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

Phan, C.-M., Bajgrowicz-Cieslak, M., Subbaraman, L. N., & Jones, L. (2016). Release of Moxifloxacin from Contact Lenses Using an In Vitro Eye Model: Impact of Artificial Tear Fluid Composition and Mechanical Rubbing. Translational Vision Science & Technology, 5(6), 3. https://doi.org/10.1167/tvst.5.6.3Purpose: 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

Antifungal ocular drug delivery via contact lenses using a novel in vitro eye model

Purpose: The purpose of this thesis was to evaluate the potential of contact lenses (CLs) as an antifungal drug delivery device, and to develop an in vitro eye model to test thereof. Methods: The first three chapters focused on developing a CL to function as a drug delivery device for natamycin, the only commercially available antifungal: • In the first experiment (Chapter 3), the in vitro uptake and release characteristics of natamycin from several commercially available CLs were evaluated • In the second experiment (Chapter 4), to improve the release characteristics of natamycin from contact lenses, an attempt was made to incorporate novel drug-encapsulated nanoparticles (Dex-b-PLA) within the CLs • In the third experiment (Chapter 5), an alternative strategy employing the incorporation of cyclodextrin (CDs) within the CL polymer matrix was evaluated as a potential modification to prolong the release of natamycin The second half of the thesis was aimed at developing a sophisticated in vitro ocular model capable of adequately measuring drug release from CLs: • In Chapter 6, the design of a novel in vitro eye model to simulate the physiological ocular environment was outlined • In Chapter 7, this model was used to evaluate the release of the antifungal fluconazole from commercially daily disposable CLs • In chapter 8, as an extension of the developed in vitro eye model, an agar eye model was developed to test the effects of natamycin and fluconazole-releasing CLs on Candida albicans Results Commercial CLs, after drug incubation with natamycin, will release the drug rapidly within the first half hour, followed by a plateau phase. However, when CL materials were loaded instead with natamycin encapsulated within novel Dex-b-PLA nanoparticles, the release duration was extended to 12 hours. Modifying the CL polymer with methacrylated CDs did not significantly improve drug release. On the contrary, high loading of CDs decreased overall drug delivery efficiency, likely resulting from unfavourable arrangements of the CDs within the polymer network. The developed ocular platform, termed Ocuflow, simulates physiological tear flow, tear volume, air exposure and mechanical wear. When this system was used to analyze the release of fluconazole from commercial CLs, the drug release was sustained for up to 24 hours. This observation significantly contrasts drug release observed in a vial, which typically follows a burst-plateau profile. When CLs releasing natamycin and fluconazole were tested on agar eye models that were inoculated with Candida albicans, the growth of the yeast was limited by natamycin-containing CLs. The cell morphology of the yeast also differed noticeably based on drug-lens combinations.   Conclusions This thesis details potential strategies to develop novel CLs for antifungal ocular drug delivery. The Ocuflow system developed from this thesis is highly versatile; not only can it be used effectively to measure drug release from CLs, but it can also be applied to other in vitro analyses with CLs

Human Steroid Sulfatase: Inhibitor Studies and Photoaffinity Labeling

Steroid sulfatase (STS) is considered to be one of the key enzymes contributing to the development of breast cancer. It catalyzes the hydrolysis of inactive sulfated steroids such as estrone sulfate (ES) to inorganic sulfate active steroids such as estrone (E1), a precursor to estradiol (E2), a key stimulator for breast cancer development. Inhibitors of STS are currently being pursued in both academia and industry as potential drugs for treating breast cancer. A series of 4-substituted estrone and estradiol derivatives were examined as inhibitors of STS. Inhibition of STS with 4-FE1, an irreversible inhibitor of STS previously studied in the Taylor group, can be enhanced by introducing a hydrophobic benzyl group at the 17-positon of 4-FE1. As with 4-FE1, the inhibition was concentration and time-dependent. Only 14% of the activity could be recovered after extensive dialysis. Introducing substituents at the 2-position of 4-formyl estrogen derivatives resulted in loss of concentration and time-dependent inhibition and a considerable decrease in inhibitor affinity. Studies with estrogen derivatives substituted at the 4-position with groups other than a formyl revealed that a relatively good reversible inhibitor can be obtained simply by introducing an electron withdrawing group at this position. These types of inhibitors are non-competitive inhibitors suggesting an alternative steroid binding site. A series of estrone derivatives were examined as photoaffinity labels of STS. 4-azidoestrone suflate and 4-azidoestrone phosphate exhibited properties that are suitable for photoaffinity labeling studies with STS. These labels may be useful for ascertaining pathways of substrate entry into the STS active site. 16-diazoestrone phosphate was not a photoaffinity label of STS. 2- and 4-azido estrone and 16-diazoestrone all acted as photoaffinity labels of STS. These compounds may be useful for ascertaining pathways of product release from the STS active site

Antifungal ocular drug delivery via contact lenses using a novel in vitro eye model

Purpose: The purpose of this thesis was to evaluate the potential of contact lenses (CLs) as an antifungal drug delivery device, and to develop an in vitro eye model to test thereof. Methods: The first three chapters focused on developing a CL to function as a drug delivery device for natamycin, the only commercially available antifungal: • In the first experiment (Chapter 3), the in vitro uptake and release characteristics of natamycin from several commercially available CLs were evaluated • In the second experiment (Chapter 4), to improve the release characteristics of natamycin from contact lenses, an attempt was made to incorporate novel drug-encapsulated nanoparticles (Dex-b-PLA) within the CLs • In the third experiment (Chapter 5), an alternative strategy employing the incorporation of cyclodextrin (CDs) within the CL polymer matrix was evaluated as a potential modification to prolong the release of natamycin The second half of the thesis was aimed at developing a sophisticated in vitro ocular model capable of adequately measuring drug release from CLs: • In Chapter 6, the design of a novel in vitro eye model to simulate the physiological ocular environment was outlined • In Chapter 7, this model was used to evaluate the release of the antifungal fluconazole from commercially daily disposable CLs • In chapter 8, as an extension of the developed in vitro eye model, an agar eye model was developed to test the effects of natamycin and fluconazole-releasing CLs on Candida albicans Results Commercial CLs, after drug incubation with natamycin, will release the drug rapidly within the first half hour, followed by a plateau phase. However, when CL materials were loaded instead with natamycin encapsulated within novel Dex-b-PLA nanoparticles, the release duration was extended to 12 hours. Modifying the CL polymer with methacrylated CDs did not significantly improve drug release. On the contrary, high loading of CDs decreased overall drug delivery efficiency, likely resulting from unfavourable arrangements of the CDs within the polymer network. The developed ocular platform, termed Ocuflow, simulates physiological tear flow, tear volume, air exposure and mechanical wear. When this system was used to analyze the release of fluconazole from commercial CLs, the drug release was sustained for up to 24 hours. This observation significantly contrasts drug release observed in a vial, which typically follows a burst-plateau profile. When CLs releasing natamycin and fluconazole were tested on agar eye models that were inoculated with Candida albicans, the growth of the yeast was limited by natamycin-containing CLs. The cell morphology of the yeast also differed noticeably based on drug-lens combinations.   Conclusions This thesis details potential strategies to develop novel CLs for antifungal ocular drug delivery. The Ocuflow system developed from this thesis is highly versatile; not only can it be used effectively to measure drug release from CLs, but it can also be applied to other in vitro analyses with CLs

Implementation of Staff Education to Standardize the Use of Positions During the First Stage of Labor

This project aims to educate labor and delivery (L&D) nurses on effective laboring positions that can aid fetal descent during the first stage of labor. In an L&D unit of a south Bay Area County hospital, there is a lack of standardization of knowledge and practices on laboring positions among the nursing staff. Evidence shows that upright positions and frequent mobility are effective in shortening the duration of labor and minimizing unnecessary cesarean deliveries. Based on the evidence, a project was implemented using verbal education of evidence-based laboring positions. An educational handout was also provided along with a recorded video presentation that can be utilized for staff development training. To evaluate the success of the educational training, staff nurses completed a pre-and post-education survey to gauge their confidence level in implementing the laboring positions. Despite the limited timeframe and small pool of participants, the survey results show a significant increase in confidence levels among the nursing staff after receiving the educational training

Efficient Raman converter in the yellow range with high spatial and spectral brightness

International audienceWe present a Raman converter emitting at 583 nm on the second Stokes order of a line of propan-2-ol pumped by a microlaser at 532 nm in the sub-nanosecond regime. We used a mixture of liquids to adapt the transmission band of a photonic bandgap fiber. The internal conversion efficiency is 67% in photon numbers, and the output power is 1.06 mW, corresponding to a maximum peak power of 338 W. The beam delivered by the converter presents a Gaussian spatial structure and a high spectral brightness, typically more than five times higher than supercontinuum sources in this spectral range

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

Bajgrowicz, M., Phan, C.-M., Subbaraman, L. N., & Jones, L. (2015). Release of Ciprofloxacin and Moxifloxacin From Daily Disposable Contact Lenses From an In Vitro Eye Model. Investigative Opthalmology & Visual Science, 56(4), 2234. https://doi.org/10.1167/iovs.15-16379Purpose.: 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

Development of an In Vitro Ocular Platform to Test Contact Lenses

The definitive version of Development of an in Vitro Ocular Platform to Test Contact Lenses was published by Emerald www.emeraldinsight.com in Journal of Visualized Experiments, (110) (2016) https://doi.org/10.3791/53907Currently, in vitro evaluations of contact lenses (CLs) for drug delivery are typically performed in large volume vials,1-6 which fail to mimic physiological tear volumes.7 The traditional model also lacks the natural tear flow component and the blinking reflex, both of which are defining factors of the ocular environment. The development of a novel model is described in this study, which consists of a unique 2-piece design, eyeball and eyelid piece, capable of mimicking physiological tear volume. The models are created from 3-D printed molds (Polytetrafluoroethylene or Teflon molds), which can be used to generate eye models from various polymers, such as polydimethylsiloxane (PDMS) and agar. Further modifications to the eye pieces, such as the integration of an explanted human or animal cornea or human corneal construct, will permit for more complex in vitro ocular studies. A commercial microfluidic syringe pump is integrated with the platform to emulate physiological tear secretion. Air exposure and mechanical wear are achieved using two mechanical actuators, of which one moves the eyelid piece laterally, and the other moves the eyeballeyepiece circularly. The model has been used to evaluate CLs for drug delivery and deposition of tear components on CLs

Insights to Using Contact Lenses for Drug Delivery

Phan, C.-M. (2013). Insights to Using Contact Lenses for Drug Delivery. Clinical & Experimental Pharmacology, 04(01). https://doi.org/10.4172/2161-1459.1000145There 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.NSERC 20/20 Network for the Development of Advanced Ophthalmic Material