Formulation and In Vitro-Ex vivo Evaluation of Cannabidiol and Cannabidiol-Valine-Hemisuccinate Loaded Lipid-Based Nanoformulations for Ocular Applications.

The goal of this investigation is to develop stable ophthalmic nanoformulations containing cannabidiol (CBD) and its analog cannabidiol-valine-hemisuccinate (CBD-VHS) for improved ocular delivery. Two nanoformulations, nanoemulsion (NE) and nanomicelles (NMC), were developed and evaluated for physicochemical characteristics, drug-excipient compatibility, sterilization, thermal analysis, surface morphology, ex-vivo transcorneal permeation, corneal deposition, and stability. The saturation solubility studies revealed that among the surfactants tested, Cremophor EL had the highest solubilizing capacity for CBD (23.3 ± 0.1 mg/mL) and CBD-VHS (11.2 ± 0.2 mg/mL). The globule size for the lead CBD formulations (NE and NMC) ranged between 205 and 270 nm while CBD-VHS-NMC formulation had a particle size of about 78 nm. The sterilized formulations, except for CBD-VHS-NMC at 40 °C, were stable for three months of storage (last time point tested). Release, in terms of CBD, in the in-vitro release/diffusion studies over 18 h, were faster from the CBD-VHS nanomicelles (38 %) compared to that from the CBD nanoemulsion (16 %) and nanomicelles (33 %). Transcorneal permeation studies revealed improvement in CBD permeability and flux with both formulations; however, a greater improvement was observed with the NMC formulation compared to the NE formulation. In conclusion, the nanoformulations prepared could serve as efficient topical ocular drug delivery platforms for CBD and its analog.

Improved Topical Ophthalmic Natamycin Suspension for the Treatment of Fungal Keratitis.

Purpose: Natamycin (NT) is used as a first-line antifungal prescription in the treatment of fungal keratitis (FK) and is commercially available as a 5% w/v ophthalmic suspension. NT shows poor water solubility and light sensitivity. Thus, the present investigation is aimed to enhance the fraction of NT in solution in the commercial formulation by adding cyclodextrins (CDs), thereby improving the delivery of the drug into deeper ocular tissues. Methods: The solubility of NT in different CDs, the impact of ultraviolet (UV) light exposure, stability at 4°C and 25°C, in vitro release, and ex vivo transcorneal permeation studies were performed. Results: NT exhibited the highest solubility (66-fold) in randomly methylated-ß-cyclodextrin (RM-ßCD) with hydroxypropyl-ßCD (HP-ßCD) showing the next highest solubility (54-fold) increase in comparison to market formulation Natacyn® as control. The stability of NT-CD solutions was monitored for 2 months (last-time point) at both storage conditions. The degradation profile of NT in NT-RM-ßCD and NT-HP-ßCD solutions under UV-light exposure followed first-order kinetics exhibiting half-lives of 1.2 h and 1.4 h, respectively, an almost 3-fold increase over the control solutions. In vitro release/diffusion studies revealed that suspensions containing RM-ßCD and HP-ßCD increased transmembrane flux significantly (3.1-fold) compared to the control group. The transcorneal permeability of NT from NT-RM-ßCD suspension exhibited an 8.5-fold (P < 0.05) improvement compared to Natacyn eyedrops. Furthermore, the addition of RM-ßCD to NT suspension increases the solubilized fraction of NT and enhances transcorneal permeability. Conclusion: Therefore, NT-RM-ßCD formulations could potentially lead to a decreased frequency of administration and significantly improved therapeutic outcomes in FK treatment.

Gatifloxacin Loaded Nano Lipid Carriers for the Management of Bacterial Conjunctivitis.

Bacterial conjunctivitis (BC) entails inflammation of the ocular mucous membrane. Early effective treatment of BC can prevent the spread of the infection to the intraocular tissues, which could lead to bacterial endophthalmitis or serious visual disability. In 2003, gatifloxacin (GTX) eyedrops were introduced as a new broad-spectrum fluoroquinolone to treat BC. Subsequently, GTX use was extended to other ocular bacterial infections. However, due to precorneal loss and poor ocular bioavailability, frequent administration of the commercial eyedrops is necessary, leading to poor patient compliance. Thus, the goal of the current investigation was to formulate GTX in a lipid-based drug delivery system to overcome the challenges with the existing marketed eyedrops and, thus, improve the management of bacterial conjunctivitis. GTX-NLCs and SLNs were formulated with a hot homogenization-probe sonication method. The lead GTX-NLC formulation was characterized and assessed for in vitro drug release, antimicrobial efficacy (against methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa), and ex vivo permeation. The lead formulation exhibited desired physicochemical characteristics, an extended release of GTX over a 12 h period, and was stable over three months at the three storage conditions (refrigerated, room temperature, and accelerated). The transcorneal flux and permeability of GTX from the GTX-NLC formulation were 5.5- and 6.0-fold higher in comparison to the commercial eyedrops and exhibited a similar in vitro antibacterial activity. Therefore, GTX-NLCs could serve as an alternative drug delivery platform to improve treatment outcomes in BC.

Design of Topical Moxifloxacin Mucoadhesive Nanoemulsion for the Management of Ocular Bacterial Infections.

Ocular bacterial infections can lead to serious visual disability without proper treatment. Moxifloxacin (MOX) has been approved by the US Food and Drug Administration as a monotherapy for ocular bacterial infections and is available commercially as an ophthalmic solution (0.5% w/v). However, precorneal retention, drainage, and low bioavailability remain the foremost challenges associated with current commercial eyedrops. With this study, we aimed to design a MOX-loaded nanoemulsion (NE; MOX-NE) with mucoadhesive agents (MOX-NEM) to sustain MOX release, as well as to overcome the potential drawbacks of the current commercial ophthalmic formulation. MOX-NE and MOX-NEM formulations were prepared by hot homogenization coupled with probe sonication technique and subsequently characterized. The lead formulations were further evaluated for in vitro release, ex vivo transcorneal permeation, sterilization, and antimicrobial efficacy studies. Commercial MOX ophthalmic solution was used as a control. The lead formulations showed the desired physicochemical properties and viscosity. All lead formulations showed sustained release profiles a period of more than 12 h. Filtered and autoclaved lead formulations were stable for one month (the last time point tested) under refrigeration and at room temperature. Ex vivo transcorneal permeation studies revealed a 2.1-fold improvement in MOX permeation of the lead MOX-NE formulation compared with Vigamox® eyedrops. However, MOX-NEM formulations showed similar flux and permeability coefficients to those of Vigamox® eyedrops. The lead formulations showed similar in vitro antibacterial activity as the commercial eyedrops and crude drug solution. Therefore, MOX-NE and MOX-NEM formulations could serve as effective delivery vehicles for MOX and could improve treatment outcomes in different ocular bacterial infections.

CONTINUOUS PRODUCTION OF RALOXIFENE HYDROCHLORIDE LOADED NANOSTRUCTURED LIPID CARRIERS USING HOT-MELT EXTRUSION TECHNOLOGY.

The aim of this study was to utilize a continuous process for the production of orally administered raloxifene hydrochloride (RX-HCl) loaded nanostructured lipid carrier (NLC) formulations for extended drug release using hot-melt extrusion (HME) technology coupled with probe sonication, and also to evaluate the in vitro characteristics of the prepared NLCs. Preparation of the NLCs using HME technology involved two main steps, first formation of a pre-emulsion after extrusion and then size reduction of the pre-emulsion using probe sonication to obtain the NLCs. A screw speed of 100 rpm and a barrel temperature of 85 °C, were used in the extrusion process. NLCs prepared by HME technology showed a lower particle size compared to those prepared by the conventional probe sonication method. The prepared NLCs had high entrapment efficiency values (>90 %). In vitro drug release was evaluated using dialysis bag diffusion technique and USP apparatus I. Overall, the RX-HCl loaded NLCs had a higher rate of drug release than the pure drug. The release profile for the F4-3 NLC formulations and pure drug at the beginning and end of the stability study were comparable. The particle size of the prepared NLCs remained stable over the storage period and all PDI and zeta potential values were ≤ 0.5 and in the range of -15 to -30 mV, respectively, indicating good physical stability of the formulations. In summary, HME technology and probe sonication were successfully used to prepare RX-HCl loaded NLC formulations with shorter processing times as compared to the conventional probe sonication method, which makes this technique a uniquely more industry-friendly method.