Transfersome Hydrogel Containing 5-Fluorouracil and Etodolac Combination for Synergistic Oral Cancer Treatment.

Oral cancer is one of the most common malignancies with an increased rate of incidence. 5-Fluorouracil (5FU) is an effective chemotherapeutic indicated for oral cancer treatment. Etodolac (Et), a cyclooxygenase-2 inhibitor, can be used as an adjuvant agent to sensitize cancer cells to chemotherapy. The aim of this work was to prepare and characterize 5FU and Et dual drug-loaded transfersomes to treat oral cancer. Transfersomes were prepared by thin-film hydration method and characterized for the average particle size and zeta-potential using dynamic light scattering and scanning electron microscopy techniques. The prepared transfersomes were further characterized for their drug loading, entrapment efficiencies using amicon centrifuge tubes and drug release behavior using cellulose membrane. The synergistic activity of dual drug-loaded transfersomes was studied in FaDu oral cancer cells. Results showed that the average particle size, polydispersity index, and zeta potential were 91±6.4 nm, 0.28±0.03, and (-)46.9±9.5 mV, respectively, for 5FU- and Et (1:1)-loaded transfersomes. The highest encapsulation efficiency achieved was 36.9±3.8% and 79.8±6.4% for 5FU and Et (1:1), respectively. Growth inhibition studies in FaDu cells using different concentrations of 5FU and Et showed a combination index of 0.36, indicating a synergistic effect. The FaDu cell uptake of drug-loaded transfersomes was significantly (p<0.05) greater than that of free drugs. The transfersome hydrogel made of HPMC (2% w/w) showed similar flux, lag time, and permeation coefficient as that of drug-loaded transfersomes across excised porcine buccal tissue. In conclusion, 5FU and Et transfersome hydrogel can be developed for localized delivery to treat oral cancer.

Microneedle ocular patch: fabrication, characterization, and ex-vivo evaluation using pilocarpine as model drug.

Context: Enhacing the ocular bioavailability of drugs after their topical application is a challenge.Objective: The objective of the study was to design, fabricate, and investigate the effectiveness of microneedle ocular patch (MOP) in delivering the model drug, pilocarpine HCl across the corneal membrane.Methods: MOP mimicked commercially available contact lens design elements having a diameter of 14.20 mm and a sagittal height of 3.85 mm with a convex curvature. The base of this patch contained an array of 25 pyramid-shaped microneedles measuring 521 ± 10 µm in length. Pilocarpine loaded MOP was prepared by micromolding technique using dissolvable polyvinyl alcohol and polyvinyl pyrrolidone matrix. MOP was characterized for physical and mechanical properties using a stereomicroscope, scanning electron microscope, and texture analyzer.Results: Histological examination after MOP application on excised human cornea showed penetration of microneedles with a required insertional force of 1.04 ± 0.17 N. Flux of pilocarpine across excised cornea was significantly (p < 0.05) greater after application of MOP (704 ± 149 µg/cm2/h) compared with solution formulation (188 ± 24 µg/cm2/h). Ex-vivo pilocarpine permeation study in porcine eye globe revealed significantly (p < 0.05) greater availability in aqueous humor within 30 min of application of MOP (249 ± 85 µg/ml) compared with solution formulation (46 ± 9 µg/ml).Conclusion: MOP can be developed as a potential ophthalmic drug delivery system.

Dissolvable Microneedle-Mediated Transcutaneous Delivery of Tetanus Toxoid Elicits Effective Immune Response.

Transcutaneous immunization using a microneedle device presents a promising alternative to syringe-based injection of vaccines. The aim of this study was to investigate the effective immune response elicited after application of tetanus toxoid antigen-loaded dissolvable microneedles (TT-MN) in mice model. Dissolvable microneedles were prepared using 20% w/v of polyvinyl alcohol and polyvinyl pyrrolidone polymer mixture by micromolding technique. TT-MN were prepared by addition of tetanus toxoid to polymer mixture before casting microneedles. TT-MN were characterized using texture analyzer, stereomicroscope, and scanning electron microscope. Tetanus toxoid loading was found to be 77 ± 2 µg per microneedle array. Confocal microscopic analysis showed that the microneedles penetrated to a depth of 130 µm inside mouse skin. Complete dissolution of microneedles was achieved within 1 h after insertion in skin. Immunization studies in Swiss albino mice demonstrated significantly (p < 0.001) greater IgG, IgG1, and IgG2a antibody titers for TT-MN and intramuscular injection groups compared with naïve control. Splenocyte proliferation assay confirmed effective re-stimulation on exposure to tetanus toxoid in microneedle treatment groups. Taken together, TT-MN can be developed as minimally invasive system for transcutaneous delivery of tetanus toxoid antigen.

Microneedle scleral patch for minimally invasive delivery of triamcinolone to the posterior segment of eye.

The delivery of therapeutics to the posterior segment of the eye is achieved by invasive procedures, including intravitreal injections and implants. The topically applied formulations would not permeate through different tissue barriers of the eye to reach the posterior segment. Here, we demonstrate the effectiveness of microneedle scleral patch in delivering the model molecule, triamcinolone acetonide, to the posterior segment of the eye. Microneedle scleral patch (MSP) and microneedle corneal patch (MCP) were fabricated through the micromolding technique using rapidly dissolvable polyvinylpyrrolidone. The patches containing 25 microneedles were characterized for physical and mechanical properties, drug loading and release behavior in vitro and ex vivo porcine eye globe model. The distribution of TA administered using MSP and MCP in different ocular tissues was evaluated in the rabbit eye model. The results showed that microneedles with 545 ± 8 µm length and 279 ± 26 µm width at the base in MSP penetrate the scleral membrane with the application of 0.35 ± 0.06 N force. The needles dissolved within 60 s after insertion in the corneal and scleral tissue. The 5 min application of MSP showed a significantly (p < 0.05) greater TA disposition in the vitreous humor and choroid-retinal complex in excised porcine eye globe compared with MCP and TA nanosuspension eye drops. In rabbit model studies, the TA concentration was greatest in the choroid-retinal complex and sclera after administration through intravitreal injection and MSP, respectively. The TA disposition in the sclera was significantly (p < 0.05) greater after MSP application compared with intravitreal injection and MCP application for up to 24 h. MSP application provided a greater safety score compared with intravitreal injection. In conclusion, MSP can be developed as a minimally invasive drug delivery system to target the posterior segment of the eye.

Novel drug delivery methods for the treatment of keratitis: moving away from surgical intervention.

Introduction: Corneal ulceration is one of the leading causes of blindness especially in low- and mid-income countries (LMICs). Surgical treatment of microbial keratitis is associated with multiple challenges that include non-availability of donor corneal tissues, lack of trained corneal surgeons, and poor compliance to follow up care. As a result, the surgery fails in 70-90% cases. Therefore, improving outcome of medical treatment and thereby avoiding the need for the surgery is an unmet need in the care of corneal ulcer cases.Areas covered: In this review article, the authors have tried to compile information on the novel drug-delivery systems that have potential to enhance success of medical management. We have discussed the following systems: cyclodextrins, gel formulations, colloidal system, nanoformulations, drug-eluting contact lens, microneedle patch, and ocular inserts.Expert opinion: The goals of corneal ulcer treatment are as follows: rapid eradication of causative microorganisms, control of damage from induced inflammation and microbial toxins, and facilitation of repair. The ocular surface anatomy poses several challenges for drug delivery using standard topical therapy. The novel drug-delivery systems mentioned above aim to enhanced tear solubility; superior stability; improved bio-availability; reduced toxicity; besides facilitating targeted drug delivery and convenience of administration.

Amphotericin B containing microneedle ocular patch for effective treatment of fungal keratitis.

Topical application of poorly water-soluble antibiotics cannot achieve the desired therapeutic concentration within cornea. The purpose of this study was to fabricate, characterize and evaluate in-vivo effectiveness of amphotericin B (AmB) containing microneedle ocular patch (MOP) against fungal keratitis. MOP containing free or liposomal AmB was fabricated using micromolding technique to mimic contact lens. MOPs were prepared using dissolvable polymeric matrix including polyvinyl alcohol and polyvinyl pyrrolidone. AmB loaded MOP were studied for their physical and mechanical properties, drug loading and dissolution rate, corneal insertion and drug permeability. MOP loaded with 100 µg AmB had a compression strength of 35.1 ±â€¯6.7 N and required an insertional force of 1.07 ±â€¯0.17 N in excised human cornea. Ex-vivo corneal permeation studies revealed significant enhancement in AmB corneal retention with the application of MOP compared with free AmB or liposomal AmB application. Furthermore, AmB loaded MOP application significantly (P < 0.05) reduced the Candida albicans load within cornea as evaluated in both ex-vivo model and in-vivo rabbit infection model. Histological examination showed that AmB MOP treatment improved the epithelial and stromal differentiation of corneal membrane. AmB containing MOPs can be developed as minimally invasive corneal delivery device for effective treatment of fungal keratitis.