Ultrasound-Enhanced Delivery of Antibiotics and Anti-Inflammatory Drugs Into the Eye

Abstract

Delivery of sufficient amounts of therapeutic drugs into the eye is often a challenging task. In this study, ultrasound application (frequencies of 400 KHz to 1 MHz, intensities of 0.3–1.0 W/cm2 and exposure duration of 5 min) was investigated to overcome the barrier properties of cornea, which is a typical route for topical administration of ophthalmic drugs. Permeability of ophthalmic drugs, tobramycin and dexamethasone and sodium fluorescein, a drug-mimicking compound, was studied in ultrasound- and sham-treated rabbit corneas in vitro using a standard diffusion cell setup. Light microscopy observations were used to determine ultrasound-induced structural changes in the cornea. For tobramycin, an increase in permeability for ultrasound- and sham-treated corneas was not statistically significant. Increase of 46%–126% and 32%–109% in corneal permeability was observed for sodium fluorescein and dexamethasone, respectively, with statistical significance (p < 0.05) achieved at all treatment parameter combinations (compared with sham treatments) except for 1-MHz ultrasound applications for dexamethasone experiments. This permeability increase was highest at 400 kHz and appeared to be higher at higher intensities applied. Histologic analysis showed structural changes that were limited to epithelial layers of cornea. In summary, ultrasound application provided enhancement of drug delivery, increasing the permeability of the cornea for the anti-inflammatory ocular drug dexamethasone. Future investigations are needed to determine the effectiveness and safety of this application in in vivo long-term survival studies. (E-mail: mnabili@gwu.edu)

Model for Porosity Changes Occurring during Ultrasound-Enhanced Transcorneal Drug Delivery

“…In these experiments, an ultrasound transducer operating at 880 kHz, with intensities between 0.19 W/cm 2 and 0.56 W/cm 2 was employed. Ultrasound application in vitro at frequencies of 400 kHz-1 MHz, intensities of 0.3–1.0 W/cm 2 , and exposure duration of 5 min resulted in an increase in corneal permeability of 32–47% for Tobramycin, 46–126% for sodium fluorescein, and 32–109% for dexamethasone sodium phosphate (Nabili et al 2013). In an in vivo study, ultrasound application at frequencies of 400 kHz and 600 kHz caused an increase in drug concentration in aqueous humor samples of 2.8 times (for 400 kHz) and 2.4 times (600 kHz), as compared to sham treated samples (Nabili et al 2014).…”

Ultrasound-mediated ocular delivery of therapeutic agents: a review

“…While the majority of studies were once based on CWUS, findings on the mechanistic effects of US-mediated ocular drug delivery reoriented treatment strategy. Indeed, a large number of studies have associated drug delivery efficacy with cavitation [4,6,10,45,70]. This was confirmed with studies using low duty cycles and high pressure amplitudes.…”

“…These changes are likely related to cavitation [70,72] and could potentially explain the enhancement of drug delivery. Indeed, the corneal epithelium is the first strong lipophilic barrier of the cornea, and most of the drugs or molecules used were hydrophilic.…”

“…As it induces slight damage, cavitation events need to be well-characterized in terms of intensity (cavitation index) and exposure time. Then, a parallel should be drawn between these indicators and a scale of biological damage, such as the one used in [70]. Monitoring of cavitation and control over induced reversible damages while providing efficient delivery is a major challenge for applying this technique in the clinic.…”

Ultrasound applications to medicine part i: physical principles.

“…applications are not limited only to medical diagnosis [40], but also extends to therapeutic applications [41] [42] [43], such as the U.S. low frequency (20 to 100 kHz) used in treatment of chronic rhino sinusitis [44] in sonoforesis (transdermal drug emission U.S.), dental [45] [46], ocular surgery [47], body contouring, kidney stone disruption and removal of blood clots) as well in ultrasonic drugs [48]; U.S. use in drug delivery has been spreading in the fields of cardiology and oncology for a variety of therapeutic agents such as small drug molecules, biological products and nucleic acid [49] [50]. Not to mention U.S. promising techniques or high-intensity focused (HIFU) to treat cancerous tumors allow full and non-invasive [51], psoriasis [52], dermatology [53], vascular procedures [54], among others.…”