Topical Tacrolimus Progylcosomes Nano-Vesicles As a Potential Therapy for Experimental Dry Eye Syndrome.

The present work aimed to evaluate the efficacy of topical tacrolimus (0.01%) loaded propylene glycol (PG) modified nano-vesicles (Proglycosomes Nano-vesicles, PNVs) for the treatment of experimental dry eye syndrome (DES) in rabbits. DES was induced by topical application of atropine (1.0%) and benzalkonium chloride (0.1%) aqueous solution. PNVs treatment (PNV group) was compared with tacrolimus solution 0.01% (TAC group) and untreated group and healthy group were used as controls. PNV treated animals showed improved clinical performance with marked increase in tear production and tear break-up time (TBUT). Further, PNVs also subside ocular inflammation as evident from absence of matrix metalloprotenaise-9 and normal ocular surface temperature (32.3 ± 0.34 °C). Additionally, PNVs have positive effect on ocular and epithelial damage observed through low ocular surface staining score and improved globlet cell density. The PNV treatment was found to more effectively compared to TAC solution and most of the parameters were close to those of healthy animals. In conclusion, tacrolimus PNV formulation (0.01%) could be a potential therapy for treatment of dry eye syndrome.

Brucine-loaded transliposomes nanogel for topical delivery in skin cancer: statistical optimization, in vitro and dermatokinetic evaluation.

The aim of the present study was to develop, optimize brucine-loaded transliposomes (BRC-TL) formulation for dermal delivery of brucine for skin cancer. The BRC-TL formulations were evaluated for vesicle size, entrapment efficiency, and in vitro drug release. The optimized formulation was further evaluated for skin penetration by confocal laser microscopy and dermatokinetic study. The optimized BRC-TL formulation presented sealed lamellar shaped vesicles, with vesicles size, polydispersity index, entrapment efficiency, and in vitro drug release of 136.20 ± 2.87 nm, 0.354 ± 0.02, 86.01 ± 1.27%, and 83.09 ± 2.07%, respectively. Ex vivo permeation study showed that, developed BRC-TL formulation had a 2.4-fold increment in permeation as compared to BRC suspension. Texture analysis showed that the BRC-TL gel presented firmness of 158.91 g, consistency of 615.03 g/s, cohesiveness of - 115.26 g and a viscosity index of - 472.05 g/s. The confocal images of rat skin clearly showed the deeper penetration of rhodamine B-loaded TL formulation as compared to the Rhodamine B-hydro alcoholic solution. The optimized BRC-TL formulation demonstrated significantly higher cytotoxicity than placebo liposome and BRC suspension (P < 0.05). Further, the BRC-TL nanogel treated rat skin showed a substantial increase in CSkin max and AUC0-8 in comparison to rat skin treated with BRC conventional gel (P < 0.05). The data revealed that the developed TLs formulation could be a promising drug nanocarrier for brucine dermal delivery in the treatment of skin cancer.

Formulation development, optimization, and in vitro assessment of thermoresponsive ophthalmic pluronic F127-chitosan in situ tacrolimus gel.

To overcome problems associated with topical delivery of tacrolimus (TCS), a thermoresponsive in situ gel system containing pluronic F127 (PL), and chitosan (CS) was developed, to enhance the precorneal retention, and to sustain the release of the drug. The PL-CS in situ gel was optimized using a 2-factor-3-level central composite experimental design by selecting the concentration of PL and CS as independent variables while gelation time, gelation temperature, and spreadability as dependent variables. The optimized formulation was developed using 22.5 g PL and 0.3 g CS, gels at 33.6 °C, in 22.93 s, and showed the spreadability of 6.2 cm. In vitro studies conducted for the optimized gel revealed the sustained release of TCS (81.73% in 4 h) and improved corneal permeation (74.13% in 4 h), compared with TCS solution. The mechanism of release of TCS followed the Higuchi model with Fickian diffusion transport. Further, histopathology and HET-CAM studies revealed that the developed gel was non-irritating and safe for ocular administration.

Emerging advances in cationic liposomal cancer nanovaccines: opportunities and challenges.

Advancements in the field of cancer therapeutics have witnessed a recent surge in the use of liposomes. The physicochemical characteristics of the liposomes and their components, including the lipid phase transition temperature, vesicular size and size distribution, surface properties, and route of administration, play a significant role in the modulation of the immune response as an adjuvant and for loaded antigen (Ag). Cationic liposomes, concerning their potential ability to amplify the immunogenicity of the loaded Ag/adjuvant, have received enormous interest as a promising vaccine delivery platform for cancer immunotherapy. In the present review, the physicochemical considerations for the development of Ag/adjuvant-loaded liposomes and the cationic liposomes' effectiveness for promoting cancer immunotherapy have been summarized.

Recent Patents, Regulatory Issues, and Toxicity of Nanoparticles in Neuronal Disorders.

BACKGROUND: Form last few decades, nanoparticles have witnessed breakthroughs in the treatment of neurological disorders due to their unique physiochemical properties, which make them an effective drug delivery system. However, there is not much information available on the toxicity of nanoparticles in neuronal disorders. The toxic effect of nanoparticles on brain disorders and their regulatory issues are the primary concerns of the healthcare industry. METHODS: A strategical literature search was performed on various bibliographic databases such as Scopus, PubMed, SciFinder, Google Scholar, Medline, Google Patent, Derwent Innovation, and Orbit Intelligence for retrieval of peer-reviewed articles and patents on regulatory issues and toxicity of nanoparticles in neuronal disorders for last decade. The relevant hits of articles and patents were analyzed, and citation search for the relevant documents was carried out. RESULTS: The literature documents have been summarized regarding the existing regulatory issues and toxicity of nanoparticles on neuronal disorders with a focus on the detailed mechanism of the developmental toxicity of nanoparticles. The focus of this report is to emphasize the negative effects of nanoparticle on neuronal disorders, which may partially contribute to the management of toxicity of nanoparticles. CONCLUSION: Although nanoparticles have unique physical and chemical properties that explain the broad range of application for the central nervous system, they can also manifest neurotoxic effects due to cell necrosis, generation of free radicals, immune responses and neuroinflammation. Thus, this review highlights risk assessment, safety regulations and regulatory guidelines of nanoparticles, which may reduce adverse reactions in humans and animals.

Date seed extract-loaded oil-in-water nanoemulsion: Development, characterization, and antioxidant activity as a delivery model for rheumatoid arthritis.

Rheumatoid arthritis is an inflammatory disorder, affecting around 1% of the world population. Antioxidant activity plays important role to overcome the inflammation associated with arthritis. Phoenix dactylifera (date) seeds, generally considered as a waste product or utilized as food for domestic farm animals, have been used as a source of antioxidants at different disease conditions. The aim of the present study was to enhance the release of date seed extract in order to achieve high antioxidant activity. Nanoemulsion of methanolic extract of date seed was prepared by aqueous titration method. The selected formulations were exposed to thermodynamic stability and dispersibility tests. The optimized nanoemulsions were evaluated on the basis of droplet size (23.14 ± 0.055nm), polydispersity index (0.166 ± 0.124), percent transmittance (99.12 ± 0.0163), refractive index (1.36 ± 0.046), viscosity (cP) (12.30 ± 0.75), conductivity (µS/cm) (347.46 ± 1.10), and drug content (%) (99.67 ± 0.11). The in vitro release studies revealed that final optimized formulation has cumulative release of drug (57.51% ± 2.65%), which was more significantly greater as compared to drug suspension (26.44% ± 1.15%). Further in vitro antioxidant activity studies revealed that the developed methanolic extract of date seed-loaded nanoemulsion has more antioxidant potential when compared with methanolic extract.

3D Printing Methods for Pharmaceutical Manufacturing: Opportunity and Challenges.

BACKGROUND: A recently FDA approved 3D printed drug is paving a path for new pharmaceutical manufacturing era. The 3D printing is a novel approach of producing 3D pharmaceuticals from digital designs, in a layer-by-layer fashion. However, traditional manufacturing of drug products is being carried out from decades with well-established manufacturing processes and with well approved regulatory guidelines but these processes are too obsolete in concern of process aptitude and manufacturing flexibility. On the other hand, 3D printing provides a competitive flexibility in terms of personalized drug dosage forms with complex geometries that will be made on-demand with desired drug release kinetics, hence providing the formulator a substantial provision of improvising the safety and efficacy of the drugs. Furthermore, this novel 3D technology allows tailoring of composite tissue scaffolds and sample models for characterization that closely mimic in-vivo simulations. Nevertheless, certain limitations are there in terms of regulatory aspects hindering the launch of 3DP products in the market. METHODS: Exhaustive search were made on Google Scholar and PubMed databases concerning 3-D printing methods, drug delivery applications, and past to present evolution of personalized medicine. RESULTS: Although a high magnitude of progress have been made on 3-D printing techniques in a short span of time, still inkjet, nozzle-based deposition, stereolithography and selective laser sintering techniques are the most popular ones. Their application is adapted in the fabrication of tablets, implants, polypills and nanoparticles. CONCLUSION: 3D printing is revolutionizing the pharma expectations towards customized medicines but still there is a need to explore the aspects of cost, flexibility and bioequivalence. The present review provides a comprehensive account of various 3D printing technologies and highlights the opportunities and key challenges of 3D printing relevant to pharmaceuticals.

Magnetic Nanoparticles: A Review on Stratagems of Fabrication an d its Biomedical Applications.

BACKGROUND: The aim of this review is to provide an insight to the underlying biomedical applications of magnetic nanoparticles (MNPs). METHODS: The most specific characteristic of MNPs is their response to an applied magnetic force, and this property of MNPs has been utilized in applications such as diagnosis of diseases, drug delivery and drug targeting. Currently, MNPs have attracted great attention because of their potential as contrast agents for magnetic resonance imaging (MRI) and heat mediators for cancer therapy (hyperthermia). RESULTS: Furthermore, the MNPs are also being used to achieve targeted delivery of biological molecules. Nowadays cancer is one of the biggest challenges and our goal is not only to improve the therapeutic outcome, but also to improve the methods of treatment along with the minimum adverse effect. Some suitable conclusions have been quoted on the precise synthesis approaches by focusing the mechanism of MNPs and new modification made on the production of these nanoparticles. CONCLUSION: In this review diverse biomedical application of MNPs were also addressed and patents related remarks also made from the literature.

Experimental investigation and oral bioavailability enhancement of nano-sized curcumin by using supercritical anti-solvent process.

The biomedical applications of curcumin (CUR) are limited due to its poor oral bioavailability. In this work, CUR nanoparticles were successfully prepared by combining the supercritical anti-solvent (SAS) process with Tween 80 as a solubilizing agent and permeation enhancer. Different processing parameters that can govern the mean particle size and size distribution of nanoparticles were well investigated by manipulating the types of solvents, mixing vessel pressure, mixing vessel temperature, CO2 flow rate, solution flow rate and solution concentration. Solid state characterization was done by Fourier Transform infrared spectroscopy, differential scanning calorimetry, dynamic light scattering, scanning electron microscopy, and powder X-ray diffraction study. Solubility and dissolution profile of SAS-processed CUR were found to be significantly increased in comparison with native CUR. Further, a validated ultra-performance liquid chromatographic method with quadrupole-time of flight-mass spectrometry was developed to investigate the pharmacokinetic parameters after a single oral dose (100mg/kg) administration of CUR (before/after SAS-processed) in male Wistar rats. From the plasma concentration vs. time profile graph, oral bioavailability of SAS-processed CUR was found to be increased approximately 11.6-fold (p<0.001) as compared to native CUR.

Dorzolamide-loaded PLGA/vitamin E TPGS nanoparticles for glaucoma therapy: Pharmacoscintigraphy study and evaluation of extended ocular hypotensive effect in rabbits.

Poor drug penetration and rapid clearance after topical instillation of a drug formulation into the eyes are the major causes for the lower ocular bioavailability from conventional eye drops. Along with this, poor encapsulation efficiency of hydrophilic drug in polymeric nanoparticles remains a major formulation challenge. Taking this perspective into consideration, dorzolamide (DZ)-loaded PLGA nanoparticles were developed employing two different emulsifiers (PVA and vitamin E TPGS) and the effects of various formulation and process variables on particle size and encapsulation efficiency were assessed. Nanoparticles emulsified with vitamin E TPGS (DZ-T-NPs) were found to possess enhanced drug encapsulation (59.8±6.1%) as compared to those developed with PVA as emulsifier (DZ-P-NPs). Transcorneal permeation study revealed a significant enhancement in permeation (1.8-2.5 fold) as compared to solution. In addition, ex vivo biodistribution study showed a higher concentration of drug in the aqueous humour (1.5-2.3 fold). Histological and IR-camera studies proved the non-irritant potential of the formulations. Pharmacoscintigraphic studies revealed the reduced corneal clearance, as well as naso-lachrymal drainage in comparison to drug solution. Furthermore, efficacy study revealed that DZ-P-NPs and DZ-T-NPs significantly reduced the intraocular pressure by 22.81% and 29.12%, respectively, after a single topical instillation into the eye.

Therapeutic stratagems for vascular degenerative disorders of the posterior eye.

In this review we discuss insights into therapeutic stratagems that can selectively target the choroid, retinal cells and vitreoretinal space for the treatment of vision-threatening vascular degenerative disorders of the posterior eye. Despite the relative success of these novel drugs, new problems related to its delivery remain. Systems carrying drugs to the target site, such as nanoparticles, liposomes, vectosomes, spanlastics, micelles, dendrimers and implants are also discussed. Further, we also consider drug penetration enhancement approaches along with cutting-edge strategies for regaining vision during vision-threatening vascular degenerative disorders of the eye. Finally, challenges, such as ocular or even systemic complications associated with use of prolonged therapies and future prospects, such as combination of approaches with multidisciplinary integration to optimize delivery to the posterior eye are also addressed.

Dual approach utilizing self microemulsifying technique and novel P-gp inhibitor for effective delivery of taxanes.

In the present work, concomitant use of self-microemulsifying drug delivery systems (SMEDDS) and a novel third-generation P-gp inhibitor, GF120918 (elacridar), for the effective transport of taxanes (paclitaxel and docetaxel) across an in vitro model of the intestinal epithelium and uptake into tumor cells were investigated. On the basis of solubility studies and ternary phase diagrams, different SMEDDS formulations of taxanes were prepared and characterized. In caco-2 cell permeation study, paclitaxel-loaded SMEDDS along with GF120918 showed a four-fold increase in apparent permeability, while docetaxel-loaded SMEDDS in combination with GF120918 showed a nine-fold increase in permeability, as compared to plain drug solution. Cell uptake studies on A549 cells were performed with microemulsions formed from both SMEDDS formulations loaded with rhodamine 123 dye and showed good uptake than plain dye solution. Confocal laser scanning microscopic images further confirmed the higher uptake of both SMEDDS formulations in the presence of GF120918.

Enhanced antimalarial activity of lumefantrine nanopowder prepared by wet-milling DYNO MILL technique.

Lumefantrine (LMF) is an antimalarial drug that exhibits poor oral bioavailability, owing to its poor aqueous solubility. To improve its antimalarial activity, nanopowder formulation using DYNO MILL was prepared. Combination of HPMC E3 (4%, w/v) and Tween 80 (2.5%, w/v) as dispersing agents, favored the production of smaller LMF particles with mean size of 0.251 µm. LMF nanopowder showed enhanced dissolution rate attributed to nanonization of LMF. The IC(50) value of nano-sized LMF was found to be 0.1 ng/mL, which was 175-times lower than the IC(50) value of unmilled LMF powder (17.5 ng/mL) and 42-times lower than the IC(50) value of chloroquine (4.2 ng/mL). The in vivo antimalarial activity demonstrated an enhanced antimalarial potential of LMF nanopowder against P. Yoelii nigeriensis compared to unmilled drug. Wet-milling using DYNO MILL offers a highly effective approach to produce stable drug nanopowders. Furthermore, LMF nanopowder makes the Coartem therapy more effective.

Development and evaluation of nanosized niosomal dispersion for oral delivery of Ganciclovir.

Encapsulation of Ganciclovir in lipophilic vesicular structure may be expected to enhance the oral absorption and prolong the existence of the drug in the systemic circulation. So the purpose of the present study was to improve the oral bioavailability of Ganciclovir by preparing nanosized niosomal dispersion. Niosomes were prepared from Span40, Span60, and Cholesterol in the molar ratio of 1:1, 2:1, 3:1, and 3:2 using reverse evaporation method. The developed niosomal dispersions were characterized for entrapment efficiency, size, shape, in vitro drug release, release kinetic study, and in vivo performance. Optimized formulation (NG8; Span60:Cholesterol 3:2 molar ratio) has shown a significantly high encapsulation of Ganciclovir (89±2.13%) with vesicle size of 144±3.47 nm (polydispersity index [PDI]=0.08). The in vitro release study signifies sustained release profile of niosomal dispersions. Release profile of prepared formulations have shown that more than 85.2±0.015% drug was released in 24 h with zero-order release kinetics. The results obtained also revealed that the types of surfactant and Cholesterol content ratio altered the entrapment efficiency, size, and drug release rate from niosomes. In vivo study on rats reveals five-time increment in bioavailability of Ganciclovir after oral administration of optimized formulation (NG8) as compared with tablet. The effective drug concentration (>0.69 µg/mL in plasma) was also maintained for at least 8 h on administration of the niosomal formulation. In conclusion, niosomes can be proposed as a potential oral delivery system for the effective delivery of Ganciclovir.

Enhanced bioavailability of nano-sized chitosan-atorvastatin conjugate after oral administration to rats.

A novel approach to improve the bioavailability and stability of atorvastatin (AT) was developed by constructing a nano-sized polymer-atorvastatin conjugate. Firstly, a novel chitosan-atorvastatin (CH-AT) conjugate was efficiently synthesized through amide coupling reaction. The formation of conjugate was confirmed by (1)H NMR and FT-IR spectrometry. Nano-sized conjugate with a mean size of 215.3±14.2 nm was prepared by the process of high pressure homogenization (HPH). Scanning electron microscopy (SEM) revealed that CH-AT nano-conjugate possess smooth surface whereas X-ray diffraction (XRD) spectra demonstrated amorphous nature of nano-conjugate. Further, CH-AT nano-conjugate showed solubility enhancement of nearly 4-fold and 100-fold compared to CH-AT conjugate and pure AT, respectively. In vitro drug release studies in simulated gastric fluid and simulated intestinal fluid suggested sustained release of AT from the conjugate. Additionally, the nano-conjugate significantly reduced the acidic degradation of AT. The plasma-concentration time profile of AT after oral administration of CH-AT nano-conjugate (2574±95.4 ng/mL) to rat exhibited nearly 5-fold increase in bioavailability compared with AT suspension (583±55.5 ng/mL). Finally, variable bioavailability, as observed for AT suspension was also reduced when AT was administered in form of CH-AT nano-conjugate. Taken together these data demonstrate that chitosan conjugate nano-prodrugs may be used as sustained polymeric prodrugs for enhancing bioavailability.