Nanomicellar Topical Aqueous Drop Formulation of Rapamycin for Back-of-the-Eye Delivery

Cholkar, Kishore; Gunda, Sriram; Earla, Ravinder; Pal, Dhananjay; Mitra, Ashim K.

doi:10.1208/s12249-014-0244-2

Cited by 80 publications

(39 citation statements)

References 44 publications

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“…The encapsulation efficiency defined as % encapsulation = (L/T) × 100, where L – concentration of drugs in liposome, T – total concentration of drugs in the liposome formulation, was calculated [28]. …”

Section: Methodsmentioning

confidence: 99%

Impediment of selenite-induced cataract in rats by combinatorial drug laden liposomal preparation

Huang

Muhemaitia

2018

Libyan Journal of Medicine

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Cataract is the leading cause of blindness globally with surgery being the only form of treatment. But cataract surgery is accompanied by complications, chiefly intra-ocular infections. Hence, preventive nanoformulations may be extremely beneficial. In the present study, novel chitosan-coated liposomal formulations encapsulating a combination of drugs, lanosterol and hesperetin were prepared and characterized. The combinatorial liposomes were prepared by thin film evaporation active extrusion method. The characterization of liposomes was done by transmission electron microscopy, zeta potential, encapsulation efficiency, stability, cytotoxicity and in vitro release studies. The main difference between the chitosan-coated and uncoated combinatorial liposomes is the release of drugs as indicated by the in vitro release studies. The slow and sustained release of the drugs from chitosan-coated ones as against the burst release from uncoated indicates an increased retention time for combinatorial drugs in cornea. This leads to a delay in progression of cataract as seen from in vivo studies. Cytotoxicity studies indicate no cell toxicity of the coating of chitosan or the combination of drugs. Stability studies indicate that there were almost no changes in size, zeta potential and polydispersity index values of the combinatorial liposomes upon storage at room temperature for 60 days. Another important study is the estimation of antioxidant defense system. The estimated values of glutathione reductase, malondialdehyde and chief antioxidant enzymes point toward an upregulation of antioxidant defense system. From the results, it may be concluded that novel chitosan-coated combinatorial liposomes are effective in delaying or preventing of cataract.

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Section: Methodsmentioning

confidence: 99%

Impediment of selenite-induced cataract in rats by combinatorial drug laden liposomal preparation

Huang

Muhemaitia

2018

Libyan Journal of Medicine

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“…Furthermore, the results of ex vivo fluorescence image and the in vivo tissue distribution study in rabbits also revealed that the amount of fluorescent dye or model drug in the sclera was quite higher than that of other ocular tissues, suggesting that these organic-intercalated LDH nanocomposites might be promising carriers for topical drug delivery to the posterior segment of the eye. 51 …”

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confidence: 99%

Functional intercalated nanocomposites with chitosan-glutathione-glycylsarcosine and layered double hydroxides for topical ocular drug delivery

Xu¹,

Xu²,

Gu³

et al. 2018

IJN

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Background To enhance ocular bioavailability, the traditional strategies have focused on prolonging precorneal retention and improving corneal permeability by nano-carriers with positive charge, thiolated polymer, absorption enhancer and so on. Glycylsarcosine (GS) as an active target ligand of the peptide tranpsporter-1 (PepT-1), could specific interact with the PepT-1 on the cornea and guide the nanoparticles to the treating site. Purpose The objective of the study was to explore the active targeting intercalated nanocomposites based on chitosan-glutathione-glycylsarcosine (CG-GS) and layered double hydroxides (LDH) as novel carriers for the treatment of mid-posterior diseases. Materials and methods CG-GS-LDH intercalated nanocomposites were prepared by the coprecipitation hydrothermal method. In vivo precorneal retention study, ex vivo fluorescence images, in vivo experiment for distribution and irritation were studied in rabbits. The cytotoxicity and cellular uptake were studied in human corneal epithelial primary cells (HCEpiC). Results CG-GS-LDH nanocomposites were prepared successfully and characterized by FTIR and XRD. Experiments with rabbits showed longer precorneal retention and higher distribution of fluorescence probe/model drug. In vitro cytological study, CG-GS-LDH nanocomposites exhibited enhanced cellular uptake compared to pure drug solution. Furthermore, the investigation of cellular uptake mechanisms demonstrated that both the active transport by PepT-1 and clathrin-mediated endocytosis were involved in the internalization of CG-GS-LDH intercalated nanocomposites. An ocular irritation study and a cytotoxicity test indicated that these nanocomposites produced no significant irritant effects. Conclusions The active targeting intercalated nanocomposites could have great potential for topical ocular drug delivery due to the capacity for prolonging the retention on the ocular surface, enhancing the drug permeability through the cornea, and efficiently delivering the drug to the targeted site.

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“…A significantly reduced uptake of [3H]-abacavir in the presence of RX-10045, compared to quinine (a known inhibitor of OCT-1), clearly suggests that RX-10045 is a strong inhibitor/substrate of OCT-1. Knowledge of resolvin interaction with efflux transporters can allow pharmaceutical scientists to develop new strategies and formulations 27,28 to circumvent efflux barrier and deliver therapeutic concentrations of resolvin into target ocular tissues.…”

Section: Discussionmentioning

confidence: 99%

Interaction Studies of Resolvin E1 Analog (RX-10045) with Efflux Transporters

Cholkar

Trinh²,

Vadlapudi³

et al. 2015

Journal of Ocular Pharmacology and Therapeutics

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Purpose: Screening interactions of a resolvin E1 analog (RX-10045) with efflux transporters (P-glycoprotein [P-gp], multidrug resistance-associated protein [MRP2], and breast cancer-resistant protein [BCRP]). Methods: Madin-Darby canine kidney cells transfected with P-gp, MRP2, and BCRP genes were selected for this study.[3H]-Digoxin, [3H]-vinblastine and [3H]-abacavir were selected as model substrates for P-gp, MRP2, and BCRP. Uptake and permeability studies across cell monolayer in both apical to basal (AP-BL) and BL-AP of these substrates were conducted in the presence of specific efflux pump inhibitors and RX-10045. Cell viability studies were conducted with increasing concentrations of RX-10045. Results: Uptake studies showed a higher accumulation in the presence of inhibitors (GF120918 and ketoconazole for P-gp; MK571 for MRP2; and b-estradiol for BCRP) as well as RX-10045. Similarly, dose-dependent inhibition studies demonstrated higher accumulation of various substrates ([3H]-digoxin, [3H]-vinblastine, and [3H]-abacavir) in the presence of RX-10045. IC 50 values of dose-dependent inhibition of RX-10045 for P-gp, MRP2, and BCRP were 239 -11.2, 291 -79.2, and 300 -42 mM, respectively. Cell viability assay indicated no apparent toxicity up to 350 mM concentration. Enhanced permeability for model substrates was observed in the presence of RX-10045. Uptake studies in human corneal epithelial cells suggest that RX-10045 is a strong inhibitor of organic cation transporter-1 (OCT-1). Conclusions: In summary, the resolvin analog (RX-10045) was identified as a substrate/inhibitor for efflux transporters (MRP2 and BCRP). Also, RX-10045 appears to be a strong inhibitor/substrate of OCT-1. Novel formulation strategies such as nanoparticles, nanomicelles, and liposomes for circumventing efflux barriers and delivering higher drug concentrations leading to a higher therapeutic efficacy may be employed.

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Nanomicellar Topical Aqueous Drop Formulation of Rapamycin for Back-of-the-Eye Delivery

Cited by 80 publications

References 44 publications

Impediment of selenite-induced cataract in rats by combinatorial drug laden liposomal preparation

Impediment of selenite-induced cataract in rats by combinatorial drug laden liposomal preparation

Functional intercalated nanocomposites with chitosan-glutathione-glycylsarcosine and layered double hydroxides for topical ocular drug delivery

Interaction Studies of Resolvin E1 Analog (RX-10045) with Efflux Transporters

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