Current Drug Delivery (v.13, #1)

Meet Our Editorial Board Member by Hiraku Onishi (1-2).

Preface by Istvan Toth (3-3).

Nanostructured Lipid Carriers: A Novel Platform for Chemotherapeutics by Md. Rizwanullah, Javed Ahmad, Saima Amin (4-26).
Cancer is a disease manifested as abnormal cells division without control. If it is not detected and cured very timely, it can invade other healthy tissues resulting in metastasis. Chemotherapy is the first line treatment for cancer, but due to lack of specificity of most of the anticancer drugs, is associated with side effects that affect the quality of life. Nanostructured lipid carriers (NLC) are one of the promising nano-carriers for the development of effective targeted therapies for cancer chemotherapeutics. These bio-compatible and/or bio-degradable lipids based nanoparticles are composed of solid and liquid lipids as a core matrix dispersed in surfactant solution. NLC improve the aqueous solubility of most of the hydrophobic cancer therapeutics. Their surface modification can be used for overcoming drug resistance in cancer chemotherapy, to achieve site specific targeting for better efficacy and reduced dose related toxicity. The present review is an attempt to contemplate their pharmaceutical, biopharmaceutical aspects and application in cell targeting, gene delivery and in theranostics.

Infringement of the Barriers of Cancer Via Dietary Phytoconstituents Capsaicin Through Novel Drug Delivery System by Tapan Kumar Giri, Amit Alexander, Ajazuddin, Tapan Kumar Barman, Subhasis Maity (27-39).
Cancer is the major cause of fatality and the number of new cases is increasing incessantly. Conventional therapies and existing anticancer agents cause serious side effects and expand the patient's lifespan by a few years. There is the need to exploit alternative anticancer agents and novel drug delivery system to deliver these agents to the tumor site for the prevention of cancer. Recently, biologically active compounds isolated from plants used for the management of cancer have been the heart of interest. Capsaicin is a major pungent agent present in the chili peppers that is heavily consumed in the world. Capsaicin has demonstrated effectiveness as an anticancer agent, but a restraining factor is its pungency, extremely low aqueous solubility, and poor oral bioavailability which impede its use as an anticancer agent. Many technologies have been developed and applied to conquer this drawback. We bring to light the benefits of this phytoconstituent for treating different types of cancer. We also discussed some of the delivery approaches that have already made an impact by either delivering a drug to target tissue or increasing its bioavailability by many folds.

The hydrophobic long-chain dialkylcarbocyanine 1,1?-dioctadecyl-3,3,3?,3?-tetramethylindotricarbocyanine iodide (DiR) is an important near infrared (NIR) fluorescent dye, which has a satisfactory photo stability for continuous excitation. During the past decade, it has been widely used for in vivo monitoring of cells. With the fast emergence of novel tumor-targeted nanocarriers, the applications of DiR in the development of fluorescent or multifunctional nano-probes for in vivo tumor imaging are also reported. In these studies, DiR-loaded nanocarriers have resulted in good fluorescence images, indicating the great potential of this dye. However, some important issues about DiR-loaded nanocarriers were often overlooked. These issues include the in vivo fluorescent properties, stability, toxicity, retention and metabolization of DiR-loaded nanocarriers. This review introduced the current use and the properties of DiR-loaded nanocarriers for in vivo tumor imaging. The perspective outlook at the last section highlights the future application of DiR-loaded nanocarriers.

Preparation and Characterization of Coaxial Electrospun Fibers Containing Triclosan for Comparative Study of Release Properties with Amoxicillin and Epicatechin by D.E. Rodríguez-Félix, M.M. Castillo-Ortega, A.L Nájera-Luna, A.G. Montaño-Figueroa, I.Y. López-Peña, T. Del Castillo-Castro, F. Rodríguez-Félix, J.M. Quiroz-Castilloc, P.J. Herrera-Franco (49-56).
The optimal conditions for the fibers preparation of cellulose acetate (CA) and poly(vinyl pyrrolidone) (PVP) containing triclosan within the fiber were successfully found; the physicochemical characteristics of these fibrous membranes were corroborated by FTIR spectroscopy, thermal analysis, mechanical tests, SEM , and TEM analysis. The formation of composite fibers of CA and PVP containing triclosan at the core of the fiber was evidenced. A comparative study of the release properties of amoxicillin, epicatechin or triclosan embedded into fibers CA/PVP/CA was performed. As more interactions of the drug with CA or PVP occur, slower release of the drug into the release medium takes place. Regarding the drug delivery system design, it is important to consider the possible molecular interactions between the material components and predict how fast or slow the drug will be delivered into the corresponding medium.

Fabrication of Poly Hydroxybutyrate-Polyethylene Glycol-Folic Acid Nanoparticles Loaded by Paclitaxel by Fatemeh Rezaei, Mohammad Rafienia, Hamid Keshvari, Mansooreh Sattary, Mitra Naeimi, Hossein Keyvani (57-64).
In this study drug (paclitaxel)-loaded nanoparticles of poly hydroxybutyrate-polyethylene glycol-folic acid (PHB-PEG-FOL) were prepared by using an oil-in-water (O/W) emulsion-solvent evaporation method. The functionalization and conjugation steps in the chemical synthesis were confirmed using Fourier transform infrared (FTIR) and nuclear magnetic resonance tests (1H NMR). Morphology of nanoparticles was evaluated by scanning electron microscopy (SEM). Nanoparticles were characterized by particle size analyzer. Between two samples containing drug, the lower doses showed more homogeneous distribution, and the lowest aggregation. The drug release profiles showed a two-phase release including initial rapid release and a continuous release. MG63 cells were used to evaluate cytotoxicity. The cytotoxicity of PHB-PEG-FOL nanoparticles with drug against cancer cells was much higher and longer than free drug sample. These nanoparticles were successfully synthesized as a novel system for targeted drug delivery against cancer cells.

Development and Pharmacokinetic Evaluation of Industrially Viable Self-microemulsifying Drug Delivery Systems (SMEDDS) for Terbinafine by Ankit Baheti, Saurabh Srivastava, Deepak Sahoo, Rohit Lowalekar, Bibhu Prasad Panda, Bijay Kumar Padhi, Rajeev Raghuvanshi (65-75).
Objective: The aim of this study was to develop a formulation for lymphatic uptake with enhanced solubility of antifungal drug, terbinafine by use of self-microemulsifying drug delivery system (SMEDDS); suitable enough to be an industrially feasible and acceptable dosage form. Methods: Pseudo ternary phase diagrams were plotted using suitable oils, surfactants and co-surfactants. The optimized formulation was fabricated and characterized by various in-vitro parameters like droplet size, polydispersity index, zeta potential, cross-polarized light microscopy, thermodynamic stability, viscosity and compatibility with capsule shell. The optimized formulation was also tested in animal model for per oral conceptualization of lymphatic uptake in absence and presence of chylomicron blocker (cycloheximide) followed by the pharmacokinetic evaluation of the same. Results: The self-emulsification time, droplet size, polydispersity index of the optimized formulation remained unaffected in different media (water, 0.1N HCl and phosphate buffer pH 6.8) over the test time period. Crossed-polarized light microscopy examination of diluted SMEDDS formulation indicated that the dispersion was an isotropically stable system. The rate of dissolution for SMEDDS formulation was almost two folds than the marketed formulation (Lamisil®). Current investigation indicates a potential for uptake of the lipid based SMEDDS formulation through lymphatic route with enhanced solubility of the candidate drug terbinafine. The terbinafine SMEDDS when orally administered to rat with and without chylomicron flow blocking agent (cycloheximide) exhibited the area under the curve (AUC0-48 hr) as 7425.44 ng h/ml and 10168.17 ng h/ml respectively hence indicating absorption through the lymphatic route. Thus, the study reaffirms the use of SMEDDS formulation for the drug delivery by lymphatic uptake.

Wound Healing Effect of an in Situ Forming Hydrogel Loading Curcumin-Phospholipid Complex by Lina Du, Xue Feng, Xiaoqin Xiang, Yiguang Jin (76-82).
Wound is one of most commonly clinical diseases. Curcumin is known to improve wound healing but its bioavailability and therapeutic efficiency are very low. Here we firstly report the application of phospholipid complexes to wound healing. A curcumin-phospholipid complex (CPC) was prepared with a solvent-evaporation method. The X-ray diffraction showed that the CPC was amorphous, which was further demonstrated with the electron microscopy. Furthermore, the CPC was loaded into a poloxamer in situ forming hydrogel (ISG). The CPC ISG showed higher erosion rates than the curcumin ISG due to the amorphous structure of CPC, which could lead to increase in curcumin dissolution. The CPC ISG showed higher wound healing effect than the control on the rat skin wound model especially in the early phase. The epidermal recovery was highly improved by the CPC ISG compared to the control. The CPC ISG is a promising formulation as an effective wound healing dressing.

Development and Pharmacokinetic Evaluation of New Oral Formulations of Diacerein by Sagar D. Mandawgade, Swati Kulkarni, Arindam Pal, Saurabh Srivastava, Bijay K. Padhi, Rajeev S. Raghuvanshi (83-89).
The present research investigates development and in vivo evaluation of oral diacerein formulations with quicker and complete absorption. In vivo, diacerein gets completely metabolized to its active metabolite rhein in gut and liver, which is the only analyte detected in plasma. Incomplete absorption of diacerein from the formulation leads to colonic availability of rhein, which is associated with increased laxative effect as one of the side effects of diacerein therapy. Thus solubility improved immediate release formulation (IR) and a gastroretentive formulation (GR) was designed to achieve rapid absorption preferentially through upper part of gastro-intestinal tract; thus controlling the amount of rhein reaching to colon and minimizing the associated increased laxative effect. In vitro drug release studies of the developed formulations revealed faster and complete release of diacerein from IR and GR formulations compared to commercially available diacerein capsule Art®50. Comparative bioavailability studies conducted in healthy human volunteers revealed 1.7 fold and 1.2 fold rise in AUC0-6h for IR and GR formulations respectively, compared to Art®50 capsules. A Levy plot analysis comparing association between the time of in vitro dissolution (Tvitro) of diacerein and time of in vivo absorption (Tvivo) of rhein confirmed faster release and absorption from upper part of gastrointestinal region for both the optimized formulations.

Background: To investigate postoperative endophthalmitis (POE) prevention by moxifloxacin prophylaxis. Methods: After crystalline lens removal and intraocular lens (IOL) implantation, 18 rabbit eyes were injected intracameral with different coagulase negative staphylococci (CNS) inoculums in order to determine the minimum inoculum required for a reproducible POE model. Another 28 similar eyes were divided into Group A, which was implanted with standard IOLs with intracameral injection of 100 ?g/0.1 ml moxifloxacin, Group B implanted with moxifloxacin presoaked IOLs, Group C treated as Groups A and B, and Group D (control) implanted with standard IOLs only. At the end of surgery, all eyes were injected with the minimal inoculum that had developed POE, and treated with topical moxifloxacin for 24 hours. They were then evaluated using 3 different POE scores. Results: The minimum CNS concentration that developed reproducible POE was 5x105 CFUs/0.1 ml. Scores: 1. Clinical endophthalmitis was judged in 5/7 (71%), 4/7 (57%), 2/7 (28%) and 7/7 (100%) of Groups A-D eyes, respectively, p=0.005 and 0.057 for Groups B and C compared to D, respectively. 2. Endophthalmitis Scores for Groups A-D were 14.5±6.8, 10.6±4.5, 12.0±3.9 and 18.6±1.7, respectively, p=0.015, and ~0.07 for Groups B and C compared to D, respectively. 3. Hypoyon was noted in 2/6 (33%), 2/7 (28%), 2/7 and 6/7 (86%) of the Group A-D eyes, respectively, p=0.053, 0.03 and 0.03 for Groups A-C compared to D, respectively. Conclusion: POE can be best prevented by prophylactic moxifloxacin by presoaked IOLs treatment.

Poly(D,L-lactic-co-glycolic acid) nanoparticles (PLGA NPs) have been widely used as drug delivery systems for both small molecules and macromolecules. However, the colloidal stability problem remains unsolved. This study aims to investigate the possibility of using sodium carboxymethyl cellulose (SCMC) as a stabilizing agent of PLGA NPs. In this study, PLGA NPs were fabricated using various concentrations of SCMC (0.01, 0.1 and 0.5% w/v) by solvent displacement method. SCMC coated NPs were characterized using DLS, FTIR, DSC, colorimetric method. Particle size, polydispersity index, zeta potential values and SCMC adsorption increased with SCMC concentration. FTIR spectra, DSC thermograms and results of colorimetry suggested the interaction of SCMC and PLGA NPs. The stability of SCMC coated PLGA NPs was observed during the storage of three weeks in water. The stability of SCMC coated NPs in serum was also evaluated. Cell viability study revealed that there was no toxicity increased when SCMC was used as a stabilizing agent up to a concentration of 0.1% w/v. SCMC coated PLGA NPs bound A549 cells in a time dependent manner and with a greater extent than uncoated PLGA NPs. In conclusion, SCMC can be used to stabilize PLGA NPs by adsorbing on the surface of NPs.

The Effect of Hydrophilic and Hydrophobic Structure of Amphiphilic Polymeric Micelles on Their Transportation in Rats by Feiyang Deng, Chao Yu, Hua Zhang, Wenbing Dai, Bing He, Ying Zheng, Xueqing Wang, Qiang Zhang (105-110).
In the previous study, we have clarified how the hydrophilic and hydrophobic structures of amphiphilic polymers impact the transport of their micelles (PEEP-PCL, PEG-PCL and PEG-DSPE micelles) in epithelial MDCK cells (Biomaterials 2013, 34: 6284-6298). In this study, we attempt to clarify the behavior of the three micelles in rats. Coumarin-6 loaded micelles were injected into different sections of intestine of rats and observed by confocal laser scanning microscope (CLSM) or orally administrated and conducted pharmacokinetic study. All of the three kinds of micelles were able to cross the intestinal epithelial cells and enter blood circulation. The PEEP-PCL micelles demonstrated the fastest distribution mainly in duodenum, while the PEGDSPE micelles showed the longest distribution with the highest proportion in ileum of the three. No significant difference was observed among the pharmacokinetic parameters of the three micelles. The results were consistent in the two analysis methods mentioned above, yet there were some differences between in vivo and in vitro results reported previously. It might be the distinction between the environments in MDCK model and intestine that led to the discrepancy. The hydrophobicity of nanoparticles could both enhance uptake and hinder the transport across the mucus. However, there was no intact mucus in MDCK model, which preferred hydrophobic nanoparticles. PEEP was the most hydrophilic material constructing the micelles in the study and its uptake would be increased in rats compared to that in MDCK model, while DSPE was more hydrophobic than the others and MDCK model would be more ideal for its uptake. Considering the inconsistency of the results in the two models, whether the methods researchers were generally using at present were reasonable needs further investigation.

In vitro Percutaneous Absorption of Niacinamide and Phytosterols and in vivo Evaluation of their Effect on Skin Barrier Recovery by Alessia Offerta, Francesco Bonina, Franco Gasparri, Andrea Zanardi, Lucia Micicchè, Carmelo Puglia (111-120).
In this study, we evaluated different strategies to optimize the percutaneous absorption of niacinamide (NA) and soy phytosterols (FITO) by making use of solid lipid nanoparticles (SLN) and penetration enhancers, such as the hydrogenated lecithin. The evaluation of the skin permeation of NA and FITO has been effected in vitro using excised human skin (i.e., stratum corneum-epidermis or SCE). Furthermore, we evaluated the in vivo effect that NA and FITO has on skin barrier recovery after the topical application; using the extent of methyl nicotinate (MN)-induced erythema in damaged skin as a parameter to determine the rate of stratum corneum recovery. Results pointed out the importance of these strategies as valid tools for NA and FITO topical delivery. In fact, soy lecithin based formulations were able to increase the percutaneous absorption of the two active ingredients, while SLN guaranteed an interesting delayed and sustained release of FITO. In vivo evaluation showed clearly that the formulation containing both the actives (NA and FITO) is able to recover about 95% of skin barrier integrity eight days after tape stripping. This effect is probably due to the “synergistic effect” of NA and FITO.

Enterotoxigenic Escherichia coli (ETEC) infection is one of the major causes contributing to the development of diarrhoea and mortality in new born, suckling and newly weaned piglets. To date, no preventive/treatment strategy showed promising results, which could be due to the lack of potent vaccines, and/or due to the development of resistance of ETEC to antibiotics. Therefore, in the present investigation, a novel porous sodium alginate (SA) tablet formulation loaded with F4 fimbriae antigen was developed and tested for efficacy against ETEC infections in piglet models. Precompression parameters of the powder mixes and post compression parameters of tablets have been evaluated and results were found to be satisfactory. Loading of F4 fimbrial antigens into the tablets was achieved by inducing pores in the tablets via the sublimation of camphor followed by incubation with purified F4 fimbriae. The loaded tablets have been coated with Eudragit L100 to protect the F4 fimbriae from (a) highly acidic gastric environment; (b) proteolytic cleavage by pepsin; and (c) to promote subsequent release in the intestine. Evaluation of developed F4 fimbrial tablets in a Pig model demonstrated induction of mucosal immunity, and a significant reduction of F4+ E. coli in faeces. Therefore, F4 fimbriae loaded porous tablets could be a novel oral vaccination candidate to induce mucosal and systemic immunity against ETEC infections.

Enhancing in vivo Bioavailability in Beagle Dogs of GLM-7 as a Novel Anti-Leukemia Drug through a Self-Emulsifying Drug Delivery System for Oral Delivery by Yuli Wang, Ning Yu, Rui Guo, Meiyan Yang, Li Shan, Wei Huang, Wei Gong, Shuai Shao, Xiaoping Chen, Chunsheng Gao (131-142).
GLM-7 is a novel anti-leukemia drug in the pre-clinical study. The previous study shows that GLM-7 is a poorly water-soluble drug with low oral bioavailability. In this study, we employed the self-emulsifying drug delivery system (SEDDS) to improve the oral bioavailability of GLM-7. The GLM-7 SEDDS formulation was prepared using MCT as oil, ovolecithin as surfactant and Transcutol as co-surfactant, and the formulation parameters were optimized by the response surface methodology. The optimized GLM-7 SEDDS formulation showed a stable liquid state, and can automatically emulsify to form the isotropic emulsion once exposure to the water phase. The generated emulsion showed the spherical shape, and had an average size of about 399nm and a zeta potential of about -42mV. Compared to the GLM-7 dissolution less than 1.4% from pure GLM-7 powder (reference), the GLM-7 SEDDS formulation could remarkably enhance the in vitro dissolution to 83% in the medium of 0.1N HCL. The in vivo oral bioavailability of GLM-7 SEDDS formulation was investigated in beagle dogs. The results demonstrated that the GLM-7 SEDDS formulation significantly enhanced the plasma concentrations of GLM-7, and the Cmax reached to 878ng/ml and was 9.2 folds as high as the Cmax 95.85ng/ml of reference. Moreover, the area under the curve (AUC) of GLM-7 SEDDS formulation was 13.6 times higher than that of reference, which suggested that the SEDDS formulation remarkably increased the oral bioavailability of GLM-7.

Application of Central Composite Design in Optimization of Valsartan Nanosuspension to Enhance its Solubility and Stability by Lavakumar Vuppalapati, Sowmya Cherukuri, Vijaykumar Neeli, Padmanabha Reddy Yeragamreddy, Bhaskar Reddy Kesavan (143-157).
The objective of the present research is to prepare stable nano suspensions of Valsartan (VAL) with high solubility and dissolution. VAL is an orally administered anti-hypertensive drug with lower bio-availability of 25%, this is attributed to its lower aqueous solubility (0.082 mg/ml). VAL nano suspensions were prepared by using a bottom-up precipitation technique using five level full factorial central composite design (CCD). The optimized nano formulations NS21, NS22, NS23 showed the particle size of 268.42±8.99, 288.3±11.32, 293.46±6.92 nm, zeta potential of 20.89±0.79, 26.01 ±1.02, 21.34±0.43 mVs and the dissolution efficiency of 93.10±1.459, 91.84±1.419, 89.47±0.644 % respectively. SEM & AFM studies represent the formation of fine irregularly shaped particles with smooth surfaces on nanosization. X-rd studies confirmed the physical state conversion of crystalline drug into amorphous form. Drug excipient compatibility was studied using differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FT-IR). The investigation pragmatic the solubility and dissolution efficiency of VAL in nanosuspension was significantly higher when compared with its pure form. Finally, it is concluded that, nanosuspension approach could be an ideal, promising approach to increase the solubility and dissolution of BCS-II drugs like Valsartan.

Effect of Glycine on Adipocyte Hypertrophy in a Metabolic Syndrome Rat Model by Yazmín Reyes López, Israel Pérez-Torres, Alejandra Zúñiga-Muñoz, Verónica Guarner Lans, Eulises Díaz-Díaz, Elizabeth Soria Castro, Rodrigo Velázquez Espejel (158-169).
Glycine (Gly) lowers hypercholesterolemia, hypertriglyceridemia and hypertension but its role in preventing adipocyte hypertrophy and modulating enzymatic activity of adipocytes has not been studied. Here we evaluate the effect of 1% Gly in the diet on adipocyte hypertrophy and the modulation of lipoprotein lipase (LPL) and hormone-sensitive lipase (HSL) in a metabolic syndrome (MS) rat model with intra-abdominal obesity. 32 Wistar rats were divided into 3 groups: control (C), MS, MS plus Gly (MS+Gly), and MS+Gly plus strychnine (MS+Gly+S). MS was induced by administering 30% sucrose in the drinking water for 16 weeks. In the MS+Gly and MS+Gly+S groups, the sucrose solution plus 1% Gly and 1 % Gly plus strychnine 10 ?M were given during the last 4 weeks of the sucrose treatment. After 16 weeks of treatment, rats were sacrificed and the adipose tissue dissected. Gly in MS rats decreased body weight, intra-abdominal adipose tissue, adipocyte hypertrophy, blood pressure, triglycerides, insulin, HOMA-IR index, leptin, total fatty acids, non-esterified fatty acids and LPL activity. It increased fatty acids of the phospholipids, perilipin A expression and it decreased HSL expression, without changing LPL expression. The Gly receptor subunit-? was identified in adipocytes. In conclusion, Gly treatment regulates the activity of enzymes involved in the lipid metabolism of the adipocytes through the Gly receptor and it decreases the effects of the high sucrose diet.