Design and In Vitro Evaluation of a Slow-Release Intraocular Implant of Betamethasone.

Posterior eye diseases are a common cause of vision problems in developing countries, which have encouraged the development of new treatment models for these degenerative diseases. Intraocular implants are one of the drug delivery systems to the posterior region of the eye. Using these implants, the blood-eye barrier can be bypassed; the complications caused by repeated in vitro administrations can be eliminated, and smaller amounts of the drug would be used during the treatment process. Meanwhile, biodegradable implants have received more attention due to their biodegradable structure and the lack of need for re-surgery to remove the rest of the system from the eye. The aim of this study is to employ biodegradable implants composed of polyethylene glycol (PEG) and 3-hydroxybutyrate-co-3-hydroxyvalerat (PHBV) to deliver betamethasone to the back of the eye in the treatment of retinopathy. PHBV polymer has been selected as the main polymer with a certain ratio of drug to polymer for fabrication of enamel and different amounts of PEG with three molecular weights used as pore generators to control drug release over a period of time. Based on the analysis of the results of differential scanning calorimetry (DSC) and FTIR spectroscopy, none of the polymers were degraded in the temperature range of the manufacturing process, and among betamethasone derivatives, the best option for implant preparation is the use of its basic form. Drug release studies over a period of three months showed that implants containing PHBV HV2% and PEG 6000 had a more appropriate release profile.

Pharmaceutical implants: classification, limitations and therapeutic applications.

Controlled/sustained delivery systems have been developed rapidly which show the ability to overcome the obstacles of traditional delivery systems. Daily development of biomedical and biomaterial sciences has brought more attention to the implantable delivery systems. As a result, these systems have found their position in the medical field since they were introduced. The advances in the polymeric science along with the other fields, make the production of a wide variety of implantable systems, possible. The influence of these systems in medical field could not be denied Here', the pharmaceutical applications which have been mostly focused on, are discussed. Since these systems have proven to be beneficial, researchers are trying to adjust their defects to the desired properties. Doing so, the path that implantable delivery systems have crossed so far should be studied, and that's the aim of this review. In the present report, the advantages of these systems in chemotherapeutic, contraceptive, neuropsychology, pain management, peptide delivery, ocular delivery, cardiovascular, orthopedic, and dental fields have been evaluated.

Dexamethasone loaded multi-layer poly-l-lactic acid/pluronic P123 composite electrospun nanofiber scaffolds for bone tissue engineering and drug delivery.

In tissue engineering, it is common to mix drugs that can control proliferation and differentiation of cells into polymeric solutions as part of composite to get bioactive scaffolds. However, direct incorporation of drugs might potentially result in undesired burst release. To overcome this problem, here we developed electrospun multilayer drug loaded poly-l-lactic acid/pluronic P123 (PLLA-P123) composite scaffolds. The drug was loaded into the middle layer. The surface, the mechanical and physiochemical properties of the scaffolds were evaluated. The drug release profiles were monitored. Finally, the osteogenic proliferation and differentiation potential were determined. The scaffolds fabricated here have appropriate surface properties, but with different mechanical strength and osteogenic proliferation and differentiation. Multi-layer scaffolds where the drug was in the middle layer and PLLA-plasma and PLLA-P123 with cover layer showed the best osteogenic proliferation and differentiation than the other groups of scaffolds. The drug release profiles of the scaffolds were completely different: single layer scaffolds showed burst release within the first day, while multilayer scaffolds showed controlled release. Therefore, the multilayer drug loaded scaffolds prepared have dual benefits can provide both better osteogenesis and controlled release of drugs and bioactive molecules at the implant site.

Fabrication of long-acting insulin formulation based on poly (3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) nanoparticles: preparation, optimization, characterization, and in vitro evaluation.

The purpose of this research was the fabrication, statistical optimization, and in vitro characterization of insulin-loaded poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV) nanoparticles (INS-PHBV-NPs). Nanopar-ticles were successfully developed by double emulsification solvent evaporation method. The NPs were characterized for particle size, entrapment efficiency (EE%), and polydispersity index (PDI). The NPs also were characterized by scanning electron microscopy (SEM), Fourier transformed infrared spectroscopy (FTIR), X-ray diffraction (XRD), differential scanning calorimetry (DSC), and circular dichroism (CD). The optimum conditions were found to be 1.6% polyvinyl alcohol (PVA), 0.9% of PHBV, and 15 mg/ml of insulin with the aid of the Box-Behnken experimental design results. The optimized NPs showed spherical shape with particle size of 250.21 ± 11.37 nm, PDI of 0.12 ± 0.01, and with EE% of 90.12 ± 2.10%. In vitro drug release pattern followed Korsmeyer-Peppas model and exhibited an initial burst release of 19% with extended drug release of 63.2% from optimized NPs within 27 d. In conclusion, these results suggest that INS-PHBV-NPs could be a promising candidate for designing an injectable sustained release formulation for insulin.

Prolonged injectable formulation of Nafarelin using in situ gel combination delivery system.

The principal purpose of the present study was to prepare and characterize a complex drug delivery system consisting of Nafarelin-poly (3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) nanoparticles (NPs) in combination with sodium alginate/poloxamer 407 in situ gel. Nafarelin-loaded PHBV NPs were prepared via double emulsion solvent evaporation technique. Box-Behnken Response Surface Methodology was utilized to optimize NPs. Mean particle size, polydispersity index (PDI), entrapment efficiency (EE), and drug loading (DL) of the optimized NPs were measured. Incorporation of Nafarelin within NPs was proven by differential scanning calorimetry (DSC). The combination delivery system (CDS) was prepared by adding Nafarelin-loaded PHBV NPs to sodium alginate/poloxamer 407 solution followed by physical mixing. Morphological properties of Nafarelin-loaded PHBV NPs and CDS were evaluated by SEM. Rheological properties were employed to investigate the effects of alginate concentration on sol-gel transition temperature. The release profile of Nafarelin from both PHBV NPs and CDS were individually assessed. The cumulative release percentage from CDS was significantly lower than Nafarelin released from PHBV NPs. Based on the favorable results in this study, the CDS consisting of sodium alginate/poloxamer 407 loaded with PHBV NPs could be a promising candidate for designing a long-lasting formulation of Nafarelin.

Comparison of engineered cartilage based on BMSCs and chondrocytes seeded on PVA-PPU scaffold in a sheep model.

In this study, polyvinyl alcohol hydrogel chains were crosslinked by polyurethane in order to synthesize a suitable substrate for cartilage lesions. The substrate was fully characterized, and in vitro and in vivo investigations were conducted based on a sheep model. In vitro tests were performed based on the chondrocyte cells with the Alcian Blue and safranin O staining in order to prove the presence of proteoglycan on the surface of the synthesized substrate, which has been secreted by cultures of chondrocytes. Furthermore, the expression of collagen type I, collagen type II, aggrecan, and Sox9 was presented in the chondrocyte cultures on the synthesized substrate through RT-PCR. In addition, the H&E analysis and other related tests demonstrated the formation of neocartilage tissue in a sheep model. The results were found to be promising for cartilage tissue engineering and verified that the isolated chondrocyte cultures on the synthesized substrate retain their original composition.

Nanofibrous Scaffolds Containing Hydroxyapatite and Microfluidic-Prepared Polyamidoamin/BMP-2 Plasmid Dendriplexes for Bone Tissue Engineering Applications.

OBJECTIVE: The aim of this study is to fabricate functional scaffolds to gene delivery bone morphogenetic protein-2 (BMP-2) plasmid for bone formation in bone tissue engineering. METHODS: Dendriplexes (DPs) of generation 4 polyamidoamin (G4-PAMAM)/BMP-2 plasmid were prepared through microfluidic (MF) platform. The physiochemical properties and toxicity of DPs were evaluated by DLS, AFM, FESEM and MTT assay. In order to create a suitable environment for stem cell growth and differentiation, poly-l-lactic acid (PLLA) and poly-l-lactic acid/poly (ethylene oxide) (PLLA/PEO) scaffolds containing hydroxyapatite nanoparticles (HA) and DPs were fabricated by the electrospinning method. The osteogenic potency of the scaffolds on human adipose tissue-derived mesenchymal stem cells (hASCs) was investigated. RESULTS: The results revealed that tuning the physical properties of DPs by adjusting flow parameters in microfluidic platform can easily improve the cell viability compared to conventional bulk mixing method. Also, the result showed that the presence of HA and DPs in PLLA/PEO scaffold enhanced alkaline phosphatase (ALP) activity and increased the amount of deposited Ca, as well as, related to osteogenesis gen markers. CONCLUSION: This study indicated that on using the MF platform in preparation of DPs and loading them along with HA in PLLA/PEO scaffold, the osteogenic differentiation of hASCs could be tuned.

An improved surface for enhanced stem cell proliferation and osteogenic differentiation using electrospun composite PLLA/P123 scaffold.

Poly-L-lactic acid (PLLA) nano fibrous scaffolds prepared by electrospinning technology have been used widely in tissue engineering applications. However, PLLA scaffolds are hydrophobic in nature, moreover the fibrous porous structure produced by electrospinning makes the scaffolds even more hydrophobic which generally limits cell attachment and proliferation. Polymer blending is one of the several efforts used so far to enhance hydrophilicity and recognized as an easy cost-effective approach for the manipulation physiochemical properties of polymeric biomaterials. Pluronic block copolymers containing hydrophilic poly(ethylene oxide) (PEO) blocks and hydrophobic poly(propylene oxide) (PPO) blocks are arranged in triblock structure: PEO-PPO-PEO. It is commonly used recently to blend hydrophobic polymers to enhance hydrophilicity for pharmaceutical and tissue engineering applications. In this study, novel pluronic P123 blend PLLA electrospun nanofibre scaffolds with improved hydrophilicity and biological properties were fabricated. The surface morphology and surface chemistry of the nanofibre scaffolds were characterized by scanning electron microscope (SEM) and FTIR analyses. Surface hydrophilicity and change in mechanical properties were studied. The ability of the scaffolds to support the attachment, and proliferation and differentiation of human adipose tissue derived MSCs, were evaluated generally. The fabricated scaffolds have completely improved, hydrophilicity, similar osteogenic differentiation potential with plasma-treated PLLA nanofibre scaffold, and hence P123 blend PLLA electrospun nanofibre scaffolds are a very good and cost effective choice as a scaffold for bone tissue engineering application.

Development and characterization of electrosprayed nanoparticles for encapsulation of Curcumin.

Curcumin has been proven to be an effective herbal derived anti-inflammatory and antioxidant biocompatible agent. In this research, poly(lactic-co-glycolic acid) (PLGA) (as a biocompatible and generally recognized as safe (GRAS) polymer) nanoparticles containing Curcumin were electrosprayed from different polymeric solutions with different concentrations for the first time. Morphology of these nanoparticles in the absence/presence of Curcumin was evaluated by scanning electron microscope, transmission electron microscope, and X-ray photoelectron spectroscopy analyses. Perfectly shaped nanoparticles with an average size of 300 and 320 nm were observed for neat and Curcumin-loaded PLGA, respectively. Curcumin-loaded electrosprayed nanoparticles showed a normal moderate initial burst and then a prolonged release period. Weibull, Peppas, and modified Korsmeyer-Peppas models were applied to study the kinetic and mechanism of Curcumin release from PLGA nanoparticles. Results showed high specific surface area and spherical geometry of the nanoparticles. Effectiveness of the electrospray method as a promising technique for preparing Curcumin-loaded nanoparticles was confirmed in this study. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 285-292, 2018.

Evaluation of a novel biocompatible magnetic nanomedicine based on beta-cyclodextrin, loaded doxorubicin-curcumin for overcoming chemoresistance in breast cancer.

Codelivery of chemo-sensitizers with chemotherapeutics using combo nanomedicine is a promising platform for overcoming chemoresistance in breast cancer. However, tumor accumulation of nano-carriers based on enhanced permeability and retention (EPR) effect is confounded by heterogeneity in tumor microenvironment. Adsorption of protein corona on surface of nanoparticle boost up clearance by reticulo-endothelial system. In this study, a surface functionalized magnetic nanocomposite (NC) for codelivery of doxorubicin (DOX) and curcumin (CUR) is developed. NCs were coated with hydroxyapatite and were also cross linked with ß-cyclodextrin. NCs efficiently encapsulated DOX and CUR. Release of CUR and DOX were in a sustained pH-depended pattern. ß-cyclodextrin functionalization reduced protein corona according sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis. As shown by flowcytometric and confocal microscopy analyses, NCs internalized efficiently by human breast carcinoma cells MCF-7 and adriamycin resistant MCF-7 (MCF-7/adr) cells. 3-(4,5-Dimethyl-thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) test demonstrated superior cytotoxicity of DOX-CUR loaded NCs. Anti-tumor efficacy analyses confirmed reduction in relative tumor volume size (RTV%) compared to control group. Western blot analyses demonstrated marginal CUR mediated P-glycoprotein (P-gp) down regulation. DOX-CUR loaded NCs efficiently accumulated into the tumor via external magnet guidance. Nevertheless, the increased tumor accumulation did not correlate with pharmacologic responses such as RTV% and significant superiority over free DOX was not observed.

Efficient gene delivery to primary human retinal pigment epithelial cells: The innate and acquired properties of vectors.

The purpose of this study is designing non-viral gene delivery vectors for transfection of the primary human retinal pigment epithelial cells (RPE). In the design process of gene delivery vectors, considering physicochemical properties of vectors alone does not seem to be enough since they interact with constituents of the surrounding environment and hence gain new characteristics. Moreover, due to these interactions, their cargo can be released untimely or undergo degradation before reaching to the target cells. Further, the characteristics of cells itself can also influence the transfection efficacy. For example, the non-dividing property of RPE cells can impede the transfection efficiency which in most studies was ignored by using immortal cell lines. In this study, vectors with different characteristics differing in mixing orders of pDNA, PEI polymer, and PLGA/PEI or PLGA nanoparticles were prepared and characterized. Then, their characteristics and efficacy in gene delivery to RPE cells in the presence of vitreous or fetal bovine serum (FBS) were evaluated. All formulations showed no cytotoxicity and were able to protect pDNA from premature release and degradation in extracellular media. Also, the adsorption of vitreous or serum proteins onto the surface of vectors changed their properties and hence cellular uptake and transfection efficacy.

Preparation and characterization of a gastric floating dosage form of capecitabine.

Gastrointestinal disturbances, such as nausea and vomiting, are considered amongst the main adverse effects associated with oral anticancer drugs due to their fast release in the gastrointestinal tract (GIT). Sustained release formulations with proper release profiles can overcome some side effects of conventional formulations. The current study was designed to prepare sustained release tablets of Capecitabine, which is approved by the Food and Drug Administration (FDA) for the treatment of advanced breast cancer, using hydroxypropyl methylcellulose (HPMC), carbomer934P, sodium alginate, and sodium bicarbonate. Tablets were prepared using the wet granulation method and characterized such that floating lag time, total floating time, hardness, friability, drug content, weight uniformity, and in vitro drug release were investigated. The sustained release tablets showed good hardness and passed the friability test. The tablets' floating lag time was determined to be 30-200 seconds, and it floated more than 24 hours and released the drug for 24 hours. Then, the stability test was done and compared with the initial samples. In conclusion, by adjusting the right ratios of the excipients including release-retarding gel-forming polymers like HPMC K4M, Na alginate, carbomer934P, and sodium bicarbonate, sustained release Capecitabine floating tablet was formulated.