Current Drug Delivery (v.13, #8)

Meet Our Editorial Board Member: by Yvonne Perrie (1183-1183).

Novel Carriers for Coenzyme Q10 Delivery by Sunil Kumar, Rekha Rao, Anil Kumar, Sheefali Mahant, Sanju Nanda (1184-1204).
Background: Coenzyme Q10, a natural yellow benzoquinone, is a vitamin-like substance commonly found in blood and inner mitochondrial and cellular membranes. It is a natural antioxidant principle which plays an essential role in maintaining several biochemical pathways of body. It has exhibited many pharmacological activities in chronic heart failure, cardiofaciocutaneous syndrome, diabetes mellitus, carcinomas, autoimmune disease, cataract, asthma, periodontal disease and thyroid disorders. Moreover, it has demonstrated efficacy as nutritional supplement, in addition to its relevance in cosmetics.
Objective: Coenzyme Q10 is a potent molecule but its high molecular weight and low aqueous solubility hamper its use as a therapeutic agent. Therefore, various novel drug delivery systems have been explored and developed to overcome these limitations in literature. Hence, objective of this review is to summarize the recent works on design and development of novel drug delivery systems for CoQ10, which include liposomes, polymeric nanoparticles, polymeric micelles, solid lipid nanoparticles, nanostructured lipid carriers, self-emulsifying drug delivery systems, nanoemulsions, solid and aqueous dispersions. Further, an account of pharmaceutical studies has also been given.
Results & Conclusion: The reported studies indicate the promise of nanotechnology in enhancing the therapeutic value of CoQ10, promoting its usage as first line therapeutic agent, thus, revolutionizing its role in current medical therapy. The application of CoQ10 in pharmaceutical industry has grown tremendously in the past decade, due to its versatile nature. The successful application of this molecule in medicine, cosmetics and nutraceuticals points the way for its future development.

Background: Parkinson's disease (PD) is depicted as the most prevailed neurodegenerative disease being secondary to the Alzheimer's disease. PD is featured by severe dropping of dopamine related neurons present in substantia nigra as well as cytoplasmic inclusions. A number of therapeutic agents are available to treat initial as well as later complications of PD. However, transport of neurotherapeutics into the brain has been a consistent challenge for researchers, because of the existence of blood-brain barrier (BBB). In some last decades, nasal delivery pathway has gained extensive deliberations. Intranasal administration as a way to target neurotherapeutics to the central nervous system bypassing blood brain barrier, exhibit several advantages for treating neurodegenerative disorders. This route for transport of neurotherapeutics offers the merits of convenience of administration, avoidance of pre-systemic hepatic metabolism, and non- invasiveness.
Methods: Novel nano-sized formulations researched for intranasal transport of various actives have been reviewed using search engine “Scopus”. Feasibility of various nano-carriers systems such as nanoemulsions, lipid nanoparticles and polymeric micelles has been elaborated. The write up traces the preclinical and pharmacokinetic aspects of the nano-formulations.
Results: Nano-formulations are the rising formulations in PD treatment as they offer targeted drug delivery, enhanced therapeutic efficacy and decreased systemic side effects of neurotherapeutics. These formulations provide effective intranasal transport by encapsulating drug, protecting it from biological/ chemical degradation and extracellular transport through P-glycoprotein (P-gp) efflux thus, and enhancing CNS availability for drugs.
Conclusion: Thus, it can be put into conclusion that nano-neurotechnology; particularly application of nanotechnology has yielded potential outcomes in upcoming years.

Nanosuspension: Principles, Perspectives and Practices by Sachin Kumar Singh, Yogyata Vaidya, Monica Gulati, Sibasis Bhattacharya, Varun Garg, Narendra Kumar Pandey (1222-1246).
In the last three decades, nano-sizing of hydrophobic drugs has emerged as one of the most commonly used strategies to overcome their solubility and bioavailability related issues. Nanosuspensions offer versatile features and unique advantages over other approaches that have been utilized for this purpose. The unique inherent properties of nanosuspensions have been explored for a wide variety of applications. Commercial production of stable nanosuspensions has been made possible by the use of techniques such as media milling and high pressure homogenization. This article reviews various techniques being employed for production, characterization, merits and limitations of nanosuspensions and mechanisms that play a role in the physicochemical stability of nanosuspensions. The common strategies applied so far to overcome their stability and commercialization related aspects are also highlighted.

Background: Quality by Design (QbD) is an approach encouraged by regulatory bodies and applied by pharmaceutical industries to improve the quality of the final product. The objective of this paper is to describe via a QbD approach the available knowledge on the formulation and manufacturing of solid lipid nanoparticles (SLN) for ocular applications using hot high pressure homogeniser (HPH).
Methods: The formulation of SLN for the ocular delivery of a hydrophilic peptide is discussed based on a QbD perspective, where the knowledge is gathered from literature references.
Results: The Quality Target Product Profile (QTPP) is defined, followed by a description of the Critical Quality Attributes (CQA) and Critical Material Attributes (CMA). After having described the manufacturing process via hot HPH, the Critical Process Parameters (CPP) are discussed along with the possible control strategies.
Conclusions: The QbD approach for the development of a SLN for ocular application described in this review paper can be used as starting point for similar applications.

In the past few decades, nanoparticles have shown their advantages in anti-cancer therapy. After intravenous injection, they could preferentially arrive at tumor tissue either by extravasation from tumor vasculature or targeting vascular endothelial cells. But at the same time, their quantity in mononuclear phagocyte system (MPS) is far more than that in tumor. In this review, we discuss the advantages of MPS in spleen and liver over tumor on competing nanoparticles. The biophysical causes of spleen and liver help the MPS to capture nanoparticles, such as sufficient flux of blood stream, capillary network with fenestrations in liver and venous sinuses in spleen. Meanwhile, liver and spleen are the two major organs that contain MPS. Various properties of nanoparticles may affect their biodistribution. It is suggested that nanoparticles with proper size and shape, suitable charge, polyethyleneglycol and ligands will minimize the clearance by MPS. Several novel and promising approaches for cancer therapy are introduced in this review. This review seeks to provide guidelines for improving nanoparticles accumulation in tumor through both optimizing nanoparticles design and novel ways to design nanodelivery system for cancer therapy.

Opportunities and Challenges for Niosomes as Drug Delivery Systems by Miloni Thakkar, Brijesh S. (1275-1289).
Background: With the increase in drug resistance observed in most infectious diseases as well as some forms of cancer, and with the chances of development of new drug molecules to address this issue looking bleak, one of the most plausible ways to disease treatment is combination therapy.
Purpose: Combination therapy would ensure delay in drug resistance, if utilized rationally. However, the biggest difficulty in employing combination therapy are adverse effects due to potential drug-drug interactions and patient compliance due to multiple routes of administration or multiple dosing that may be required. To overcome these issues, researchers have utilized nanoparticle-based systems that can hold multiple drugs in a single carrier. There are several nanocarrier systems available for such purposes. However, the focus of this review will be non-ionic surfactant-based systems (niosomes) for delivery of multiple therapeutic agents. Niosomes are artificially prepared drug delivery carriers. They are structurally similar to liposomes albeit more stable than them.
Methods: Literature pertaining to combination drug delivery and various drug delivery systems was reviewed. It was conceptualized that many of the methods used to prepare various types of carriers for combination delivery of drugs may be used for niosomal systems as well.
Conclusion: We envisage that niosomes may effectively be utilized to package older drugs in newer ways. The review will thus focus on techniques that may be used for the formulation of niosomes, ways to encapsulate multiple-drug moieties, and challenges associated in preparing and optimizing such systems.

Nanoparticles for Cancer Targeting: Current and Future Directions by Suryakanta Swain, Prafulla Kumar Sahu, Sarwar Beg, Sitty Manohar Babu (1290-1302).
The targeting of pharmaceuticals is a rapidly evolving strategy to overcome the difficulties in therapeutic delivery, especially to the tumor site. Unlike traditional drug delivery systems, nanoparticles based compounds attain superior accretion in the tumor site by their active or passive mechanisms. Due to their exclusive properties like small size, large surface-to-volume ratio, tunable surface chemistry, and the ability to encapsulate various drugs, the nano-sized carriers provide longer circulation time; easy penetration into cellular membranes; efficient site-specific targeting. Recent advancements in polymeric- nanomedicines involve targeting of polymer-based nanoparticles (NPs), micelles, polyplexes, dendrimers, polymersomes, drug/protein conjugates and lipid hybrid systems to tumor pathological site. With different functional moieties, NPs improve the performance in terms of targetability, circulation longevity, enhanced intracellular penetration, stimuli-sensitivity, and carrier-mediated visualization. This review highlighted different preparative techniques and types of nanoparticles in the most recent developments in cancer treatment including promising opportunities in targeted; combination therapy; and other medical and biomedical applications. Various delivery strategies and future prospects of nanoparticles are also enlisted. Apart from that, the review discusses the potential advances and targeting of polymeric nanocarriers within the scope of cancer therapeutic system to emphasize it as an auxiliary tool to the customary drug delivery systems.

Identification of Novel Small-Molecule ASGP-R Ligands by Alexander G. Majouga, Yan A. Ivanenkov, Mark S. Veselov, Anton V. Lopuhov, Svetlana V. Maklakova, Elena K. Beloglazkina, Petr V. Binevski, Natalya L. Klyachko, Yuri B. Sandulenko, Natalia Y. Galkina, Victor E. Koteliansky (1303-1312).
During the past decade asialoglycoprotein receptor (ASGP-R) expressed predominantly by hepatocytes has attracted a considerable attention as a convenient biomolecular trap for targeted drug delivery. Currently, several selective galactose-containing ligands equipped by drug molecules, e.g. known anticancer therapeutics, as well as diagnostic tools are under active preclinical development. In this paper, we have carried out a rational in silico screening among the molecules available in ChemDiv collection and compounds provided by our colleagues to reveal potential ASGP-R binders. Thus, 3D molecular docking approach provided a set of 100 `high score` molecules that was subsequently evaluated in vitro using an advanced Surface Plasmon Resonance (SPR) technique. As a result, dozens of novel small-molecule ASGP-R ligands with high diversity in structure were identified. Several hits showed the binding affinity much more better than that determined for galactose and Nacetylgalactosamine which were used as reference compounds. The disclosed molecules can be reasonably regarded as promising molecular devices for targeted drug delivery to hepatocytes.

Background: Gemcitabine (GEM) is a highly hydrophil anticancer drug which extensively used in the clinic for the treatment of a range of solid tumors, including pancreatic and lung cancers. We have designed a drug delivery system based on single-walled carbon nanotubes (SWCNTs) for the anticancer drug GEM, which has limitations under biological conditions, by using polyethylene glycol (PEG) to obtain nanoconjugates with high loading capacity, controlled drug release and effective cytotoxicity.
Methods: Raw SWCNTs were functionalized through carboxylation, acylation, PEGylation and finally GEM conjugation via a cleavable ester bond. Different characterization techniques such as Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance spectrometer (NMR) and differential scanning calorimetry analysis (DSC) were performed to confirm the successful functionalization. Next, the influence of molecular weight (MW) of PEG on the drug loading capacity, drug release and cytotoxicity was studied.
Results: Experimental results showed that the drug loading capacity was dependent on the MW of PEG, but the drug release was independent. Also, the results revealed that the nanoconjugates with lower PEG MW caused higher cytotoxicity in A549 and MIA PaCa-2 cancer cells.
Conclusion: Our studies indicated which of PEG MWs could be useful for this drug delivery system.

Capsicum fruit is used for treating skeletomuscular disorders as a counterirritant analgesic around the globe. But its concentration-dependent irritation and concomitant withdrawal of therapy by the patients hampers its therapeutic usefulness. In the present study, a novel nanolipid approach based on elastic phospholipid vesicles was employed to encapsulate a semipurified extract of Bhut Jolokia for topical drug delivery application. The working hypothesis was that encapsulation of irritant extract into nanolipid vesicles may prevent the initial rejection of formulation and the elastic vesicles may facilitate deeper skin penetration over a shorter time period. Surface response methodology was adopted to study the effect of selected independent formulation variables on dependent variables like vesicle size and entrapment efficacy. The prepared formulations were characterized for various physicochemical parameters. The efficacy of the newly developed nonolipid vesicle formulation loaded with semipurified extract of Bhut Jolokia was tested on carrageenan and formaldehyde-induced inflammation as well as Freund's adjuvant-induced arthritis model. The novel formulations were tested on human volunteers in a Phase I clinical trial and were found to be acceptable. The study indicates that this strategy holds immense potential for topical delivery of the bioactive from Bhut Jolokia and can pave the way for its clinical applications.

The Anticancer Activity of Complex [Cu2(?-(C6H5)2CHCOO)3(bipy)2)] (ClO4) -Solid Lipid Nanoparticles on MCF-7 Cells by Ibrahim Kani, Gokhan Dikmen, Gamze Guney Eskiler, Gulsah Cecener, Berrin Tunca, Unal Egeli (1339-1350).
Recent studies have focused on the potential use of metal-based complexes for the treatment of cancer. However, there are some limitations of metal-based ligands for the treatment of cancer due to their toxic effects. In the present study, a novel bimetallic Cu(II) complex, [Cu2(?-(C6H5)2CHCOO)3 (bipy)2)](ClO4), has firstly been synthesized and characterized by FT-IR, and X-ray crystallography. Furthermore, Cu(II) complex-loaded solid lipid nanoparticles (SLNs) were initially prepared by hot homogenization method to overcome their toxic effects. After characterization, comparative cytotoxic and apoptotic activities of the complex and Cu(II) complex-SLNs on human breast cancer cells (MCF-7) and human umbilical vein endothelial cells (HUVEC) were determined. Cu(II) complex demonstrated considerable in vitro cytotoxic effects on MCF-7 (p<0.05) and induced apoptotic cell death (88.02 ± 3.95%) of MCF-7 cells. But, the complex has also toxic effects (69.5%) on HUVEC control cells. For this purpose, Cu(II) complex-loaded solid lipid nanoparticles (SLN) were firstly produced, with a distrubution range of 190±1.45 nm to 350±1.72 nm and zeta potentials of ?27.4±1.98 mV and ?18.2±1.07 mV, respectively. The scanning electron microscopy (SEM) images of SLNs were also obtained. In vitro studies have shown that Cu(II) complex-SLNs help in reducing the side effect of Cu(II) complex (29.9%) on HUVEC control cells. Therefore, metal based complex might potentially be used for cancer treatment through nanoparticle based drug delivery systems.

A Lipid Base Formulation for Intramuscular Administration of a Novel Sulfur Donor for Cyanide Antagonism by Kristof Kovacs, Prashanth K. Jayanna, Anna Duke, Brittany Winner, Melaeni Negrito, Siva Angalakurthi, Jorn C.C. Yu, Petra F&#252;redi, Krisztina Lud&#225;nyi, Peter Sipos, Gary A. Rockwood, Ilona Petrikovics (1351-1357).
This study represents a new formulation of the novel Cyanide (CN) antidote, Dimethyl trisulfide (DMTS), for intramuscular administration. This is a naturally occurring organosulfur molecule with the capability of reacting with CN more efficiently than the present sulfur donor type CN therapy of Thiosulfate (TS). Two types of micelles (PEG2000-DSPE and PEG2000-DSPE/TPGS) were prepared and tested for their ability to encapsulate the liquid, highly lipophilic and volatile drug, DMTS. The micellar encapsulation for DMTS does not only eliminate the possible muscle necrosis at the injection sites, but the rate of evaporation within the micelles is suppressed, that can provide a level of stability for the formulation. The method of micelle preparation was optimized and it was demonstrated that the PEG2000-DSPE preparation can dissolve up to 2.0 mg/ml of the antidote candidate. Keeping the injection volume minimized this could provide a maximum DMTS dose of 12.5 mg/kg. However, even this low dose of DMTS showed a remarkable in vivo therapeutic efficacy (2 X LD50 protection) in a mice model when injected intramuscularly. These in vitro and in vivo findings proved the efficacy of DMTS in combating CN intoxication, and the presented work gives valuable insight to micelle preparation and sets the bases for a more advanced future formulation of DMTS.

Ursolic Acid Nanocrystals for Dissolution Rate and Bioavailability Enhancement: Influence of Different Particle Size by Jiaxin Pi, Zhidong Liu, Hao Wang, Xing Gu, Shuya Wang, Bing Zhang, Hansen Luan, Zhuangzhi Zhu (1358-1366).
Background: Ursolic acid (UA), a natural pentacyclic triterpenoid, has been reported to possess a variety of pharmacological activities, but the poor oral bioavailability of UA owing to the poor aqueous solubility and membrane permeability limits the further clinical application.
Objective: The purpose of the present study was to develop UA nanocrystals and microcrystals employing high pressure homogenization (HPH) and to evaluate their effects on UA oral bioavailability.
Method: The crystalline morphology of UA nanocrystals and microcrystals prepared by HPH was observed by scanning electron microscopy and the crystalline state was characterized by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). The dissolution rate of UA nanocrystals in different pH conditions was tested. Oral bioavailability of UA nanocrystals and microcrystals comparing with UA coarse suspension was evaluated in SD rats after 50 mg·kg-1 administration.
Results: UA nanocrystals and microcrystals, the size of which ranged between 291.7 nm and 1299.3 nm were obtained. The results of DSC and PXRD revealed a degree of crystalline-amorphous transformation during HPH preparation. A significant increase was observed in the dissolution rate of UA nanocrystals. The relative bioavailability of UA nanocrystals and microcrystals exhibited 2.56 and 1.40-fold enhancement than that of UA coarse suspension, respectively, along with an increased peak concentration and a prolonged retention.
Conclusion: The nanosized UA crystal is a viable and efficient approach to improve the oral bioavailability of UA.