Current Drug Delivery - Volume 13, Issue 6, 2016

The convergence of nano and biotechnology is enabling scientific and technical knowledge for improving human well being. Carbon nanotubes have become most fascinating material to be studied and unveil new avenues in the field of nanobiotechnology. The nanometer size and high aspect ratio of the CNTs are the two distinct features, which have contributed to diverse biomedical applications. They have captured the attention as nanoscale materials due to their nanometric structure and remarkable list of superlative and extravagant properties that encouraged their exploitation for promising applications. Significant progress has been made in order to overcome some of the major hurdles towards biomedical application of nanomaterials, especially on issues regarding the aqueous solubility/dispersion and safety of CNTs. Functionalized CNTs have been used in drug targeting, imaging, and in the efficient delivery of gene and nucleic acids. CNTs have also demonstrated great potential in diverse biomedical uses like drug targeting, imaging, cancer treatment, tissue regeneration, diagnostics, biosensing, genetic engineering and so forth. The present review highlights the possible potential of CNTs in diagnostics, imaging and targeted delivery of bioactives and also outlines the future opportunities for biomedical applications.

Background: Glaucoma is an ocular disorder characterized by optic nerve damage which ultimately causes a progressive and an irreversible loss of vision, often characterized by an elevated intraocular pressure. Lowering the intraocular pressure (IOP) is the mainstay for glaucoma treatment but the neuroprotective agents would represent a promising class as the next-generation therapy. Evidence synthesis: Protein kinases are involved considerably in signal transduction pathways confirmed by various mechanisms giving the evidence of Rho-kinase to be a versatile therapeutic target. Rho associated protein kinases also known as ROCK are serine/threonine kinases, belonging to the Ras superfamily of GTPases. The activation of Rho Kinase results in various actin-myosin arbitrated processes where contraction of actomyosin in the resident trabecular meshwork (TM) cells and extracellular matrix is responsible for the outflow of aqueous humour. Another major drawback of the currently available antiglaucoma drugs is their topical use which poses a problem for patient compliance. The patient intolerability and adherence to the existing therapy therefore call for newer drug delivery systems that would increase the clinical efficacy of the drugs. Conclusion: The neuroprotective agents are not considered suitable to be administered through the traditional topical or oral route. This complementary drug therapy requires a delivery system that could release the drug to the optic nerve in a sustained manner and also increase patient compliance and tolerability. This review summarizes the use of ROCK inhibitors that could prevent the damage to the optic nerve along with the reduction in IOP and novel drug delivery systems to increase the efficacy of the drugs.

Colorectal cancer is the third most common type of cancer in both, men and women. The development of metastasis is very frequent, especially in patients with advanced stage, who require intensive chemotherapy that often results in poor response and significant morbidity. The undesirable effects of intensive chemotherapy on normal cells and the development of multidrug resistance are two of the main causes of treatment failure. Recent advances in nanotechnology allow to target cancer cells using cytotoxic drugs without affecting normal cells. Nanocarriers such as liposomes, polymeric nanoparticles and carbon nanotubes, among others, are able to improve drug distribution and bioavailability, cytotoxic concentration in the tumor mass and drug delivery to tumor tissue and, at the same time, reduce side effects. Current research studies are being conducted to develop new biomaterials that improve the characteristics of these nanomolecules. Several preclinical assays have disclosed the efficacy of nanotherapy in colon cancer, although further clinical trials will be necessary to demonstrate its efficacy. This review discusses the current status and the potential advantages of using nanocarrier-based drug delivery systems for colorectal cancer.

In recent period of time the mesoporous silica nanoparticles (MSNs) have been extensively utilised in controlled release (CR) applications. This burgeoning research is favoured because of the unique characteristics of the MSNs such as, ordered and homogenous pore network, high surface area and pore volumes, silanol-containing surfaces, and relatively low toxic in nature. However, for an effective targeted drug delivery, these materials offer numerous challenges such as, to reduce the complications and toxicity and avoid any undesired interactions of the MSNs with the untargeted healthy cells and membranes. A range of concepts and techniques have been implied to overcome these challenges. This article presents an overview on the recent research advancements in CR of drugs and bioactive compounds from the MSNs. Based on the past researches that took place over the last 15 years, the article illustrates three particular areas: 1) unmodified MSNs, 2) modified MSNs, and 3) biocompatibility, bio-toxicity, tissue responses and cellular uptakes of the MSNs. The three encompassed areas of research describe enormous diversities and complexities which span the aspects of complex designs and syntheses, types of silica materials being used, drug loadings, types of drug used, and ranges of biological evaluations of the MSNs. Perspectives and insights are presented into a range of aspects such as, syntheses, characterisations, functionalisation and incorporations of biomacromolecules into the MSNs; drug loadings and drug release kinetics; biological evaluations such as, biocompatibility, bio-toxicity and intracellular drug delivery; and, the effects of size, shape, morphology, structural and textural properties of the MSNs.

Background: Colloidal systems are most prominent delivery systems mainly used as vehicles for the transportation, targeting the various types of biomolecules, proteins, peptides, synthetic medicinal agents. Objective: To provide concise information on patents that are directly or indirectly related to the nanoemulsions. Methods: The ample of research work going on with such system, in which small insoluble particle/droplets are dispersed within the immiscible secondary liquid referred to as continuous phase, is enormous. A highly praised colloidal system is nanoemulsion which possesses ‘nano’ sized droplets of one phase dispersed within second continuous phase. Results: The characteristic features of nanoemulsion are their optical clarity, clear or bluish tint appearance and small globule size (20-200 nm) which makes them insensitive to gravitational instability, dilution and temperature. Above of all, achieving said properties using lower surfactant concentration and by supplying external energy differentiate them from microemulsion, which uses higher amount of surfactant thereby making them toxic for human body. Due to such variable advantages, researchers are engaged in going for the protecting their ideas in nanoemulsions by filling various patents. Conclusion: Patents in this review, covers various areas (types of drug delivery and applications) where nanoemulsion are used. Literature revealed that filing of patents on nanoemulsion increased tremendously during last 5 years and will increase in upcoming time as 21st century will be called as the century of nanomedicine.

Background: The use of triptans in the treatment of migraine was a breakthrough. Their selective agonistic action at serotonin (5-hydroxytryptamine) receptors has provided insights into the pathophysiology of migraine and represented a significant advance in migraine pharmacotherapy. Sumatriptan was the first synthesized triptan available for clinical use in the United States. Although it revolutionized the treatment of migraine, it demonstrated some drawbacks, e.g. poor oral bioavailability, erratic absorption, and high rate of headache recurrence. New triptans have been developed namely; almotriptan, zolmitriptan, rizatriptan, eletriptan, frovatriptan and naratriptan, with each one demonstrating specific pharmacokinetic parameters that may be translated into clinical advantage. Although second generation triptans possess better bioavailability compared to sumatriptan, they all still need improvement. Objective: This review illustrates a survey for the available researches aimed to enhance triptans’ bioavailability and hence effectiveness, either by investigating alternative routes of administration, other than oral route and/or designing appropriate formulations. Results: Promising results were gained by many researchers after studying different routes for triptans’ administration, e.g. nasal, buccal, sublingual, transdermal and pulmonary using well designed formulations, e.g. nanocarriers, microcarriers, orodispersible tablets or films, in situ gels, microneedles for transdermal application, etc. Conclusion: Utilizing alternative routes for triptans’ administration in addition to designing appropriate formulations, were successful approaches. However, further investigations should be conducted to establish their bioavailability and in vitro- in vivo correlation studies are also required, to confirm the potential of the designed formulations for use in humans, hence novel efficient triptans’ formulations may appear on the market in the near future.

The use of different drug classes as host modulating agents has been postulated to have significance as an adjunctive remedy curing chronic periodontitis. In this study nano-structured films containing doxycyclin (DOX) were evaluated for such purpose. Nano DOX/chitosan particulate system was prepared using spray drying technique and was then incorporated in PVA-based films. The particles were evaluated for particle size, zeta potential and possible drug/polymer interaction. The films were also tested for in-vitro drug release and clinical efficacy compared with placebo and DOX-loaded films. The formed particles had a zeta potential of + 13.8 mV and particle size of 52.86 nm with a polydispersity of PDI=0.946. No significant drug/polymer interaction was detected by DSC thermal analysis. In-vitro DOX release was sustained for about a week with the nano-structured films showing 23% of the drug released compared with 44% released from DOX films. Clinical efficacy was done on 150 periodontal pockets from patients suffering from moderate chronic periodontitis. Following scaling and root planning they were divided into three groups; group I receiving nano-structured (DOX), group II receiving DOX and group III receiving placebo films. Evaluation was done both clinically and biochemically at base-line, 1 week, 1 month and 2 months following drug application. Clinical findings indicated a significant effect of both nano-structured and DOX films in improving the measured parameters compared with the control and placebo groups.

Background: Mycobacterium tuberculosis (M. TB) remains the prime cause of bacterial mortality and morbidity world-wide. Therefore, effective delivery and targeting of drug to the cellular tropics is essentially required to generate significant results for tuberculosis treatment. The aim of the present study was to develop and characterize ligand anchored pH sensitive liposomes (TPSL) as dry powder inhaler for the targeted delivery of drugs in the target site i.e. lungs. Method: Ligand anchored PSL (TPSL) was prepared by thin film hydration for the combined delivery of Isoniazid (INH) and Ciprofloxacin HCl (CIP HCl) using 4-aminophenyl-α-D mannopyranoside (Man) as surface functionalized ligand and characterized using different parameters. Results: It was observed that size of the ligand anchored liposomes (TPSL) was slightly more than the non-ligand anchored liposomes (PSL). Drug release was studied at different pH for 24 hrs and it was observed that liposomes exhibited slow release at alkaline pH (58-64%) as compared to macrophage pH (81-87%) where it increased dramatically due to the destabilization of pH sensitive liposome (PSL). In vitro cellular uptake study showed that much higher concentration was achieved in the alveolar macrophage using ligand anchored liposomes as compared to its counterpart. In vivo study showed that maximum drug accumulation was achieved in the lung by delivering drug using ligand anchored PSL as compared to conventional PSL. Conclusion: It was concluded that ligand anchored pH sensitive liposome is one of the promising systems for the targeted drug therapy in pulmonary tuberculosis.

Background: Herpes keratitis is the most common infectious cause of blindness in the developed world. It may be treated by acyclovir (ACV), however this antiviral drug is poorly soluble with low ocular bioavailability requiring high and frequent dosing. Nanostructured lipid carriers (NLCs) were investigated to improve the ocular bioavailability of ACV by enhancing corneal penetration as well as prolonging the exposure of infected cells to the antiviral agent. Methods: Cell uptake studies, ex vivo tolerance and cell uptake efficacy as well as in vivo corneal permeation of the developed lipid based formulations were investigated. NLCs were fabricated by the hot microemulsion technique and coated with 0.5% w/v chitosan. NLCs were capable of increasing the cell uptake of encapsulated fluorescein and ACV as examined by fluorescence microscopy and high performance liquid chromatography (HPLC) respectively. Results: When entrapped in NLCs, the antiviral efficacy of ACV was increased by 3.5 fold after 24 hrs of exposure. The in vivo corneal permeation of the formulation was studied on Albino rabbits with NLCs capable of increasing the corneal bioavailability by 4.5 fold when compared to a commercially available ACV ophthalmic ointment. Conclusion: NLCs enhanced the ocular bioavailability and antiviral properties of ACV through cell internalisation, sustained release, and increased corneal permeation.

Background: Use of nucleic acids to treat acquired or inherited hepatic diseases has considerable potential. Although recombinant viruses are popular vectors, interest in cheaper, often less immunogenic, non-viral modalities, is increasing. Thus hepatotropic, galactosylated lipoplexes directed to the hepatic asialoglycoprotein receptor (ASGP-R) are promising candidates. Objective: Here we examine the effect that galactosyl ligand spacer length has on the transfection activity of ASGP-Rtargeted lipoplexes in the human hepatoma cell line HepG2. Methods: Galactosyl ligands with spacer lengths in the range 2.4-24.1 Å were prepared and formulated into lipoplexes that were characterized by cryo-TEM, band shift, dye displacement and nuclease digestion assays. Cytotoxicity and transfection profiles were determined in liver-derived HepG2 cells and the renal ASGP-R-negative HEK293 line. Results: Lipoplexes, which formed at endpoint +/- charge ratios in the range 1:1-3:1, accorded cargo DNA good protection from serum nuclease digestion and were well-tolerated by both cell lines. Transfection activities in the hepatoma cell line decreased markedly in the presence of a competing ASGP-R cognate ligand and also as the ligand spacer length increased, while activities in HEK293 cells were significantly lower (P <0.05-0.001). Conclusion: Targeted lipoplexes enter HepG2 cells by receptor mediation and the uptake of transfecting complexes and those displaying more rigid short and medium length spacers is more efficient. This observation will inform the design of hepatotropic lipoplexes that are suitable for applications in vivo.

Background: Tetrandrine (Tet), a kind of herbal medicine belonging to the family of bis-benzylisoquinoline alkaloid, has gained more attraction for its potential anti-tumor effects. However, its potential utilization in clinic is greatly hampered by the poor pharmacokinetcs profile due to its insolubility. Recently, biodegradable polymeric nanoparticles with amphilic copolymers as drug carriers have shown better bioavailability against tumor as promising tumor-targeted drug delivery system. Methods: In the current study, Tet-loaded nanoparticles (Tet-NPs) was prepared with amphiphilic block copolymer as drug carriers. The physiochemical characterization, in vitro and in vivo antitumor effect of nanoparticles were evaluated. Results: In vitro study demonstrated the superior cell inhibitory effect of Tet-NPs. Most importantly, the viability of cells exposed to Tet-NPs was significant lower than that of cells treated with free Tet at lower equivalent doses. Moreover, Tet- NPs induced apoptosis and inhibited the proliferation of cells more effectively than free did at the equivalent concentration. Western blot showed that the expression of anti-apoptotic protein Bcl-2, Bcl-XL was significantly promoted while the pro-apoptotic Bax was significantly inhibited by the treatment of Tet-NPs. Conclusion: Data from the current study suggested that Tet-NPs is a promising delivery nano-system for the treatment of osteosarcoma.

The low bioavailability and consequently the poor therapeutic response of traditional ophthalmic formulations is caused by reduced pre-corneal residence time of the formulation in contact with the ocular surface. The use of colloidal carrier systems, namely lipid nanoparticles in combination with in situ gelling polymers, is an excellent strategy which results in the exponential increase of the bioavailability of ophthalmic drugs. In the present study, we have developed thermoresponsive eyedrops prepared with nanostructured lipid carriers (NLC) dispersions for the controlled delivery of ibuprofen. Lipid solubility studies and DSC measurements have proved that the lipids solubilise ibuprofen and present a good compatibility. NLC were prepared based on the melt-emulsification and ultrasonication technique and lipid nanoparticles with a Z-average of 120-150 nm, polydispersity index below 0.3, highly positive zeta potential and an efficacy of encapsulation of ~87% were obtained. The cytotoxicity of NLC was evaluated by the Alamar Blue reduction assay using the Y-79 human retinoblastoma cell line, and no relevant toxicity was observed after exposure to 0-100 μg/mL NLC for up to 72 hours. The HET-CAM assay was used to assess the product eye compatibility, confirming that the developed product does not exhibit irritant potential. The in vitro release studies showed ibuprofen release over several hours.

A central composite design was applied to design a novel gastric floating drug delivery system comprising propranolol HCl in Terminalia catappa gum and to evaluate the buoyancy, in vitro drug release behavior, and pharmacokinetic parameters. All formulations exhibited good buoyancy properties in vitro reflected by floating lag time of 1-110 sec, total floating time of 9-16 h and prolonged release behaviour (upto 12 h). Statistically optimised formulation (PBGRso) was orally administered to human volunteers under both fasted and fed conditions to evaluate gastric floating behavior under different food conditions by X-ray evaluation. In vivo studies of optimised formulations revealed that the gastric residence time of floating tablets was enhanced in the fed but not in the fasted state. Pharmacokinetic studies of the optimised Terminalia catappa formulation and a commercial product (Ciplar LA 80) carried out on healthy human volunteers showed a significant improvement in the bioavailability (132%) of propranolol HCl released from from the experimental Terminalia catappa formulations compared with Ciplar LA 80.

Background: Amphotericin B eye drops are widely used in the treatment of ocular infections. However, amphotericin’s toxicity leads to low patient compliance and aggravation of symptoms. This work describes the development of a microemulsion system containing amphotericin B, aiming for its use in ocular applications. Methods: The microemulsion was developed by the titration technique. The physicochemical characteristics were determined with both loaded and unloaded amphotericin B-microemulsion. The nanostructures were analyzed by polarized light microscopy. The microdilution method was used to establish the minimum inhibitory concentration against fungal strains, and, therefore, evaluate the microemulsion activity. Additionally, in order to evaluate the microemulsion toxicity an in vitro toxicity assay against red blood cells was performed. Results: The performed studies showed that the presence of amphotericin B loaded into the system did not induce serious changes in the physicochemical properties of the microemulsion when compared to the unloaded system. The spectrophotometric studies depicted amphotericin B-self-associated species, which allow predicting its behavior in vitro. The high pressure liquid chromatography results revealed high drug content entrapment in the microemulsion droplet. Finally, the amphotericin B-microemulsion in vitro susceptibility test showed high activity against Candida strains and a low toxicity profile against red blood cells when compared to Fungizone®. Conclusion: The physicochemical characterization of the microemulsion demonstrated that its characteristics are compatible with the topical ocular route, making it eligible for consideration as a new and interesting amphotericin B-deliverydosage form to be used as eye drop formulation.

In present investigation, an innovative attempt has been made to enhance the solubility and dissolution rate of Repaglinide (RPGD) using hydrothermally treated water insoluble dietary bamboo fibers (HVBF) as potential nutraceutical used in the treatment of diabetes mellitus. RPGD was selected as a model drug due to its low aqueous solubility and dissolution rate. Characterization of HVBF demonstrated the outstanding features like high surface area, maximum drug loading and increase dissolution rate and making HVBF as an excellent drug carrier. RHVBF (Repaglinide loaded HVBF) tablets were prepared using direct compression method. Pre and post-compression parameters for blend and tablets were studied and found within acceptable limits. RHVBF and tablet showed significantly improved dissolution rate, when compared with pure crystalline RPGD, physical mixture, RVBF and commercial marketed tablet. This fact was further supported by FT-IR, DSC, XRPD and FESEM studies followed by in-vitro drug release profile. Stability studies showed no changes after exposing to accelerated conditions for a period of 3 months with respect to physical characteristics and in-vitro drug release studies. In a nut shell, it can be concluded that HVBF is a novel, smart and promising carrier for poorly water soluble drugs, when administered orally.