Goutham R. Adelli

Indomethacin-Loaded Solid Lipid Nanoparticles for Ocular Delivery: Development, Characterization, and In Vitro Evaluation

PURPOSE The goal of this study was to develop and characterize indomethacin-loaded solid lipid nanoparticles (IN-SLNs; 0.1% w/v) for ocular delivery. METHODS Various lipids, homogenization pressures/cycles, Tween 80 fraction in the mixture of surfactants (Poloxamer 188 and Tween 80; total surfactant concentration at 1% w/v), and pH were investigated in the preparation of the IN-SLNs. Compritol(®) 888 ATO was selected as the lipid phase for the IN-SLNs, as indomethacin exhibited a highest distribution coefficient and solubility in this phase. RESULTS Homogenization at 15,000 psi for 6 cycles resulted in the smallest particle size. Increase in the Poloxamer 188 fraction resulted in decrease in the entrapment efficiency (EE). The mean particle size, polydispersity index, zeta-potential, and EE of the optimized formulation were 140 nm, 0.16, -21 mV, and 72.0%, respectively. IN-SLNs were physically stable post-sterilization and on storage for a period of 1 month (last timepoint tested). A dramatic increase in the chemical stability and in vitro corneal permeability of indomethacin was observed with the IN-SLN formulation in comparison to the indomethacin solution- (0.1% w/v) and indomethacin hydroxypropyl-beta-cyclodextrin-based formulations (0.1% w/v). CONCLUSION Results from this study suggest that topical IN-SLNs could significantly improve ocular bioavailability of indomethacin.

Topical ophthalmic lipid nanoparticle formulations (SLN, NLC) of indomethacin for delivery to the posterior segment ocular tissues

PURPOSE The objective of the present study was to formulate indomethacin (IN)-loaded solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) and to investigate their potential use in topical ocular delivery. METHODS IN SLNs (0.1% w/v) and NLCs (0.8% w/v) were prepared, characterized and evaluated. Their in vitro release and flux profiles across the cornea and sclera-choroid-RPE (trans-SCR) tissues and in vivo ocular tissue distribution were assessed. Furthermore, chitosan chloride (CS) (mol. wt.<200kDa), a cationic and water-soluble penetration enhancer, was used to modify the surface of the SLNs, and its effect was investigated through in vitro transmembrane penetration and in vivo distribution tissue studies. RESULTS For the IN-SLNs, IN-CS-SLNs and IN-NLCs, the particle size was 226±5, 265±8, and 227±11nm, respectively; the zeta potential was -22±0.8, 27±1.2, and -12.2±2.3mV, respectively; the polydispersity index (PDI) was 0.17, 0.30, and 0.23, respectively; and the entrapment efficiency (EE) was 81±0.9, 91.5±3.2 and 99.8±0.2%, respectively. The surface modification of the SLNs with CS increased the ocular penetration of IN. The NLCs maintained significantly higher IN concentrations in all ocular tissues tested compared to the other formulations evaluated in vivo. CONCLUSION The results suggest that lipid-based particulate systems can serve as viable vehicles for ocular delivery. The NLC formulations demonstrated increased drug loading capability, entrapment and delivery to anterior and posterior segment ocular tissues.

Evaluation of topical hesperetin matrix film for back-of-the-eye delivery

PURPOSE The goal of the present study was to develop a poly (ethylene oxide) N10 (PEO N10) based melt-cast matrix system for efficient and prolonged delivery of hesperetin (HT), a promising bioflavonoid, to the posterior segment of the eye through the topical route. METHODS HT film was prepared by melt-cast method using PEO N10 and cut into 4mm×2mm segments, each weighing 8mg. This film was evaluated with respect to in vitro release rates and also transmembrane delivery across Spectra/Por® membrane (MWCO: 10,000 Daltons) and isolated rabbit corneas. Ocular tissue concentrations were also determined postapplication of the film in ex vivo and in vivo models. RESULTS HT release from the film was determined to be about 95.3% within 2h. In vitro transcorneal flux was observed to be 0.58±0.05μg/min/cm(2) across the isolated rabbit cornea. High levels of HT were detected in the retina-choroid (RC) and vitreous humor (VH) in the ex vivo model following topical application of the film. Significant levels of HT were observed in both anterior and posterior segment ocular tissues 1h post topical application of the 10 and 20%w/w HT films on the rabbit eye. Moreover, HT was detected in the VH and RC even after 6h following topical application of the film in vivo. CONCLUSION The results from this study suggest that the melt-cast films can serve as a viable platform for sustained topical delivery of bioflavonoids, and other therapeutic agents, into the back-of-the eye tissues.

Ocular Disposition of the Hemiglutarate Ester Prodrug of ∆ 9 -Tetrahydrocannabinol from Various Ophthalmic Formulations

PurposeThe overall goal of this project is to enhance ocular delivery of ∆9-Tetrahydrocannabinol (THC) through the topical route.MethodsSolubility, stability and in vitro transcorneal permeability of the relatively hydrophilic hemiglutarate ester derivative, THC-HG, was studied in the presence of surfactants. The solutions were characterized with respect to micelle size, zeta potential and solution viscosity. In vivo studies were carried out in New Zealand albino rabbits. A previously reported promising THC-HG ion-pair formulation was also studied in vivo.ResultsAqueous solubility and stability and in vitro transcorneal permeability of THC-HG was enhanced significantly in the presence of surfactants. THC levels in the ocular tissues (except cornea) were found to be below detection limits from mineral oil, surfactant or emulsion based formulations containing THC. In contrast, micellar and ion pair based THC-HG formulations produced significantly higher total THC concentrations in the anterior ocular chamber.ConclusionIn this study, although delivery of THC to the anterior chamber ocular tissues could be significantly increased through the prodrug and formulation approaches tested, further studies are needed to increase penetration to the back-of-the eye.

Ocular Disposition of Ciprofloxacin from Topical, PEGylated Nanostructured Lipid Carriers: Effect of Molecular Weight and Density of Poly (ethylene) glycol

Ciprofloxacin (CIP) is an antibacterial agent prescribed for the treatment of ocular infections. The objective of the present project is to investigate the effect of surface PEG functionalization of the Nano structured lipid carriers (NLCs) on formulation stability, ocular penetration and distribution. CIP NLCs were tested with different molecular weight (poly ethylene glycol) PEGs ranging from (2K to 20K) grafted onto the phospholipid and with different chain lengths (14-18 carbons) of phospholipids derivatized with PEG-2K. Drug load in the formulations was maintained at 0.3%w/v. Formulations prepared were evaluated with respect to in vitro release, transcorneal permeation, autoclavability, morphological characteristics and in vivo ocular tissue distribution. Scanning Transmission electron microscopy (STEM) studies revealed that the PEG-CIP-NLCs were spherical in shape. Transcorneal penetration of CIP was optimum with PEG molecular weight in between 2K-10K. Carbon chain length of the phospholipid, however, did not affect transcorneal penetration of CIP. In vivo ocular tissue CIP concentrations attained from the various formulations was consistent with the in vitro data obtained. The results suggest that surface functionalization of PEGs, within a specified range of molecular weight and surface packing density, significantly enhance trans-ocular penetration and impart sterilization-stabilization characteristics into the formulations.

Diclofenac sodium ion exchange resin complex loaded melt cast films for sustained release ocular delivery

Abstract Purpose: The goal of the present study is to develop polymeric matrix films loaded with a combination of free diclofenac sodium (DFSfree) and DFS:Ion exchange resin complexes (DFS:IR) for immediate and sustained release profiles, respectively. Methods: Effect of ratio of DFS and IR on the DFS:IR complexation efficiency was studied using batch processing. DFS:IR complex, DFSfree, or a combination of DFSfree + DFS:IR loaded matrix films were prepared by melt-cast technology. DFS content was 20% w/w in these matrix films. In vitro transcorneal permeability from the film formulations were compared against DFS solution, using a side-by-side diffusion apparatus, over a 6 h period. Ocular disposition of DFS from the solution, films and corresponding suspensions were evaluated in conscious New Zealand albino rabbits, 4 h and 8 h post-topical administration. All in vivo studies were carried out as per the University of Mississippi IACUC approved protocol. Results: Complexation efficiency of DFS:IR was found to be 99% with a 1:1 ratio of DFS:IR. DFS release from DFS:IR suspension and the film were best-fit to a Higuchi model. In vitro transcorneal flux with the DFSfree + DFS:IR(1:1)(1 + 1) was twice that of only DFS:IR(1:1) film. In vivo, DFS solution and DFS:IR(1:1) suspension formulations were not able to maintain therapeutic DFS levels in the aqueous humor (AH). Both DFSfree and DFSfree + DFS:IR(1:1)(3 + 1) loaded matrix films were able to achieve and maintain high DFS concentrations in the AH, but elimination of DFS from the ocular tissues was much faster with the DFSfree formulation. Conclusion: DFSfree + DFS:IR combination loaded matrix films were able to deliver and maintain therapeutic DFS concentrations in the anterior ocular chamber for up to 8 h. Thus, free drug/IR complex loaded matrix films could be a potential topical ocular delivery platform for achieving immediate and sustained release characteristics.

Development of a Δ9-Tetrahydrocannabinol Amino Acid-Dicarboxylate Prodrug With Improved Ocular Bioavailability.

Purpose The aim of the present study was to evaluate the utility of the relatively hydrophilic Δ9-tetrahydrocannabinol (THC) prodrugs, mono and di-valine esters (THC-Val and THC-Val-Val) and the amino acid (valine)-dicarboxylic acid (hemisuccinate) ester (THC-Val-HS), with respect to ocular penetration and intraocular pressure (IOP) lowering activity. THC, timolol, and pilocarpine eye drops were used as controls. Methods THC-Val, THC-Val-Val, and THC-Val-HS were synthesized and chemically characterized. Aqueous solubility and in vitro transcorneal permeability of THC and the prodrugs, in the presence of various surfactants and cyclodextrins, were determined. Two formulations were evaluated for therapeutic activity in the α-chymotrypsin induced rabbit glaucoma model, and the results were compared against controls comprising of THC emulsion and marketed timolol maleate and pilocarpine eye drops. Results THC-Val-HS demonstrated markedly improved solubility (96-fold) and in vitro permeability compared to THC. Selected formulations containing THC-Val-HS effectively delivered THC to the anterior segment ocular tissues in the anesthetized rabbits: 62.1 ng/100 μL of aqueous humor (AH) and 51.4 ng/50 mg of iris ciliary bodies (IC) (total THC). The duration and extent of IOP lowering induced by THC-Val-HS was 1 hour longer and 10% greater, respectively, than that obtained with THC and was comparable with the pilocarpine eye drops. Timolol ophthalmic drops, however, exhibited a longer duration of activity. Both THC and THC-Val-HS were detected in the ocular tissues following multiple dosing of THC-Val-HS in conscious animals. The concentration of THC in the iris-ciliary bodies at the 60- and 120-minute time points (53 and 57.4 ng/50 mg) were significantly greater than that of THC-Val-HS (24.2 and 11.3 ng/50 mg). Moreover, at the two time points studied, the concentration of THC was observed to increase or stay relatively constant, whereas THC-Val-HS concentration decreased by at least 50%. A similar trend was observed in the retina-choroid tissues. Conclusions A combination of prodrug derivatization and formulation development approaches significantly improved the penetration of THC into the anterior segment of the eye following topical application. Enhanced ocular penetration resulted in significantly improved IOP-lowering activity.

Controlled release tablet formulation containing natural Δ9-tetrahydrocannabinol

Abstract Cannabinoids are increasingly being used in the treatment of chemotherapy-induced nausea and vomiting (CINV) because of their action on the cannabinoid receptors, CB1 and CB2. The currently marketed capsule formulations (sesame oil based and crystalline powder) are required to be administered frequently to maintain therapeutic levels, which leads to non-compliance. In the present study, oral controlled release tablet formulations of Δ9-tetrahydrocannabinol (THC) were prepared using the lipids Precirol® and Compritol®. Release profiles using THC-lipid matrices and/or with the lipids in the external phase (blend) were evaluated. The effect of directly compressible diluents lactose mixture (Ludipress®), dicalcium phosphate anhydrous (Emcompress®) and microcrystalline cellulose (Avicel® 102) on tablet characteristics and in vitro drug release was also investigated. Further, in vitro THC release in the presence of a lipase inhibitor, Pluronic® F68, was also studied. A 24 h zero-order THC release profile was obtained with a combination of Precirol® and Compritol® in the compression blend. Addition of Pluronic® F68 did not alter THC release in vitro. These optimized tablets were chemically and physically stable for 3 months, the last time point tested, at 25 °C/60% RH. The overall results demonstrate the feasibility of preparing oral THC tablets for once a day administration which can improve CINV management.

Chapter 78 – Ocular Delivery of Tetrahydrocannabinol

In recent years, discovery of the cannabinoid receptors in the ocular tissues has opened up the possible utility of tetrahydrocannabinol (THC) and other cannabinoids in the management of several ocular diseases and conditions. The biopharmaceutical characteristics of THC, however, do not favor transmembrane diffusion. Additional physiological barriers, atypical of ocular drug delivery, makes THC delivery to the ocular tissues through the topical route even more challenging. Thus, careful formulation design and consideration is needed to translate the potential of THC into the preclinical and clinical settings. This chapter reviews some of the ocular conditions that can be impacted by THC, and the barriers to its delivery through the topical route. Strategies to improve ocular penetration of THC have also been discussed.