Chau-Minh Phan

In vitro uptake and release of natamycin from conventional and silicone hydrogel contact lens materials.

Objectives: To investigate the uptake and release of the antifungal ocular drug, natamycin from commercially available conventional hydrogel (CH) and silicone hydrogel (SH) contact lens (CL) materials and to evaluate the effectiveness of this delivery method. Methods: Five commercial SH CLs (balafilcon A, comfilcon A, galyfilcon A, senofilcon A, and lotrafilcon B) and four CH CLs (etafilcon A, omafilcon A, polymacon, vifilcon A) were examined in this study. These lenses were incubated with natamycin solubilized in dimethyl sulfoxide, and the release of the drug from these lenses, in Unisol 4 pH 7.4 at 32±1°C, was determined using UV-visible spectrophotometry at 305 nm over 24 hours. Results: There was a significant uptake of natamycin between 0 hour and 24 hours (P<0.05) for all CL materials. However, there was no significant difference between any of the lens materials, regardless of their composition (P>0.05). There was a significant difference in release between all the SH materials (P<0.05) and CH materials (P<0.05). All CL materials showed a significant increase in the release of natamycin until 1 hour (P<0.05), which was followed by a plateau (P>0.05). Overall, the release of natamycin was higher in CH than SH lenses (P<0.001). Conclusions: All CLs released clinically relevant concentrations of natamycin within 30 minutes, but this release reached a plateau after approximately 1 hour. Further CL material development will be necessary to produce a slow and sustained drug releasing device for the delivery of natamycin.

In vitro uptake and release of natamycin Dex-b-PLA nanoparticles from model contact lens materials

Purpose: To evaluate the uptake and release of the antifungal agent natamycin encapsulated within poly(D,L-lactide)-dextran nanoparticles (Dex-b-PLA NPs) from model contact lens (CL) materials. Methods: Six model CL materials (gel 1:poly(hydroxyethyl methacrylate, pHEMA); gel 2:85% pHEMA: 15% [Tris(trimethylsiloxy)silyl]-propyl methacrylate (TRIS); gel 3: 75% pHEMA: 25% TRIS; gel 4: 85% N,N dimethylacrylamide (DMAA): 15% TRIS; gel 5:75% DMAA: 25% TRIS; and gel 6: DMAA) were prepared using a photoinitiation procedure. The gels were incubated in: (1) natamycin dissolved in deionized (DI) water and (2) natamycin encapsulated within Dex-b-PLA NPs in dimethylsulfoxide/DI water. Natamycin release from these materials was monitored using UV–visible spectrophotometry at 304 nm over 7 d. Results: Natamycin uptake by all model CL materials increased between 1 and 7 d (p < 0.001). The uptake of natamycin-NPs was higher than the uptake of the drug alone in DI water (p < 0.05). Drug release was higher in materials containing DMAA than pHEMA (p < 0.05). All gels loaded with natamycin-NPs also released more drug compared to gels soaked with natamycin in DI water (p < 0.001). After 1 h, CL materials loaded with natamycin alone released 28–82% of the total drug release. With the exception of gel 6, this burst released was reduced to 21–54% for CL materials loaded with natamycin-NPs. Conclusions: Model CL materials loaded with natamycin-Dex-b-PLA NPs were able to release natamycin for up to 12 h under infinite sink conditions. DMAA-TRIS materials may be more suitable for drug delivery of natamycin due to the higher drug release observed with these materials.

Release of Ciprofloxacin and Moxifloxacin From Daily Disposable Contact Lenses From an In Vitro Eye Model

PURPOSE To analyze the release of two fluoroquinolones, ciprofloxacin and moxifloxacin, from conventional hydrogel (CH) and silicone hydrogel (SH) daily disposable contact lenses (CLs), comparing release from a fixed-volume vial and a novel in vitro eye model. METHODS Four CH CLs (nelfilcon A, omafilcon A, etafilcon A, ocufilcon B) and three SH CLs (somofilcon A, narafilcon A, delefilcon A) were used. The lenses were incubated in drug solutions for 24 hours. After the incubation period, the lenses were placed in two release conditions: (1) a vial containing 4.8 mL PBS for 24 hours and (2) an in vitro eye model with a flow rate at 4.8 mL over 24 hours. RESULTS Release in the vial for both drugs was rapid, reaching a plateau between 15 minutes and 2 hours for all lenses. In contrast, under physiological flow conditions, a constant and slow release was observed over 24 hours. The amounts of ciprofloxacin released from the lenses ranged between 49.6 ± 0.7 and 62.8 ± 0.3 μg per lens in the vial, and between 35.0 ± 7.0 and 109.0 ± 5.0 μg per lens in the eye model. Moxifloxacin release ranged from 24.0 ± 4.0 to 226.0 ± 2.0 μg per lens for the vial, and between 13.0 ± 2.0 and 151.0 ± 10.0 μg per lens in the eye model. In both systems and for both drugs, HEMA-based CLs released more drugs than other materials. CONCLUSIONS The parameters of the release system, in particular the volume and flow rate, have a significant influence on measured release profiles. Under physiological flow, release profiles are significantly slower and constant when compared with release in a vial.

Inhibition of steroid sulfatase with 4-substituted estrone and estradiol derivatives

Steroid sulfatase (STS) catalyzes the desulfation of biologically inactive sulfated steroids to yield biologically active desulfated steroids and is currently being examined as a target for therapeutic intervention for the treatment of breast cancer. We previously demonstrated that 4-formyl estrone is a time- and concentration-dependent inhibitor of STS. We have prepared a series of 4-formylated estrogens and examined them as irreversible STS inhibitors. Introducing a formyl, bromo or nitro group at the 2-position of 4-formylestrone resulted in loss of concentration and time-dependent inhibition and a considerable decrease in binding affinity. An estradiol derivative bearing a formyl group at the 4-position and a benzyl group at the 17β-position yielded a potent concentration and time-dependent STS inhibitor with a K(I) of 85 nM and a k(inact) of 0.021 min(-1) (k(inact)/K(I) of 2.3 × 10(5)M(-1)min(-1)). Studies with estrone or estradiol substituted at the 4-position with groups other than a formyl group revealed that good reversible inhibitors can be obtained by introducing small electron withdrawing groups at this position. An estradiol derivative with fluorine at the 4-position and a benzyl group at the 17β-position yielded a potent, reversible inhibitor of STS with an IC(50) of 40 nM. The introduction of relatively small electron withdrawing groups at the 4-position of estrogens and their derivatives may prove to be a general approach to enhancing the potency of estrogen-derived STS inhibitors.

In vitro drug release of natamycin from β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin-functionalized contact lens materials

Purpose: The antifungal agent natamycin can effectively form inclusion complexes with beta-cyclodextrin (β-CD) and 2-hydroxypropyl-β-cyclodextrin (HP-βCD) to improve the water solubility of natamycin by 16-fold and 152-fold, respectively (Koontz, J. Agric. Food. Chem. 2003). The purpose of this study was to develop contact lens materials functionalized with methacrylated β-CD (MβCD) and methacrylated HP-βCD (MHP-βCD), and to evaluate their ability to deliver natamycin in vitro. Methods: Model conventional hydrogel (CH) materials were synthesized by adding varying amounts of MβCD and MHP-βCD (0, 0.22, 0.44, 0.65, 0.87, 1.08% of total monomer weight) to a monomer solution containing 2-hydroxyethyl methacrylate (HEMA). Model silicone hydrogel (SH) materials were synthesized by adding similar concentrations of MβCD and MHP-βCD to N,N-dimethylacrylamide (DMAA)/10% 3-methacryloxypropyltris(trimethylsiloxy)silane (TRIS). The gels were cured with UV light, washed with ethanol and then, hydrated for 24 h (h). The model materials were then incubated with 2 mL of 100 μg/mL of natamycin in phosphate buffered saline (PBS) pH 7.4 for 48 h at room temperature. The release of natamycin from these materials in 2 mL of PBS, pH 7.4 at 32 ± 2 °C was monitored using UV–vis spectrophotometry at 304 nm over 24 h. Results: For both CH and SH materials, functionalization with MβCD and MHP-βCD improved the total amount of drugs released up to a threshold loading concentration, after which further addition of methacrylated CDs decreased the amount of drugs released (p < 0.05). The addition of CDs did not extend the drug release duration; the release of natamycin by all model materials reached a plateau after 12 h (p < 0.05). Overall, DMAA/10% TRIS materials released significantly more drug than HEMA materials (p < 0.05). The addition of MHP-βCD had a higher improvement in drug release than MβCD for both HEMA and DMAA/10% TRIS gels (p < 0.05). Conclusions: A high loading concentration of methacrylated CDs decreases overall drug delivery efficiency, which likely results from an unfavorable arrangement of the CDs within the polymer network leading to reduced binding of natamycin to the CDs. HEMA and DMAA/10% TRIS materials functionalized with MHP-βCD are more effective than those functionalized with MβCD to deliver natamycin.

Contact lenses for antifungal ocular drug delivery: a review

Introduction: Fungal keratitis, a potentially blinding disease, has been difficult to treat due to the limited number of approved antifungal drugs and the taxing dosing regimen. Thus, the development of a contact lens (CL) as an antifungal drug delivery platform has the potential to improve the treatment of fungal keratitis. A CL can serve as a drug reservoir to continuously release drugs to the cornea, while limiting drug loss through tears, blinking, drainage and non-specific absorption. Areas covered: This review will provide a summary of currently available methods for delivering antifungal drugs from commercial and model CLs, including vitamin E coating, impregnated drug films, cyclodextrin-functionalized hydrogels, polyelectrolyte hydrogels and molecular imprinting. This review will also highlight some of the main factors that influence antifungal drug delivery with CLs. Expert opinion: Several novel CL materials have been developed, capable of extended drug release profiles with a wide range of antifungal drugs lasting from 8 h to as long as 21 days. However, there are factors, such as first-order release kinetics, effectiveness of continuous drug release, microbial resistance, ocular toxicity and potential complications from inserting a CL in an infected eye, that still need to be addressed before commercial applications can be realized.

Release of Fluconazole from Contact Lenses Using a Novel In Vitro Eye Model.

Purpose Rapid drug release followed by a plateau phase is a common observation with drug delivery from contact lenses (CLs) when evaluated in a vial. The aim of this study was to compare the release of fluconazole from seven commercially available daily disposable CLs using a conventional vial-based method with a novel in vitro eye model. Methods An eye model was created using two 3-dimensional printed molds, which were filled with polydimethylsiloxane to obtain an inexpensive model that would mimic the eyeball and eyelid. The model was integrated with a microfluidic syringe pump, and the flow-through was collected in a 12-well microliter plate. Four commercial daily disposable conventional hydrogels (nelfilcon A, omafilcon A, etafilcon A, ocufilcon B) and three silicone hydrogels (somofilcon A, narafilcon A, delefilcon A) were evaluated. These CLs were incubated with fluconazole for 24 h. The drug release was measured in a vial containing 4.8 mL of phosphate-buffered saline and in the polydimethylsiloxane eye model with a 4.8-mL tear flow across 24 h. Results Overall, conventional hydrogel CLs had a higher uptake and release of fluconazole than silicone hydrogel CLs (p < 0.05). A higher drug release was observed in the vial condition compared with the eye model (p < 0.001). In the vial system, the drugs were rapidly released from the CL within the first 2 h, followed by a plateau phase. In contrast, drug release in the eye model under low tear volume was sustained and did not reach a plateau across 24 h (p < 0.05). Conclusions Rapid drug release results from using a vial as the release system. Under low tear volume at physiological tear flow, commercial CLs can maintain a sustained drug release profile for up to 24 h. However, eyes with fungal keratitis may have increased tearing, which would significantly accelerate drug release.

The Use of Contact Lenses as Biosensors.

&NA; The tear film is a complex multilayer film consisting of various proteins, enzymes, and lipids and can express a number of biomarkers in cases of disease. The development of a contact lens sensor presents a noninvasive alternative for the detection and management of various diseases. Recent work has resulted in the commercialization of a device to monitor intraocular pressure for up to 24 h, and there are extensive efforts underway to develop a contact lens sensor capable of continuous glucose tear film monitoring to manage diabetes. This clinical perspective will highlight the major developments within this field and list some of the major challenges that still need to be addressed.

Insights to Using Contact Lenses for Drug Delivery

There has been considerable interest in the potential application of contact lenses for ocular drug delivery. This short communication provides an overview of the challenges faced by delivering drugs using contact lenses, highlights the solutions to limitations that have already been achieved, and describes the barriers that remain before commercial application can be realized.

Release of Moxifloxacin from Contact Lenses Using an In Vitro Eye Model: Impact of Artificial Tear Fluid Composition and Mechanical Rubbing

Purpose The aim of this study was to evaluate and compare the release of moxifloxacin from a variety of daily disposable (DD) contact lenses (CLs) under various conditions using a novel in vitro eye model. Methods Four commercially available DD conventional hydrogel (CH) CLs (nelfilcon A, omafilcon A, etafilcon A, and ocufilcon B) and three silicone hydrogel (SH) CLs (somofilcon A, narafilcon A, and delefilcon A) were evaluated. These lenses were incubated in moxifloxacin for 24 hours. The release of the drug was measured using a novel in vitro model in three experimental conditions: (1) phosphate buffered saline (PBS); (2) artificial tear solution (ATS) containing a variety of proteins and lipids; and (3) ATS with mechanical rubbing produced by the device. Results Overall, CH CLs had a higher drug release than SH CLs (P < 0.05) under all conditions. Typically, a higher drug release was observed in PBS than ATS (P < 0.05). For CH, drug release was found to be higher in ATS with rubbing than PBS or ATS (P < 0.05). For most lens types, ATS with rubbing produced higher drug release than ATS alone (P < 0.05). Generally, the release kinetics for all conditions were sustained over the 24-hour testing period, and no burst release was observed (P < 0.05). Conclusions Moxifloxacin release from a CL into ATS is lower when compared to release into PBS. When mechanical rubbing is introduced, the amount of drugs released is increased. Translational Relevance Results suggest that sophisticated in vitro models are necessary to adequately model on-eye drug release from CL materials.