vitamin E/ ethanol solutions are shown in Figure 6. Interestingly,

Figure 7. Lidocaine release by O2OPTIX loaded with 0.36 g vitamin E/g of lens. Lidocaine was loaded into the lenses by soaking in 10 mg/mL drug/ethanol for 24 h (ethanol) and subsequently soaked in 10 mg/mL drug/PBS for 1 day (ethanol + PBS (1 day)) or 7 days (ethanol + PBS (7 days) prior to release in 2 mL of PBS. Drug was also loaded by soaking the lens in 10 mg/mL drug/PBS solution for 7 days (PBS).

simultaneous approach and not subjected to packaging released lidocaine for 70 h, but the release duration decreased to 40 and 7 h for the lenses that were subjected to packaging for 1 and 7 days, respectively. It is noted that the release duration of 7 h is comparable to that from the sequential approach for the same vitamin E loading. While the release duration reduces during packaging, the simultaneous approach of drug loading is still preferable because of the high drug solubility in ethanol which can allow larger drug loading, and also the shorter duration of the drug uptake step, along with the elimination of the extra step that is required in the sequential drug loading. For further discussion on the packaging effect on drug release please see the Supporting Information. 3.3. Mechanisms of Drug Transport. 3.3.1. Surface Tension of Lidocaine. The increased lidocaine uptake in the lenses due to vitamin E incorporation and the vitamin E release into the drug−aqueous solutions could be attributed to surface activity of the lidocaine molecules. The surface tension of lidocaine at the air−liquid interface was measured to explore the

Figure 6. (a) Lidocaine, (b) bupivacaine, and (c) tetracaine release in PBS by O2OPTIX with various vitamin E loadings. Drugs were loaded by soaking in drug/ethanol−vitamin E solution for 24 h.

the drug release durations are significantly longer for the simultaneous loading of vitamin E and drug compared to the cases described above in which the drug was loaded by soaking the vitamin E containing lenses in drug−PBS solution. For instance, for O2OPTIX with 0.37 g vitamin E/g pure lens loading, the drug release durations of lidocaine and bupivacaine are 70 and 32 h, respectively, which are much larger than 6.2 and 10.2 h for lenses through drug/PBS uptake. In addition, the total drug uptake amount by the lens is independent of vitamin E loading, which is again very different from the behavior reported above for the sequential drug loading. The release of drugs plotted in Figure 6 was accompanied by a slow elusion of 1482

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surface activity and to determine the critical micelle concentration (cmc). The surface tension is plotted as a function of the drug concentration on logarithmic scale in Figure 8. The results

Figure 9. Partition coefficient (K) of vitamin E loaded silicone hydrogel at various lidocaine hydrochloride concentrations. Figure 8. Relationship between surface tension and lidocaine concentration in PBS. The average slope of the surface tension isotherm within the surface-active concentration range is −3.3094 mN/m.

clearly demonstrate that lidocaine is surface active and it forms micelles above a concentration of 360 mg/mL, which is much higher than the concentrations explored in our loading-release studies. While the surface tension data support adsorption of lidocaine at the interface of vitamin E aggregates in the lenses, the release of vitamin E into the aqueous solutions cannot be attributed to partitioning into the lidocaine micelles because the drug concentrations in the release experiments are less than the measured cmc. It is however possible that the vitamin E solubility increases due to interactions with the submicellar lidocaine aggregates that can exist below the cmc. 3.3.2. Adsorption of Lidocaine to the Vitamin E Aggregates. To explore the possibility of lidocaine adsorption to the vitamin E aggregates in the lenses, the partition coefficient of lidocaine in vitamin E was determined. First, the drug partition coefficient in the control silicone hydrogel (Kgel) was determined by the equation

K gel =

Cgel,f C w,f

=

Figure 10. Relationship between the lidocaine partition coefficient in vitamin E (Kve) and the bulk drug concentration.

determined as

K ve =

(1)

where Cgel,f and Cw,f are the drug concentrations in the lens and in the aqueous medium after the concentrations are in equilibrium at the end of the drug loading step. In the above equation, Vgel and Vw are the gel and fluid volumes, respectively, and the gel concentration Cgel,f can be determined by dividing the mass of drug released by the lens during the drug release into a perfect sink by the gel volume. Similarly, the overall apparent drug partition coefficient in a vitamin E loaded silicone hydrogel (Kve−gel) can be defined as

K ve − gel = =

C ve − gel,f C w,f C ve − gel,f C w,i − C ve − gel,f (Vve − gel /Vw )

C w,f

=

K ve − gelVve − gel − K gelVgel Vve

(3)

The partition coefficient of lidocaine in vitamin E was determined by measuring drug uptake in vitamin E loaded silicone hydrogels prepared in the lab. The silicone hydrogel was soaked in a 5 mL of 0.35 g/mL vitamin E/ethanol for 24 h, which resulted in a loading of 0.28 ± 0.01 g vitamin E/g pure gel. The hydrogel, with or without vitamin E, was then soaked in 5 mL of lidocaine/PBS solution with various concentrations until equilibrium was reached. The equilibrium drug loading in the hydrogel was subsequently determined by conducting drug release in fresh PBS as described earlier, and the results of Kgel, Kve, and Kve−gel at different initial soaking lidocaine concentration are shown in Figure 12. Assuming that lidocaine is adsorbing at the surface of the vitamin E aggregates inside the lenses, we model the adsorption through a Langmuir adsorption model. The surface concentration of the drug on the vitamin E aggregates (Γ) can thus be related to the free drug concentration in the aqueous phase(C) by the equation

Cgel,f C w,i − Cgel,f (Vgel /Vw )

C ve,f

Γ= (2)

Γ∞kadC kd + kadC

(4)

where Γ∞ is the surface concentration at the maximum packing on the surface and kad and kd are the rate constants for adsorption and desorption of the drug on the vitamin E surface, respectively. In addition, the previously obtained Kve can be

In addition, the drug uptake by the vitamin E loaded silicone hydrogel is the sum of the amount of drug uptake by pure hydrogel and by vitamin E aggregates in the gel, and thus the drug partition coefficient in vitamin E aggregates can be 1483

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where α is the parameter that depends on the microstructure, including particle size and aspect ratio of the vitamin E aggregates, ϕ is the volume ratio of vitamin E in the dry gel, and (ϕ − ϕ*) is the fraction that is present as the vitamin E particles. The fraction ϕ* is assumed to be soluble in the gel and thus not contributing to the formation of the vitamin E aggregates. For the lidocaine diffusion through the vitamin E loaded silicone hydrogel, the effective diffusion coefficient Deff can be estimated by considering the gel and the vitamin aggregates as barriers in series. Thus

related as

C 1 VC = w = K ve C ve SΓ (5) where V and S are the volume and surface area of vitamin E aggregates, respectively. By combining eqs 4 and 5, we can derive the relation

kdV 1 VC = = K ve kadS Γ∞ SΓ

(6)

heff h +l h0 l = 0 = + Deff Keff Deff Keff Deff K gel DsK ve

Therefore, if the Langmuir adsorption model successfully describes the interaction between lidocaine and vitamin E, the inverse of Kve should be linear to the bulk drug concentration, and the parameter V/SΓ∞ can be obtained from the slope. The good fitting of experimental results to this linear model, as shown in Figure 13, further supports the validity of the assumption of surface binding of drug, and the value of V/SΓ∞ was determined as 0.0447 mL/mg. The packing of lidocaine at the air−liquid interface can be estimated from the slope of the surface tension isotherm within the surface-active concentration range in Figure 8, which is −3.3094 mN/m. By utilizing the Gibbs isotherm,50 i.e.

∂σ ∂ ln C

where Ds is the surface diffusivity of drug on the interface between vitamin E aggregates and the gel matrix. Keff, Kgel, and Kve are the lidocaine partition coefficients in the vitamin E loaded silicone hydrogel, pure silicone hydrogel, and vitamin E aggregates, respectively, where Keff can be determined as Kgel (1 − ϕ) + Kvϕ. The drug release duration from the vitamin E loaded lens (τ) can now be scaled as

τ≈

= − RT Γ T ,P

h0 2 Dgel

h2 Deff

(11)

By combining eqs 8−11, the drug release duration increase ratio between vitamin E loaded lenses to pure lenses can be expressed as

(7)

where R is the gas constant, T is the temperature, and Γ is the surface concentration of the solute, we obtain a value of 124.3 Å2/molecule for the packing of lidocaine at the air−liquid interface. On assuming the same value for packing at the surface of the vitamin aggregates, we obtain a value of about 14 nm for the ratio V/S. Our prior studies on timolol delivery by the vitamin E loaded silicone hydrogels suggest that the vitamin E aggregates are thin disks with an aspect ratio of 16.9.40 By assuming the shape as these vitamin E aggregates as disklike with aspect ratio 16.9 and V/S ratio of 14 nm, we can obtain the average thickness and radius of the aggregates to be 21 and 350 nm, respectively. 3.3.3. Model for Transport of Lidocaine in the Vitamin E Loaded Lenses. Since lidocaine adsorbs on the surface of the vitamin E aggregates, the transport of drug is likely a combination of diffusion in gel and surface diffusion over the vitamin E aggregates. Because of the small thickness compared to the radius of the gel, transport can be modeled as one-dimensional diffusion along a series of vitamin E barriers separated by the gel matrix. For a diffusion-controlled release, the release duration from a pure lens (τ0) can be scaled as

τ0 ≈

(10)

h2Dgel ⎛ ⎞ ⎛ φ⎞ τ = 2 = Keff ⎜1 + α⎜1 + ⎟(φ − φ*)⎟ ⎝ ⎝ ⎠ 3⎠ τ0 h0 Deff ⎛ Dgel ⎛ ⎛ ⎞⎞ φ⎞ 1 × ⎜⎜ + ⎜α⎜1 + ⎟(φ − φ*)⎟⎟⎟ ⎠⎠ 3⎠ K veDs ⎝ ⎝ ⎝ K gel

(12)

From our previous studies, for O2OPTIX, α is about 35 and ϕ* is 0.0937.40 Equation 12 was fitted to the experimental data by using the function “fminsearch” in MATLAB to obtain the parameter Dgel/Ds for each drug. The parameter Kve is concentration dependent, and so an average value of all experiments data included here was used in the fitting. The model fitting results are shown in Figure 11, and the fitted Dgel/Ds are 0.0291, 0.0319, and 0.0460 for lidocaine, bupivacaine, and tetracaine, respectively. Earlier studies have shown that the release behavior of most drugs by the contact lens, with or without vitamin E, is independent of the drug loading approaches.40,41 However, the

(8)

where h0 is the half-thickness of pure lens and and Dgel is the diffusion coefficient of the drug inside the pure gel matrix. When vitamin E was loaded into the lens, the gel half-thickness h increases due to vitamin E uptake, and by assuming isotropic expansion, it can be expressed as h = h0 (1 + ϕ/3), and thus the length of the tortuous path l along the vitamin E barriers should scale as

⎛ φ⎞ l = αh(φ − φ*) = αh0⎜1 + ⎟(φ − φ*) ⎝ 3⎠

Figure 11. Model fitting for drug release increase by vitamin E loading inside O2OPTIX.

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drug release duration and the drug loading capacity of these three anesthetic drugs by vitamin E loaded lens through drug/ ethanol uptake are significantly different than those through drug/PBS uptake. When lidocaine is loaded into the lens through drug/ethanol solution, lidocaine is uncharged and it likely partitions in the hydrophobic regions of the silicone hydrogel matrix after ethanol evaporation, and the drug loading capacity is simply determined by the equilibrium ethanol uptake of the lens. When vitamin E is also included in the drug/ ethanol solution, while the total loading capacity is not affected, the uncharged lidocaine loading now should distribute in both the hydrophobic silicone region of the gel matrix and the vitamin E aggregates based on the respective partition coefficient. Since the uncharged lidocaine will be converted to the charged form once it encounters the PBS during drug release, the extra resistance of lidocaine transport observed form the lenses through drug/ ethanol uptake should arise from the drug diffusion through the hydrophobic regions inside the vitamin E/hydrogel matrix. Essentially, after the drug and vitamin E loaded lens is submerged in PBS, uncharged drug diffuses across or around the vitamin E barriers into the hydrophilic regions, where a majority of the molecules ionize and then diffuse through the gel matrix into the external PBS. Since the rate-limiting step in this case is the transport of drug from the hydrophobic reservoir across or around the vitamin E barriers, the time scale for drug transport should not scale as the square of the gel thickness, which is the expected scaling for rate processes controlled by diffusion in gel. To further examine the above assumptions on the mechanism of lidocaine transport by vitamin E loaded silicone hydrogel, the lab-synthesized silicone hydrogel with different thickness was used to conduct the drug uptake/ release experiments. As shown in Figure 12, the synthesized silicone hydrogel (with and without vitamin E) demonstrated similar lidocaine transport behaviors as those by commercial O2OPTIX. While the 0.2 mm thick pure gel released 90% of the loaded lidocaine in about 5 h, the hydrogel with 0.25 g vitamin E/g pure gel loading can extend the release duration to 15 and 48 h through drug/PBS and drug/ethanol uptake, respectively. The loading capacity increased with vitamin E loading through drug/PBS uptake but was relatively unchanged through drug/ ethanol uptake, which is the same behavior as we observed from O2OPTIX. Figure 13 shows the lidocaine release results by silicone hydrogel with various thicknesses, in which drugs were loaded through drug/PBS uptake. The drug release time increased when the vitamin E loading or the gel thickness increased. If eq 8 for lidocaine transport is valid, then the kinetic release time should be proportion to the square of gel thickness; i.e., if we define a scaled time as time/(gel thickness/0.1 mm)2, then the release results from gels with different thickness should overlap when plotted against the scaled time, and the results are shown in Figure 13b. For both the gels with or without vitamin E loading, the % releases overlapped for different thicknesses, which support the validity of our proposed transport mechanisms. For the lidocaine release by gel through drug/ethanol uptake, if the additional drug release resistance arises due to detour around vitamin E aggregates from hydrophobic regions to hydrophilic regions of hydrogel matrix, the drug release time should not be proportional to the square of thickness. As shown in Figure 14, the significant difference between the scaled releases of vitamin E loaded gel with different thicknesses suggested that the mechanism

Figure 12. Lidocaine release from pure 0.2 mm thick silicone hydrogel or gel with vitamin E loading (0.25 g vitamin E/g pure gel). Lidocaine were loaded into hydrogels through drug/PBS solution (10 mg/mL) or drug/(ethanol + vitamin E) solution (10 mg/mL).

Figure 13. Lidocaine release by silicone hydrogel with or without vitamin E loading (0.25 g vitamin E/g pure gel) with various thickness. Lidocaine was loaded into the sample through soaking the gel into 10 mg/mL drug/ PBS solution. 1485

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such as antibiotics should be taken into consideration in future works.

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ASSOCIATED CONTENT S Supporting Information * Packaging effect on drug release from lidocaine/vitamin E loaded silicone hydrogel contact lens; effect of the pH and salinity of package solution on drug transport. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION Corresponding Author *Ph 352-392-2592; Fax 352-392-9513; e-mail Chauhan@che. ufl.edu.

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ACKNOWLEDGMENTS This research was partially supported by Opportunity Seed Funds (2009) from the University of Florida. REFERENCES

(1) Wilson, S. E. New Engl. J. Med. 2004, 351, 470−475. (2) Sandoval, H. P.; de Castro, L. E. F.; Vroman, D. T.; Solomon, K. D. J. Cataract Refract. Surg. 2005, 31, 221−233. (3) Duffey, R. J.; Leaming, D. J. Refract. Surg. 2005, 21, 87−91. (4) Reynolds, A.; Moore, J. E.; Naroo, S. A.; Moore, C. B.; Shah, S. Clin. Exp. Ophthalmol. 2010, 38, 168−182. (5) Gimbel, H. V.; Anderson Penno, E. E.; van Westenbrugge, J. A.; Ferensowicz, M.; Furlong, M. T. Ophthalmology 1998, 105, 1839− 1848. (6) Gimbel, H. V.; Levy, S. G. Curr. Opin. Ophthalmol. 1998, 9, 3−8. (7) Paysse, E. A. Trans. Am. Ophthalmol. Soc. 2004, 102, 341−372. (8) Davis, E. A.; Hardten, D. R.; Lindstrom, R. L. Int. Ophthalmol. Clin. 2000, 40, 67−75. (9) Schwartz, G. S.; Park, D. H.; Schloff, S.; Lane, S. S. J. Cataract Refract. Surg. 2001, 27, 781−783. (10) Smith, R. J.; Maloney, R. K. Ophthalmology 1998, 105 (9), 1721−1726. (11) Nissman, S. A.; Tractenberg, R. E.; Babbar-Goel, A.; Pasternak, J. F. Am. J. Ophthalmol. 2008, 145, 623−629. (12) Autrata, R.; Rehurek, J. J. Cataract Refract. Surg. 2003, 29, 661− 668. (13) Engle, A. T.; Laurent, J. M.; Schallhorn, S. C.; Toman, S. D.; Newacheck, J. S.; Tanzer, D. J.; Tidwell, J. L. J. Cataract Refract. Surg. 2005, 31, 681−686. (14) Edwards, J. D.; Bower, K. S.; Sediq, D. A.; Burka, J. M.; Stutzman, R. D.; VanRoekel, C. R.; Kuzmowych, C. P.; Eaddy, J. B. J. Cataract Refract. Surg. 2008, 34, 1288−1294. (15) Brilakis, H. S.; Deutsch, T. A. J. Refract. Surg. 2000, 16, 444− 447. (16) Cherry, P. M. Ophthalmic Surg. Lasers 1996, 27, S477−480. (17) Demers, P.; Thompson, P.; Bernier, R. G.; Lemire, J.; Laflamme, P. J. Cataract Refract. Surg. 1996, 22, 59−62. (18) Holden, B. A.; Sankaridurg, P. R.; Sweeney, D. F.; Stretton, S.; Naduvilath, T. J.; Rao, G. N. Cornea 2005, 24, 156−161. (19) Tomas Barberan, S.; Fagerholm, P. Acta Ophthalmol. Scand. 1999, 77, 135−138. (20) Verma, S.; Corbet, M. C.; Marshall, J. Ophthalmology 1995, 102, 1918−1924. (21) McNamara, N. A.; Polse, K. A.; Brand, R. J.; Graham, A. D.; Chan, J. S.; McKenney, C. D. Am. J. Ophthalmol. 1999, 127, 659−665. (22) Creech, J. L.; Chauhan, A.; Radke, C. J. Ind. Eng. Chem. Res. 2001, 40, 3015−3026. (23) Li, C. C.; Chauhan, A. Ind. Eng. Chem. Res. 2006, 45, 3718− 3734. (24) Karlgard, C. C. S.; Wong, N. S.; Jones, L. W.; Moresoli, C. Int. J. Pharm. 2003, 257, 141−151. (25) Gulsen, D.; Chauhan, A. Int. J. Pharm. 2005, 292, 95−117.

Figure 14. Lidocaine release by silicone hydrogel with or without vitamin E loading (0.25 g vitamin E/g pure gel) with various thickness. Lidocaine was loaded through soaking the gels into 10 mg/mL drug/ (ethanol + vitamin E) solution.

proposed above for increased release time for simultaneous loading of vitamin E and drug is plausible.

4. CONCLUSIONS In this study we investigated the potential of providing extended anesthetics delivery by vitamin E loaded silicone hydrogel contact lenses for postoperative pain control, especially for patients who undergo PRK for vision correction. The thermodynamic properties of these anesthetic drugs, including the amphiphile behaviors and the dependency of ionization equilibrium on the pH, significantly affect the mechanisms of drug transport by vitamin E loaded silicone hydrogel contact lenses. The drug molecules adsorb and diffuse along the surface of the vitamin E barriers, reducing the barrier effect in comparison to the effect for both hydrophobic and hydrophilic drugs. The binding isotherm of the surface active anesthetic drugs can be described by the Langmuir isotherm. The binding data provide an indirect means for determining the surface area to volume ratio of the vitamin E barriers, which along with previously determined aspect ratios can be utilized to determine the thickness and the radius of the vitamin E barriers. The vitamin E loaded silicone contact lens can provide continuous anesthetics release for about 1 day. The lenses can be replaced daily to provide continuous release of the drugs. The release duration by lenses through drug/vitamin E−ethanol uptake can be further increased, while the packaging effect needs to be overcome for future practical use. Future in vivo studies are also needed to further evaluate the feasibility of sustained anesthetic release by contact lenses. Furthermore, the potential complexity of drug interactions between the anesthetics and other ophthalmic drugs involved in postoperative treatment 1486

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(26) Gulsen, D.; Li, C. C.; Chauhan, A. Curr. Eye Res. 2005, 30, 1071−1080. (27) Kapoor, Y.; Chauhan, A. J. Colloid Interface Sci. 2008, 322, 624− 633. (28) Kapoor, Y.; Chauhan, A. Int. J. Pharm. 2008, 361, 222−229. (29) Kapoor, Y.; Thomas, J. C.; Tan, G.; John, V. T.; Chauhan, A. Biomaterials 2009, 30, 867−878. (30) Ali, M.; Horikawa, S.; Venkatesh, S.; Saha, J.; Hong, J. W.; Byrne, M. E. J. Controlled Release 2007, 124, 154−162. (31) Venkatesh, S.; Sizemore, S. P.; Byrne, M. E. Biomaterials 2007, 28, 717−724. (32) Alvarez-Lorenzo, C.; Hiratani, H.; Gomez-Amoza, J. L.; MartinezPacheco, R.; Souto, C.; Concheiro, A. J. Pharm. Sci. 2002, 91, 2182− 2192. (33) Hiratani, H.; Alvarez-Lorenzo, C. J. Controlled Release 2002, 83, 223−230. (34) Hiratani, H.; Alvarez-Lorenzo, C. Biomaterials 2004, 25, 1105− 1113. (35) Hiratani, H.; Fujiwara, A.; Tamiya, Y.; Mizutani, Y.; AlvarezLorenzo, C. Biomaterials 2005, 26, 1293−1298. (36) Hiratani, H.; Mizutani, Y.; Alvarez-Lorenzo, C. Macromol. Biosci. 2005, 5, 728−733. (37) Ciolino, J. B.; Hoare, T. R.; Iwata, N. G.; Behlau, I.; Dohlman, C. H.; Langer, R.; Kohane, D. S. Invest. Ophthalmol. Vis. Sci. 2009, 50, 3346−3352. (38) White, C. J.; McBride, M. K.; Pate, K. M.; Tieppo, A.; Byrne, M. E. Biomaterials 2011, 32, 5698−5705. (39) Kim, J.; Conway, A.; Chauhan, A. Biomaterials 2008, 29, 2259− 2269. (40) Peng, C. C.; Kim, J.; Chauhan, A. Biomaterials 2010, 31, 4032− 4047. (41) Kim, J.; Peng, C. C.; Chauhan, A. J. Controlled Release 2010, 148, 110−116. (42) Peng, C. C.; Chauhan, A. J. Controlled Release 2011, 154, 267− 274. (43) Kim, J.; Chauhan, A. Int. J. Pharm. 2008, 353, 205−222. (44) Yılmaz, T.; Aydemir, O.; Ö zercan, I.; Ü stü n dağ , B. Ophthalmologica 2000, 221, 159−166. (45) Bilgihan, K.; Adiguzel, U.; Sezer, C.; Akyol, G.; Hasanreisoglu, B. Ophthalmologica 2001, 215, 192−196. (46) Ohta, Y. J. Clin. Biochem. Nutr. 2004, 35, 35−45. (47) Ohta, Y.; Yamasaki, T.; Niwa, T.; Majima, Y. J. Ocul. Pharmacol. Ther. 2000, 16, 323−335. (48) Nagata, M.; Kojima, M.; Sasaki, K. J. Ocul. Pharmacol. Ther. 1999, 15, 345−350. (49) Kojima, M.; Shui, Y. B.; Murano, H.; Sasaki, K. Ophthalmic Res. 1996, 28, 64−71. (50) Gibbs, J. W. Scientific Papers of J. Willard Gibbs: Thermodynamics; Longmans, Green and Co.: 1906; Vol. 1.

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