Pharmaceutical Nanotechnology - Volume 9, Issue 2, 2021

Background: Curcumin is a natural phenolic compound exhibiting multiple bioactivities that have been evaluated in vitro, in vivo as well as through clinical studies in humans. Some of them include antimicrobial, antioxidant, anti-inflammatory, and central nervous system protective effects. Further, curcumin is generally recognized as a safe substance because of its low toxicity. However, its molecular structure is susceptible to changes in pH, oxidation, photodegradation, low aqueous solubility, and biotransformation compromising its bioavailability; these drawbacks are successfully addressed through nanotechnology. Objective: The present review systematizes findings on the enhancement of curcumin’s beneficial effects when it is loaded and co-loaded into different types of nanosystems covering liposomes, polymeric and solid-lipid nanoparticles, nanostructured lipid carrier, lipid-polymeric hybrids, self- -assembled and protein-based core-shell systems in relation to its antimicrobial, antioxidant, anti-inflammatory and central nervous system protective bioactivities. Conclusion: Curcumin is a versatile molecule capable of exerting antimicrobial, antioxidant, anti- inflammatory, and central nervous system protective effects in an enhanced manner using the possibilities offered by the nanotechnology-based approach. Its enhanced bioactivities are associated with increments in solubility, stability, bioavailability, as well as in improved intracellular uptake and cell internalization. These advantages, in addition to curcumin’s low toxicity, indicate the potential of curcumin to be loaded and co-loaded into nanosystems capable of providing a controlled release and targeted administration.

Background: Mycophenolic acid (MPA), an immunosuppressive agent, is used orally to reduce corneal graft rejection. However, its oral use is associated with gastrointestinal side effects. Objectives: This study aims to prepare: MPA nanoparticle eye drops and a validated analytical method. Methods: Aqueous MPA eye drops were prepared by nanoencapsulation of MPA using nanomerics MET (N-palamitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan) at a MET and MPA ratio of 7.5: 1 g g-1 in the presence of glycerol (2.75% w/w). A validated MPA formulation drug substance assay was then conducted. Results: MET-MPA formulations were prepared as well as a validated assay. Assay validation parameters for the analysis of MPA in the formulation were satisfactory [Plate count = 16458, capacity Factor = 2.4, Tailing Factor = 1.02, linearity = 0.999 (0.016-0.5 mg mL-1), limit of detection = 0.056 mg mL-1, limit of quantification = 0.17 mg mL-1, accuracy = 98%, intraday and interday relative standard deviation = 0.45% and 4% respectively]. The candidate formulation (z-average mean = 66 ± 0.4 nm, polydispersity index = 0.12 ± 0.012, drug content = 1.14 ± 0.003 mg mL-1, zeta potential = +8.5 ± 1.4 mV, pH = 7.4 ± 0.02, osmolarity = 309 ± 1.5 mOSm L-1, viscosity = 1.04 ± 0.001 mPa.s) was then found to be stable for 14 days with respect to drug content at refrigeration, room and accelerated (40ºC) temperature. All other formulation parameters were within the ocular comfort range. Conclusion: A validated assay (ICH and US FDA guidelines) for new MPA nanoparticle eye drops has been developed.

Background: Honey bee propolis is one of the natural products reported in various traditional systems of medicines, including Ayurveda. Caffeic acid phenethyl ester (CAPE) is an active constituent of propolis which is well known for its anticancer potential. The therapeutic effects of CAPE are restricted owing to its less aqueous solubility and low bioavailability. Objective: In this study CAPE loaded folic acid conjugated nanoparticle system (CLFPN) was investigated to enhance solubility, achieve sustained drug release, and improved cytotoxicity of CAPE Methods: Formulation development, characterization, and optimization were carried out by the design of experiment approach. In vitro and in vivo cytotoxicity study was carried out for optimized formulations. Results: Developed nanoparticles showed particle size and encapsulation efficiency of 170 ± 2-195 ± 3 nm and 75.66 ± 1.52-78.80 ± 1.25%, respectively. Optimized formulation CLFPN showed sustained drug release over a period of 42 h. GI50 concentration was decreased by 46.09% for formulation compared to CAPE in MCF-7 cells, indicating the targeting effect of CLFPN. An improved in vitro cytotoxic effect was reflected in the in vivo Daltons Ascites Lymphoma model by reducing tumor cell count. Conclusion: The desired nanoparticle characteristic with improved in vivo and in vitro cytotoxicity was shown by the developed formulation. Thus it can be further investigated for biomedical applications.

Background: Mirabegron (MBN), a β-3 adrenergic agent, is used in the treatment of overactive bladder. MBN has alow water solubility, high first-pass metabolism, and low bioavailability, consequently having poor absorption in the gastrointestinal tract. Objective: The present study is intended to formulate Mirabegron-loaded solid lipid nanoparticles (MBN-SLN) coated with PEG-400 to bypass hepatic first-pass metabolism and to improve its oral bioavailability. Methods: MBN-SLNs were developed using glyceryl monostearate by pre-emulsion-ultrasonication method, which was then optimized applying Box-Behnken Design. The optimized batch of MBN-SLN was selected for surface-modification with PEG-400 (MBN-PEG-SLN) and characterized by photon correlation spectroscopy, DSC, and XRD. Bioavailability studies were conducted in Wistar rats after oral administration of plain MBN dispersion, MBN-SLN, and MBN-PEG-SLN. Results: Stable MBN-SLNs and MBN-PEG-SLN of the optimized batch having a mean particle size of 162.7 nm and 149.9 nm; zeta potential of -39.1 mV and -30.9 mV; % entrapment of 89.90% and 90.12%, respectively, were developed. The results of the in vitro drug release studies demonstrated a significant slow release of MBN from MBN-SLN (69.38%) and MBN-PEG-SLN (61.33%) as compared to the dispersion of pure drug (92.10%). The relative bioavailability, as a result of the in vivo studies, of MBN from MBN-PEG-SLN increased by 2-fold, based on the Cmax values, in comparison with the plain MBN dispersion. Conclusion: Thus, the study established that the oral bioavailability of MBN could be improved by the administration of MBN-PEG-SLN. The obtained results indicate SLNs as a potential drug delivery system for improving the bioavailability of poorly bioavailable drugs such as MBN by abating the first-pass metabolism.

Background: Envisaging the poor solubility (56 ngml1) and permeability of tetrahydrocurcumin (THCC), it was formulated into lipidic nanostructures to enhance its bioavailability upon topical application to promote the healing process for skin inflammatory disorders. Lack of literature on a suitable method for determining THCC per se and nanoformulations prompted us to develop an RP-HPLC method to detect the drug in its nanostructures and in pig ear skin post dermatokinetics. Objective: The present investigation aimed to develop a simple, precise and RP-HPLC method for the quantitative estimation of THCC in prepared lipidic nanostructures, its ointment, and in skin homogenate obtained post dermatokinetic study. Methods: THCC encapsulated nanostructures and ointment were formulated using a modified emulsification method and embedded into an ointment base to enhance its spreadability and improve patient compliance. A fast and sensitive reverse-phase high-performance liquid chromatography method was developed using a Hypersil BDS reverse phase C18 column (4.6 mm × 250 mm, 5 μm) with mobile phase comprising tetrahydrofuran (THF) and 1 mgmL-1 citric acid (4:6), at a flow rate of 1.0 mLmin-1 with a run time of 20 min. Results: THCC nanostructures were successfully prepared using the spontaneous microemulsification method. THCC was detected at 282 nm and revealed two peaks which were attributed to the keto-enol tautomerism in the molecule with retention times of 6.23 min and 11.06 min, respectively. The assay of THCC in nanostructures and ointment was found to be 98.30 % and 99.98 %, with an entrapment efficiency 77.00±2.74 %. The dermatokinetic studies revealed sufficient release of THCC from its ointment up to 24 hr with a concentration of 1382 μgcm-2, for causing a therapeutic effect. Conclusion: The method was found to be reproducible and robust, as shown by the low coefficient of variation and a constant analyte/IS ratio. It was successfully employed for the estimation of THCC assay in nanostructures and its ointment and dermatokinetic analysis in the skin.

Objective: The aim of the present study was to design a surface modified chitosan nanoparticle system for vaginal delivery of acyclovir for effective drug uptake into vaginal mucosa. Methods: Acyclovir-loaded chitosan nanoparticles, with and without modification by poloxamer 407, were prepared by ionic gelation method. The effects of two independent variables, chitosan to sodium tripolyphosphate mass ratio (X1) and acyclovir concentration (X2), on drug entrapment in nanoparticles were studied using 3² full factorial design. The surface response and counterplots were drawn to facilitate an understanding of the contribution of the variables and their interaction. The nanoparticles were evaluated for drug entrapment, size with zeta potential, morphological analysis by TEM, solid-state characterization by FTIR, DSC, XRD, in vitro dissolution, in vitro cell uptake using HeLa cell line and in vivo vaginal irritation test in Wistar rats. Results: Chitosan nanoparticle formulation with chitosan to sodium tripolyphosphate mass ratio of 2:1 and acyclovir concentration of 2 mg/mL resulted in the highest entrapment efficiency. The resulting nanoparticles revealed spherical morphology with a particle size of 191.2 nm. The surface modification of nanoparticles with poloxamer resulted in higher drug entrapment (74.3±1.5%), higher particle size (391.1 nm) as a result of dense surface coating, lower zeta potential and sustained drug release compared to unmodified nanoparticles. The change in the crystallinity of the drug during nanoparticle formulation was observed in DSC and XRD study. Cellular uptake of poloxamer-modified chitosan nanoparticles was found to be higher than chitosan nanoparticles in HeLa cells. Safety of nanoparticle formulations by vaginal route was evident when tested in female rats. Conclusion: Conclusively, poloxamer-modified CH NP could serve as a promising and safe delivery system with enhanced cellular drug uptake.

Background: Ferric carboxymaltose (FCM) formulation consists of iron-carbohydrate nanoparticles where iron-oxyhydroxide as a core is covered by a carbohydrate shell. The present work provides an improved synthesis process of FCM as an intravenous iron, active pharmaceutical ingredient. Methods: Water-soluble FCM complex was prepared from the reaction of ferric hydroxide precipitation with an aqueous solution of oxidized maltodextrin (MD) at optimum temperature and pH conditions. A systematic approach was followed to obtain the optimal weight ratio of the maltodextrin/ ferric chloride for FCM synthesis process with suitable-sized nanoparticles. Physical characterization of newly synthesized ferric carboxymaltose (FCM-NP) was performed to establish its equivalency with the reference product (Ferinject). Results: The size distribution of the whole nanoparticles determined by dynamic light scattering (DLS) was in the range of 15-40 nm with an average particle size of 26 ± 6.6 and 25.8 ± 4.9 for FCM-NP and Ferinject, respectively. X-ray diffraction (XRD) results of FCM-NP and Ferinject indicated the Akaganeite structure of iron-oxyhydroxide. The iron content of particles (cores) measured by Atomic absorption spectroscopy (AAS) was almost equal for the two formulations. The Fourier transform infrared (FTIR) spectra of Ferinject and FCM-NP were approximately similar. Conclusion: Various analytical methods, including FTIR spectroscopy, XRD analysis, DLS technique, TEM, and AAS were employed. It was observed that the specifications of FCM-NP obtained by these analyses were almost identical to those of Ferinject. Accordingly, the two formulations were considered comparable.