Encapsulation of Azithromycin Ion Pair in Liposome for Enhancing Ocular Delivery and Therapeutic Efficacy on Dry Eye.

The aim of this work was to design a novel ocular delivery carrier based on liposomes loaded with azithromycin (AZM) for the treatment of dry eye (DE) disease. To improve the drug loading efficiency, an AZM-cholesteryl hemisuccinate (CHEMS) ion pair (ACIP) was first prepared, and the successful formation of the ACIP was characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and X-ray powder diffraction (XRD), which demonstrated a stable interaction between CHEMS and AZM. The ACIP-loaded liposome (ACIP-Lip) appeared as spherical particles under TEM, with a uniform particle size of 60 ± 2 nm and zeta potential of -20.3 ± 4.6 mV. The entrapment efficiency (EE) and drug loading (DL) of ACIP-Lip were greatly improved to 95.6 ± 2.0 and 9.2 ± 0.7%, respectively, which was attributed to the enhanced loading capacity of the liposomes through use of the ion pair and addition of MCT. ACIP-Lip also exhibited a high stability during a 3 month storage period at both 4 and 25 °C. In vitro release of AZM from ACIP-Lip was pH-dependent, with a more rapid release at pH 6.0 than at pH 7.4, which is beneficial for ocular therapy. Furthermore, the corneal permeation of AZM was enhanced by ACIP-Lip, demonstrating an apparent permeability coefficient ( Papp × 106) of 8.92 ± 0.56 cm/s, which was approximately 2-fold greater that of the AZM solution. Finally, an in vivo pharmacodynamical study showed that the essential symptoms of DE rats were significantly improved by ACIP-Lip, as it was highly efficient and superior compared to hyaluronic acid sodium eye drops available on the market. Hence, ACIP-Lip is a promising formulation for DE treatment.

Application and functional characterization of POVACOAT, a hydrophilic co-polymer poly(vinyl alcohol/acrylic acid/methyl methacrylate) as a hot-melt extrusion carrier.

OBJECTIVE: The aim of this study was to evaluate the applicability of POVACOAT™, a hydrophilic PVA copolymer, as a solid dispersion (SD) carrier for hot-melt extrusion (HME). METHODS: Bifendate (DDB), a water-insoluble drug, was chosen as the model drug. DDB was hot-melt extruded by a co-rotating twin screw extruder with POVACOAT™. The SD formability of POVACOAT™ was investigated by varying the composition ratios. Solid state characterization was evaluated by differential scanning calorimetry, powder X-ray diffraction, scanning electron microscopy and Fourier transformation infrared spectroscopy. In order to have a better knowledge of the mechanism of dissolution enhancement, dissolution study, phase solubility study and crystallization study of DDB from supersaturated solutions were performed. In addition, the storage stability of the extrudate containing 10% DDB was investigated. RESULTS: Physical characterizations showed that DDB was amorphous up to 15% drug loading. The phase solubility study revealed an AL-type curve. Moreover, POVACOAT™ was found to have an inhibitory effect on crystallization from supersaturated solutions. Compared with the pure DDB and physical mixture, the dissolution rate and solubility of extrudates were significantly enhanced and the drug loading markedly affected the dissolution of SDs. Furthermore, the stability test indicated that 10% DDB-SD was stable during storage (40 °C/75% RH). CONCLUSION: The results of this study demonstrate that POVACOAT™ is a valuable excipient for the formulation of solid dispersions prepared by HME to improve dissolution of poorly water-soluble drugs.

Preparation, characterization, stability and in vitro-in vivo evaluation of pellet-layered Simvastatin nanosuspensions.

The objective of the present study was to develop stable pellets-layered Simvastatin (SIM) nanosuspensions with improved dissolution and bioavailability. The nanosuspensions were prepared with 7% HPMC, antioxidant 0.03% butylated hydroxyanisole and 0.2% citric acid (m/v) by low temperature grinding. After that, SDS with SIM was in a ratio of 1:5 (m/m), was evenly dispersed in the nanosuspensions. Then, they were layered on the surface of sugar pellets. The mean particle size of the SIM nanosuspensions was 0.74 µm, and 80.6% of the particles was below 1 µm in size. The pellets could re-disperse into nanoparticle status in the dissolution medium. In 900 mL pH 7.0 phosphate solutions, the dissolution of the layered pellets was better than that of commercial tablets. Also, nearly 100% of the drug dissolved from the pellets within 5 min under sink conditions. During the stability studies, SIM pellets exhibited good physical and chemical stability. The relative bioavailability of SIM and Simvastatin ß-hydroxy acid (SIMA) for nanosuspensions layered pellets compared with commercial tablets was 117% and 173%, respectively. The bioavailability of SIMA was improved significantly (p < 0.05), confirming the improvement of bioavailability. Thus, the present study demonstrates that the pellet-layered SIM nanosuspensions improved both the dissolution and bioavailability of SIM.

Enzyme/pH dual stimuli-responsive nanoplatform co-deliver disulfiram and doxorubicin for effective treatment of breast cancer lung metastasis.

OBJECTIVES: Metastasis is still one of the main obstacles in the treatment of breast cancer. This study aimed to develop disulfiram (DSF) and doxorubicin (DOX) co-loaded nanoparticles (DSF-DOX NPs) with enzyme/pH dual stimuli-responsive characteristics to inhibit breast cancer metastasis. METHODS: DSF-DOX NPs were prepared using the amphiphilic poly(ε-caprolactone)-b-poly(L-glutamic acid)-g-methoxy poly(ethylene glycol) (PCL-b-PGlu-g-mPEG) copolymer by a classical dialysis method. In vitro release tests, in vitro cytotoxicity assay, and anti-metastasis studies were conducted to evaluate pH/enzyme sensitivity and therapeutic effect of DSF-DOX NPs. RESULTS: The specific pH and enzyme stimuli-responsiveness of DSF-DO NPs can be attributed to the transformation of secondary structure and the degradation of amide bonds in the PGlu segment, respectively. This accelerated drug release significantly increased the cytotoxicity to 4T1 cells. Compared with the control group, the DSF-DOX NPs showed a strong inhibition of in vitro metastasis with a wound healing rate of 36.50% and a migration rate of 18.39%. Impressively, in vivo anti-metastasis results indicated that the metastasis of 4T1 cells was almost completely suppressed by DSF-DOX NPs. CONCLUSION: DSF-DOX NPs with controllable tumor site delivery of DOX and DSF were a prospectively potential strategy for metastatic breast cancer treatment.

Enhanced oral absorption and anticancer efficacy of cabazitaxel by overcoming intestinal mucus and epithelium barriers using surface polyethylene oxide (PEO) decorated positively charged polymer-lipid hybrid nanoparticles.

Polymer-lipid hybrid nanoparticles, PMONPs, were developed to improve the oral absorption of cabazitaxel (CTX), a semi-synthetic taxane derivative, by overcoming multiple gastrointestinal barriers. The nano-carrier is comprised of a poly(ε-caprolactone) (PCL) and chain triglyceride (MCT) hybrid core for drug loading, and a positively charged surface while slightly concealed with a polyethylene oxide (PEO) shell by insertion of poloxamer 188, with the aim of improving the intestinal mucus permeation and epithelial cell uptake. The CTX-loaded PMONPs (CTX-PMONPs) were optimized with 10% MCT content in the core, and characterization showed they were on the nanoscale with a size of 170.2±5.7nm, zeta potential of +40.90±3.05mV, drug loading of 11.5%, and sustained release property. Enhanced mucus permeation of PMONPs were confirmed in a bulk permeation test, in situ SPIP and intestinal distribution study, and is likely attributed to the combined effect of positive charge and hydrophilic PEO layer on the surface. Meanwhile, promoted cellular uptake was found in mucus-secreting cells evaluation, in which potential adsorptive transcytosis, caused by positively charged surface, played a key role. Furthermore, lymphatic transport was positively demonstrated, contributing to the high oral absorption of CTX-PMONPs. The oral bioavailability of CTX was elevated from 7.7% (CTX solution (CTX-Sol)) to 56.6% after oral administration of CTX-PMONPs, approximately 7.3 times higher than that of CTX-Sol. An in vivo anticancer efficiency study showed that CTX-PMONPs orally exhibited a good tumor inhibition effect, and reduced the CTX-caused systemic toxicity compared with intravenous CTX-Sol. In conclusion, PMONPs are able to efficiently orally deliver the anticancer drug, CTX, into systemic circulation, and can achieve the desired oral anticancer effect. This surface modified polymer-lipid hybrid nanoparticle is likely to be a promising carrier for oral delivery of small molecule anticancer drugs.

Synergistic breast tumor cell killing achieved by intracellular co-delivery of doxorubicin and disulfiram via core-shell-corona nanoparticles.

Combination therapy with different functional chemotherapeutic agents based on nano-drug delivery systems is an effective strategy for the treatment of breast cancer. However, co-delivery of drug molecules with different physicochemical properties still remains a challenge. In this study, an amphiphilic poly (ε-caprolactone)-b-poly (l-glutamic acid)-g-methoxy poly (ethylene glycol) (PCL-b-PGlu-g-mPEG) copolymer was designed and synthesized to develop a nanocarrier for the co-delivery of hydrophilic doxorubicin (DOX) and hydrophobic disulfiram (DSF). The amphiphilic copolymer self-assembled into core-shell-corona structured nanoparticles with the hydrophobic PCL core for DSF loading (hydrophobic interaction) and anionic poly (glutamic acid) shell for DOX loading (electrostatic interaction). DSF and DOX co-loaded nanoparticles (Co-NPs) resulted in high drug loading and precisely controlled DSF/DOX ratio via formulation optimization. Compared with free drug solutions, DSF and DOX delivered by the Co-NPs were found to have improved intracellular accumulation. Results of cytotoxicity assays showed that DSF/DOX delivered at the weight ratio of 0.5 and 1 could achieve a synergistic cytotoxic effect on breast cancer cell lines (MCF-7 and MDA-MB-231). In vivo imaging confirmed that the core-shell-corona nanoparticles could efficiently accumulate in tumors. In vivo anti-tumor effect results indicated that Co-NPs showed an improved drug synergistic effect on antitumor activity compared with the free drug combination. Therefore, it can be concluded that core-shell-corona nanoparticles prepared by PCL-b-PGlu-g-mPEG could be a promising co-delivery system for drug combination therapy in the treatment of breast cancer.

Strategies for improving the payload of small molecular drugs in polymeric micelles.

In the past few years, substantial efforts have been made in the design and preparation of polymeric micelles as novel drug delivery vehicles. Typically, polymeric micelles possess a spherical core-shell structure, with a hydrophobic core and a hydrophilic shell. Consequently, poorly water-soluble drugs can be effectively solubilized within the hydrophobic core, which can significantly boost their drug loading in aqueous media. This leads to new opportunities for some bioactive compounds that have previously been abandoned due to their low aqueous solubility. Even so, the payload of small molecular drugs is still not often satisfactory due to low drug loading and premature release, which makes it difficult to meet the requirements of in vivo studies. This problem has been a major focus in recent years. Following an analysis of the published literature in this field, several strategies towards achieving polymeric micelles with high drug loading and stability are presented in this review, in order to ensure adequate drug levels reach target sites.

Preparation and in vitro-in vivo evaluation of none gastric resident dipyridamole (DIP) sustained-release pellets with enhanced bioavailability.

The objective of this study was to develop none gastric resident sustained-release pellets loaded with dipyridamole with a high bioavailability. Two different kinds of core pellets, one containing citric acid as a pH-modifier (CAP) and, the other without pH-modifier (NCAP) were prepared by extrusion-spheronization and then coated with mixtures of enteric soluble and insoluble polymers (referred to as CAP(1) and NCAP(1)) or insoluble polymer alone (referred to as CAP(2) and NCAP(2)). The relative bioavailability of the sustained-release pellets was studied in fasted beagle dogs after oral administration using a commercially available immediate release tablet (IRT) as a reference. The in vitro release, in vivo absorption and in vitro-in vivo correlation were also evaluated. Results revealed that the plasma drug concentrations after administration of CAP(2), NCAP(1) and NCAP(2) were undetectable, indicating that the drug release was almost zero from the preparations throughout the gastro-intestinal tract. The C(max), T(max) and AUC((0→24)) of CAP(1) were 0.78 ± 0.23 (µg/ml), 3.80 ± 0.30 (h), and 6.74 ± 0.47 (µg/mlh), respectively. While the corresponding values were 2.23 ± 0.32 (µg/ml), 3.00 ± 0.44 (h) and 9.42 ± 0.69 (µg/mlh) for IRT. The relative bioavailability of CAP(1) was 71.55% compared with IRT. By combined incorporation of a pH-modifier into the core of pellets to modify the inner micro-environment and employing mixtures of enteric soluble and insoluble polymers as a retarding layer, drugs with high solubility in stomach and limited solubility in small intestine, such as DIP, could be successfully formulated as sustained release preparations with no pH-dependence in drug release and enhanced bioavailability.

A floating multiparticulate system for ofloxacin based on a multilayer structure: In vitro and in vivo evaluation.

The purpose of this research was to develop a novel gastroretentive multiparticulate system with floating ability. This system was designed to provide drug-loaded pellets coated with three successive coatings-the retarding film (ethyl cellulose), the effervescent layer (sodium bicarbonate) and the gas-entrapped polymeric membrane (Eudragit RL 30D). The floating pellets were evaluated for SEM, floating characteristic parameters, in vitro release and bioavailability in New Zealand rabbits. The zero-order release theory model is designed to interpret the release processes. Due to the swelling property, high flexibility and high water permeability, Eudragit RL 30D was used as a gas-entrapped polymeric membrane. The obtained pellets exhibit excellent floating ability and release characteristics. Analysis of the release mechanism showed a zero-order release for the first 8h because of the osmotic pressure of the saturated solution inside of the membrane, which was in accordance with that predicted. Abdominal X-ray images showed that the gastroretention period of the floating barium sulfate-labeled pellets was no less than 6h. The relative bioavailability of the floating pellets compared with reference tablets was 113.06 ± 23.83%. All these results showed that the floating pellets are a feasible approach for the gastroretentive drug delivery system.

Preparation and evaluation of nicotinic acid sustained-release pellets combined with immediate release simvastatin.

This study was performed to prepare high-dose nicotinic acid (NA) loaded sustained-release pellets coated with double polymer and simvastatin (SIM). The uncoated pellets were prepared by extrusion-spheronization and the double ethylcellucose (EC) films were coated in a bottom-spray fluidized bed coater. SIM was milled by wet grinding and then the milled suspension was layered on the coated pellets. Results showed that coated with 1.5% subcoating and 1% outer coating composed of EC and polyvinyl pyrrolidone K30 (PVP(K30)) in ratios of 5:1 and 2:1, NA release behavior was very similar to the reference (NER/S; SIMCOR, Abbott) in different media. And SIM was delivered more rapidly than that of the reference, while the SIM layer had no influence on NA release. During 6-month storage at 40°C/75% RH, the two drugs exhibited stable dissolution behavior. It was observed that the content uniformity of SIM was provided by the present preparation and SIM was stable if adding light magnesium oxide in the grinding procedure. Results indicated it was possible to prepare high-dose sustained-release NA pellets combined with little-dose immediate release SIM by spraying double EC polymer and SIM milled suspension on NA pellets in a bottom-spray fluidized bed coater, respectively.