Shihui Yu

A novel pH-induced thermosensitive hydrogel composed of carboxymethyl chitosan and poloxamer cross-linked by glutaraldehyde for ophthalmic drug delivery

In this work, a stimuli-responsive three dimensional cross-linked hydrogel system containing carboxymethyl chitosan (CMC) and poloxamer composed of a poly (ethylene oxide)/poly (propylene oxide)/poly (ethylene oxide) (PEO-PPO-PEO) block copolymer was constructed, and its aqueous solution was found to undergo a reversible sol-gel transition upon a temperature and/or pH change at a very low concentration. The hydrogels were synthesized via a cross-linking reaction using glutaraldehyde (GA) as the cross-linking agent. The structures of the hydrogels were characterized by FTIR, XRD, NMR and SEM studies and the swelling behaviour was studied in different buffered solutions. The results obtained indicated that cross-linked F127-CMC underwent discontinuous phase transition in different temperature and pH solutions. The hydrogels at 35°C and pH 7.4 were found to have larger pores than at the other three conditions which resulted in greater swelling. The result of rheological studies showed that the gelation temperature was 32-33°C and the viscosity of the hydrogel increased quickly after gelation. In an addition, the cytotoxicity and in vitro release was studied at different pH values and temperature. The results of a CCK-8 (Cell Counting Kit-8) assay showed that the hydrogel and its physical mixture solution were not cytotoxic to human corneal epithelial cells at a low concentration. Using the drug nepafenac (NP) as a model drug, the controlled drug release behaviour of these hydrogels was investigated. Owing to the formation of F127-CMC/NP retarding the diffusion rate of NP, a sustained release of NP from the hydrogel can be obtained. The release rate was found to be maximum at 35°C and pH 7.4. From these preliminary evaluations, it is possible to conclude that the hydrogels have an excellent potential for application in ophthalmic drug delivery systems.

Liposome incorporated ion sensitive in situ gels for opthalmic delivery of timolol maleate

This study was aimed to design a liposomal based ion-sensitive in situ ophthalmic delivery system of timolol maleate (TM). The TM liposome was produced by the reverse evaporation technique coupled with pH-gradients method (REVPR), and then was incorporated into deacetylated gellan gum gels. The TM liposome was demonstrated to be a round and uniform shape in TEM pictures. Compared with the TM eye drops, the TM liposome produced a 1.93 folds increase in apparent permeability coefficients (Papp), resulting in a significant increase of the corneal penetration. The TM-loaded liposome incorporated ion sensitive in situ gels (TM L-ISG) showed longer retention time on corneal surface compared with the eye drops using gamma scintigraphy technology. Draize testing showed that TM L-ISG was non-irritant for ocular tissues. The biggest efficacy of TM L-ISG occurred 30 min after eye drops administration, and efficacy disappeared after 240min. Then, compared with the eye drops, the optimal TM L-ISG could quickly reduce the intraocular pressure and the effective time was significantly longer (P≤0.05). These results indicate that liposome incorporated ion sensitive in situ gels have a potential ability for the opthalmic delivery.

Bioadhesive chitosan-loaded liposomes: A more efficient and higher permeable ocular delivery platform for timolol maleate

The aim of this study was to develop and characterize a novel colloidal system, namely, timolol maleate chitosan coated liposomes (TM-CHL) to enhance the ocular permeation, precorneal residence time and bioavailability. The resulting TM-CHL was the most promising formulation with a mean particle size of 150.7nm and an EE% of 75.83±1.61%. In vitro release of the TM-CHL showed an extended drug release profile. The TM-CHL exhibited significant mucin adhesion and compared with commercial eye drops, TM-CHL produced a 3.18-fold increase in the apparent permeability coefficient (Papp), resulting in a significant enhancement of corneal permeation. In addition, the gamma scintigraphic study and the pharmacokinetic study showed that TM-CHL could be retained at the corneal surface for longer time compared with eye drops. The ocular irritation study indicated that the developed liposomes produced no significant irritant effects. Furthermore, pharmacodynamics results showed that the maximum intraocular pressure(IOP) produced by TM-CHL was (19.67±1.14) mmHg compared with the (23.80±1.49) mmHg for TM eye drops, revealing that TM-CHL was more effective in reducing the IOP. These results demonstrate that CHL is a potentially useful carrier for ocular drug delivery, which could improve the efficacy of TM.

Enhanced cellular uptake and anti-proliferating effect of chitosan hydrochlorides modified genistein loaded NLC on human lens epithelial cells.

This study was attempted to increase the cellular uptake of developed genistein loaded nanostructured lipid carriers (NLC) into human lens epithelial (HLE) cells by chitosan hydrochlorides coatings when applied in post lens capsule (PCO) treatment, and to provide further understanding of the uptake and anti-proliferation mechanisms inside. NLCs were produced using melt-emulsification method and were subsequently coated with chitosan hydrochlorides by adsorption. The uptake of various particle sizes were evaluated and visualized by confocal laser scanning microscopy (CLSM), showing a size-dependent manner. The uptake of NLC was proved to be endocytosed in an energy dependent and clathrin-mediated endocytosis to HLE cells by the decrease in uptake at lower temperature, when pre-saturated by blank NLC and in the presence of NaN3 and sucrose. CH coating improved the uptake percentage of NLC irrespective of the particle size, without influencing the uptake mechanism. Cell apoptosis was tested using PI and Annexin V-FITC/PI staining, followed by flow cytometer analysis. Higher anti-proliferation effect was observed for CH-NLC in inhibiting the growth of HLE cells by causing more apoptosis. Results above indicate that GEN-NLC surface modified by chitosan hydrochlorides could enhance the trans-cellular performance and anti-proliferating effect as PCO therapy.

Nanostructured lipid carrier surface modified with Eudragit RS 100 and its potential ophthalmic functions

This study was carried out to evaluate the ocular performance of a cationic Eudragit (EDU) RS 100-coated nanostructured lipid carrier (NLC). The genistein encapsulated NLC (GEN-NLC) was produced using the melt-emulsification technique followed by surface absorption of EDU RS 100. The EDU RS 100 increased the surface zeta potential from −7.46 mV to +13.60 mV, by uniformly forming a spherical coating outside the NLC surface, as shown by transmission electron microscopy images. The EDU RS 100 on the NLC surface effectively improved the NLC stability by inhibiting particle size growth. The obtained EDU RS 100-GEN-NLC showed extended precorneal clearance and a 1.22-fold increase in AUC (area under the curve) compared with the bare NLC in a Gamma scintigraphic evaluation. The EDU RS 100 modification also significantly increased corneal penetration producing a 3.3-fold increase in apparent permeability coefficients (Papp) compared with references. Draize and cytotoxicity testing confirmed that the developed EDU RS 100-GEN-NLC was nonirritant to ocular tissues and nontoxic to corneal cells. These results indicate that the NLC surface modified by EDU RS 100 significantly improves the NLC properties and exhibits many advantages for ocular use.

Preparation and investigation of controlled-release glipizide novel oral device with three-dimensional printing

The purpose of this study was to explore the feasibility of combining fused deposition modeling (FDM) 3D printing technology with hot melt extrusion (HME) to fabricate a novel controlled-release drug delivery device. Glipizide used in the treatment of diabetes was selected as model drug, and was successfully loaded into commercial polyvinyl alcohol (PVA) filaments by HME method. The drug-loaded filaments were printed through a dual-nozzle 3D printer, and finally formed a double-chamber device composed by a tablet embedded within a larger tablet (DuoTablet), each chamber contains different contents of glipizide. The drug-loaded 3D printed device was evaluated for drug release under in vitro dissolution condition, and we found the release profile fit Korsmeyer-Peppas release kinetics. With the double-chamber design, it is feasible to design either controlled drug release or delayed drug release behavior by reasonably arranging the concentration distribution of the drug in the device. The characteristics of the external layer performed main influence on the release profile of the internal compartment such as lag-time or rate of release. The results of this study suggest the potential of 3D printing to fabricate controlled-release drug delivery system containing multiple drug concentration distributions via hot melt extrusion method and specialized design configurations.

Potential advantages of a novel chitosan-N-acetylcysteine surface modified nanostructured lipid carrier on the performance of ophthalmic delivery of curcumin

The transient precorneal retention time and low penetration capacity into intraocular tissues are the key obstacles that hinder the ophthalmic drug delivery of many therapeutic compounds, especially for drugs with poor solubility and permeability. To break the stalemate, N-acetyl-L-cysteine functionalized chitosan copolymer (CS-NAC), which exhibit marked bioadhesion and permeation enhancing effect, was synthesized. The curcumin encapsulated NLC (CUR-NLC) was produced and optimized followed by surface absorption of CS-NAC. After coating, changed particle size from 50.76 ± 2.21 nm to 88.64 ± 1.25 nm and reversed zeta potential from −20.38 ± 0.39 mV to 22.51 ± 0.34 mV was observed. The in vitro CUR release from NLC was slower than that of CUR-NLC and chitosan hydrochlorides (CH) coated NLC due to the inter and/or intramolecular disulfide formation of thiomers on the surface of nanocarriers. The modification also significantly enhanced transcorneal penetration compared with CH-NLC and the uncoated ones. The effect on bioadhesion and precorneal retention were evaluated by in vivo imaging technique and ocular pharmacokinetics studies revealing that the clearance of the formulations was significantly delayed in the presence of CS-NAC and the effect was positively related to the degree of thiolation. In summary, CS-NAC-NLC presented a series of notable advantages for ophthalmic drug application.

Controlled delivery of carvedilol nanosuspension from osmotic pump capsule: in vitro and in vivo evaluation.

This study intended to develop a novel controlled delivery osmotic pump capsule of carvedilol nanosuspension. The capsule is assembled using a semi-permeable capsule shell with contents including nanosuspension drying powder, mannitol and Plasdone S-630. The physical characteristics of semi-permeable capsule walls were compared among different coating solutions under different temperature. The composition of the coating solution and drying temperature appeared to be important for the formation of the shells. Carvedilol nanosuspension was prepared by precipitation-ultrasonication technique and was further lyophilized. Response surface methodology was used to investigate the influence of factors on the responses. The optimized formulation displayed complete drug delivery and zero-order release rate. The TEM and particle size analysis indicated that the morphology of the resultant nanoparticle in the capsule was spherical shaped with a mean size of 252±19 nm. The in vivo test in beagle dogs demonstrated that the relative bioavailability of the novel system was 203.5% in comparison to that of the marketed preparation. The capsule successfully controlled the release of carvedilol and the fluctuation of plasma concentration was minimized. The system is a promising strategy to improve the oral bioavailability for poorly soluble drugs and preparing it into elementary osmotic pump conveniently.

A novel application of electrospinning technique in sublingual membrane: characterization, permeation and in vivo study

Abstract Isosorbide dinitrate–polyvinylpyrrolidone (ISDN–PVP) electrospinning fibers were formulated and explored as potentially sublingual membrane. The addition of polyethylene glycol (PEG) to the formulation improved flexibility and reduced fluffiness of the fiber mat. The scanning electron microscopy (SEM) demonstrated that the fibers tended to be cross-linking, and the crosslinking degree increased with the increase of PEG amount. The differential scanning calorimetry (DSC) indicated that ISDN existed in non-crystalline state in the fibers (except at the highest drug content). The infrared spectroscopy suggested that ISDN had better compatibility with the ingredients owing to the hydrogen bonding (or hydrophobic interactions). The fibers were highly favorable for the fabrication of sublingual membrane due to neutral pH, large folding endurance and rapid drug release (complete dissolution within 120 s). The permeation study of ISDN through both dialysis membrane (DM) and porcine sublingual mucosa (SM) were carried out. A significant relationship of drug permeation rate through DM and SM was built up, which indicated that DM could be used to partly simulate SM and assess formulation. The pharmacokinetic study in rats demonstrated that the electrospinning fiber membrane had a higher Cmax and lower Tmax compared to the reference preparation, and the relative bioavailability of the fiber membrane was 151.6%.

A novel hydrogel with dual temperature and pH responsiveness based on a nanostructured lipid carrier as an ophthalmic delivery system: enhanced trans-corneal permeability and bioavailability of nepafenac

The aim of the current study was to encapsulate nepafenac (NP) in in situ hydrogel modified nanostructured lipid carrier (NP-NLC-Gel) nanoparticles as an efficient ocular delivery system to improve its transcorneal penetration and precorneal retention. NP-NLC nanoparticles were prepared by a melt emulsification method. The synthesized hydrogel, composed of poloxamer 407 and carboxymethyl chitosan, was a liquid solution at low temperature and pH and then turned to a semisolid on the surface of the cornea. The enhanced transcorneal penetration of the NLC was evaluated using isolated rabbit corneas, with a significant increase of 2.36-fold in the apparent permeability coefficient compared to that of the NP eye drops (p < 0.05). Precorneal retention assessed by fluorescence imaging technology in vivo showed that NP-NLC-Gel had a longer retention time on the corneal surface compared with the NP eye drops. The in vivo ocular tolerance study indicated that there was no difference in irritation between the NP eye drops and NP-NLC-Gel. The concentration of nepafenac in the aqueous humor and lacrimal fluid was determined using HPLC. The AUC0−∞ of NP-NLC-Gel was increased up to 6.3- and 1.9-fold in the aqueous humor and lacrimal fluid, respectively, as compared with the eye drops. In conclusion, NP-NLC-Gel possesses a greater potential as an ocular drug delivery system compared with the NP eye drops.