Modern drug delivery strategies applied to natural active compounds

Introduction: Colloidal drug delivery systems (CDDSs) are innovative carriers that have been studied in pharmaceutical field from many years to overcome unfavorable physical and chemical features of synthetic drugs. Recently the use of CDDS as carriers for phytochemicals has seen an exponential increase which, in some cases, has led to the rediscovery of ancient and forgotten natural molecules.

Area covered: This article focuses on the main features of CDDS, particularly micro- and nanoemulsions, vesicular carriers and micro- and nanoparticles, loaded with natural active compounds. A detailed review of the literature is presented, introducing the importance of these systems in terms of their capability to optimize the stability of phytochemicals, their absorption through biological membranes and their bioavailability.

Expert opinion: The delivery of phytochemicals is problematic due to poor solubility, poor permeability, low bioavailability, instability in biological milieu and extensive first-pass metabolism. Global research efforts investigating nanotechnology have attempted to overcome these limitations rediscovering and, in some cases, ‘discovering ex novo’ unexpected virtues and benefits associated to these compounds. The ‘nanotechnological approach’ can definitely enhance the pharmacokinetics and therapeutic index of natural active compounds and improve their performance in therapy.     

Multiple linear regression applied to predicting droplet size of complex perfluorocarbon nanoemulsions for biomedical applications

Multiple linear regression (MLR) modeling as a novel methodological advancement for design, development, and optimization of perfluorocarbon nanoemulsions (PFC NEs) is presented. The goal of the presented work is to develop MLR methods applicable to design, development, and optimization of PFC NEs in broad range of biomedical uses. Depending on the intended use of PFC NEs as either therapeutics or diagnostics, NE composition differs in respect to specific applications (e.g. magnetic resonance imaging, drug delivery, etc). PFC NE composition can significantly impact on PFC NE droplet size which impacts the NE performance and quality. We demonstrated earlier that microfluidization combined with sonication produces stable emulsions with high level of reproducibility. The goal of the presented work was to establish correlation between droplet size and composition in complex PFC-in-oil-in-water NEs while manufacturing process parameters are kept constant. Under these conditions, we demonstrate that MLR model can predict droplet size based on formulation variables such as amount and type of PFC oil and hydrocarbon oil. To the best of our knowledge, this is the first report where PFC NE composition was directly related to its colloidal properties and MLR used to predict colloidal properties from composition variables.     

Hexamethyldisiloxane-based nanoprobes for (1) H MRI oximetry

Quantitative in vivo oximetry has been reported using ¹⁹F MRI in conjunction with reporter molecules, such as perfluorocarbons, for tissue oxygenation (pO₂). Recently, hexamethyldisiloxane (HMDSO) has been proposed as a promising alternative reporter molecule for ¹H MRI‐based measurement of pO₂. To aid biocompatibility for potential systemic administration, we prepared various nanoemulsion formulations using a wide range of HMDSO volume fractions and HMDSO to surfactant ratios. Calibration curves (R₁ versus pO₂) for all emulsion formulations were found to be linear and similar to neat HMDSO for low surfactant concentrations (< 10% v/v). A small temperature dependence in the calibration curves was observed, similar to previous reports on neat HMDSO, and was characterized to be approximately 1 Torr/ °C under hypoxic conditions. To demonstrate application in vivo, 100 µL of this nanoemulsion was administered to healthy rat thigh muscle (Fisher 344, n = 6). Dynamic changes in mean thigh tissue pO₂ were measured using the PISTOL (proton imaging of siloxanes to map tissue oxygenation levels) technique in response to oxygen challenge. Changing the inhaled gas to oxygen for 30 min increased the mean pO₂ significantly (p < 0.001) from 39 ± 7 to 275 ± 27 Torr. When the breathing gas was switched back to air, the tissue pO₂ decreased to a mean value of 45 ± 6 Torr, not significantly different from baseline (p > 0.05), in 25 min. A first‐order exponential fit to this part of the pO₂ data (i.e. after oxygen challenge) yielded an oxygen consumption‐related kinetic parameter k = 0.21 ± 0.04 min^?1. These results demonstrate the feasibility of using HMDSO nanoemulsions as nanoprobes of pO₂ and their utility to assess oxygen dynamics in vivo, further developing quantitative ¹H MRI oximetry. Copyright © 2011 John Wiley & Sons, Ltd.     

Utilization of nanoemulsions to enhance bioactivity of pharmaceuticals,supplements, and nutraceuticals: Nanoemulsion delivery systems and nanoemulsion excipient systems

ABSTRACT

Introduction: The efficacy of many hydrophobic bioactives (pharmaceuticals, supplements, and nutraceuticals) is limited due to their relatively low or highly variable bioavailability. Nanoemulsions consisting of small lipid droplets (r < 100 nm) dispersed in water can be designed to improve bioavailability.

Areas covered: The major factors limiting the oral bioavailability of hydrophobic bioactive agents are highlighted: bioaccessibility, absorption and transformation. Two nanoemulsion-based approaches to control these processes and improve bioavailability are discussed: nanoemulsion delivery systems (NDS) and nanoemulsion excipient systems (NES). In NDS, hydrophobic bioactives are dissolved within the lipid phase of oil-in-water nanoemulsions. In NES, the bioactives are present within a conventional drug, supplement, or food, which is consumed with an oil-in-water nanoemulsion. Examples of NDS and NES utilization to improve bioactive bioavailability are given.

Expert opinion: Considerable progress has been made in nanoemulsion design, fabrication, and testing. This knowledge facilitates the design of new formulations to improve the bioavailability of pharmaceuticals, supplements, and nutraceuticals. NDS and NES must be carefully designed based on the major factors limiting the bioavailability of specific bioactives. Research is still required to ensure these systems are commercially viable, and to demonstrate their safety and efficacy using animal and human feeding studies.     

紫杉醇-油酸和鸦胆子油分子配型组装纳米乳给药系统研究

目的优化紫杉醇-油酸(PTX-OA)和鸦胆子油(BJO)分子配型组装纳米乳给药系统(PTX-OA/BJO CMNEs)的处方及制备工艺。方法通过酯化反应制备得PTX-OA并建立检测PTX-OA的HPLC方法。采用超声乳化法制备PTX-OA/BJO CMNEs。单因素实验选出对PTX-OA/BJO CMNEs粒径影响较大的3个因素,L16(43)正交试验以这3个因素油相质量浓度(A)、聚山梨酯-80用量(B)和超声功率(C)为考察因素,以平均粒径为评价标准,优选PTX-OA/BJO CMNEs的处方及制备工艺。对优选条件制备的PTX-OA/BJO CMNEs进行制剂学评价及体外细胞毒实验。结果 HPLC法检测PTX-OA在5~25μg/m L线性关系良好,回归方程Y=12.709 X+6.252 0,r=0.999 5。最优处方为油相质量浓度为6.50 mg/m L,聚山梨酯-80-油相比例为3.5∶6.5,超声乳化功率为120 W。制备的PTX-OA/BJO CMNEs外观良好,平均包封率为(100.6±1.9)%,平均粒径(108.7±2.3)nm,多分散系数(PDI)为0.232±0.038。透射电子显微镜(TEM)形态观察表明PTX-OA/BJO CMNEs粒径接近100 nm,分布较均一;其体外释放度在48 h达到67%。PTX-OA/BJO CMNEs溶液置于4℃,避光环境下保存60d,包封率、粒径基本保持不变,稳定性较好。体外细胞毒实验显示,BJO与PTX-OA联用对Hep G-2细胞生长抑制具有一定的协同作用。结论优化后的PTX-OA/BJO CMNEs制备工艺简单易行,且药物之间具有增强细胞毒作用,为PTX和BJO联合用药的抗肿瘤作用机制的研究奠定了基础。     

A novel combination of intramuscular vaccine adjuvants,nanoemulsion and CpG produces an effective immune response against influenza A virus

BackgroundVaccination is the most effective approach to prevent infection with highly pathogenic avian influenza (HPAI). Adjuvants are often used to induce effective immune responses and overcome the immunological weakness of recombinant HPAI antigens. Given the logistical challenges of immunization to HPAI during pandemic situations, vaccines administered via the intramuscular (I.M.) route would be of value.MethodsA new formulation of nanoemulsion adjuvant (NE02) suitable for I.M. vaccination was developed. This NE02 was evaluated alone and in combination with CpG to develop H5 immune responses in mouse and ferret models. Measures of recombinant H5 (rH5) specific immunity evaluated included serum IgG and IgG subclasses, bronchoalveolar lavage fluid IgA, and cytokines. The activation of NF-kB was also analyzed. The efficacy of the vaccine was assessed by performing hemagglutination inhibition (HAI), virus neutralization (VN) assays, and viral challenges in ferrets.ResultsI.M. vaccination with rH5-NE02 significantly increased rH5-specific IgG and protected ferrets in the viral challenge model providing complete protection and sterile immunity in all animals tested. Combining NE02 and CpG produced accelerated antibody responses and this was accompanied by an elevation of IFN-γ and IL-17 responses and the downregulation of IL-5. The combination also caused a synergistic effect on NF-kB activation. In immunized ferrets after viral challenge, the rH5-NE02 + CpG vaccine via I.M. achieved at least 75% and 88% seroconversion of HAI and VN antibody responses, respectively, and improved body temperature stabilization and weight loss over NE02 alone.ConclusionsThe I.M. injection of NE02 adjuvanted rH5 elicits strong and broad immune responses against H5 antigens and effectively protects animals from lethal H5 challenge. Combining this adjuvant with CpG enhanced immune responses and provided improvements in outcomes to viral challenge in ferrets. The results suggest that combinations of adjuvants may be useful to enhance H5 immune responses and improve protection against influenza infection.     

In Vitro and In Vivo evaluation of a novel folate-targeted theranostic nanoemulsion of docetaxel for imaging and improved anticancer activity against ovarian cancers

Ovarian cancer ranks fifth in cancer related deaths for women in USA. The high mortality rate associated with ovarian cancer is due to diagnosis at later stages of disease and the high recurrence rate of 60–80%. Recurrent ovarian cancers are more likely to present as multidrug resistance (MDR) leading to unfavorable response from 2^nd and 3^rd line chemotherapy. Nanoemulsions (NEs) are emerging as an attractive drug delivery system to overcome MDR challenges. NEs can also minimize exposure of therapeutic cargo to normal tissues potentially reducing side effects. In >80% of ovarian cancers, Folate Receptor-α (FR-α) is expressed at 10- to 100-fold higher levels than on non-pathological tissues. Therefore, folate (FA) is being evaluated as an active targeting moiety for FR-α⁺ ovarian cancer. To improve therapeutic outcome with reduced toxicity, we developed NMI-500, a FA targeted gadolinium (Gd) annotated NE loaded with docetaxel (DTX). NMI-500 has been developed as theranostic agents as Gd will enable physician to acquire real time pharmacodynamics data on NE + DTX accumulation in target lesions. In present study, characterization for key translational metrics of NMI-500 showed size distribution in range of 120 to 150 nm and zeta potential around ?45 mV. Active targeting of FA was evaluated against FR-α⁺ KB cells and results demonstrated significant improvement in cell association which was surface ligand density dependent. We found that NMI-500 was able to inhibit tumor growth in a spontaneous transgenic ovarian cancer model with improved safety profile and this growth inhibition could be longitudinally followed by MRI. These results indicate NMI-500 warrants advancement to clinical trials.     

矾冰纳米乳的长期毒性试验

目的：观察矾冰纳米乳长期给药对家兔的毒性反应。方法：48只家兔,随机分为8组,即完整皮肤对照组（基质组）、完整皮肤矾冰纳米乳低、中、高剂量组,破损皮肤对照组、破损皮肤矾冰纳米乳低、中、高剂量组,每组各6只。各组连续皮肤涂药13周后进行常规观察、血液学、血液生化、系统尸检、组织病理学检查。结果：矾冰纳米乳各剂量组动物的外观行为、体重、脏器系数、血液学和血液生化指标与对照组比较无显著性差异,组织病理学检查未见明显异常。停药后也未见药物延迟性毒性反应。结论：矾冰纳米乳长期皮肤用药对家兔无明显毒性反应。     

Preparation,characterization, and antimicrobial activity of nanoemulsions incorporating citral essential oil

Citral is a typical essential oil used in the food, cosmetic, and drug industries and has shown antimicrobial activity against microorganisms. Citral is unstable and hydrophobic under normal storage conditions, so it can easily lose its bactericide activity. Nanoemulsion technology is an excellent way to hydrophilize, microencapsulate, and protect this compound. In our studies, we used a mixed surfactant to form citral-in-water nanoemulsions, and attempted to optimize the formula for preparing nanoemulsions. Citral-in-water nanoemulsions formed at S_o 0.4 to 0.6 and ultrasonic power of 18 W for 120 seconds resulted in a droplet size of < 100 nm for nanoemulsions. The observed antimicrobial activities were significantly affected by the formulation of the nanoemulsions. The observed relationship between the formulation and activity can lead to the rational design of nanoemulsion-based delivery systems for essential oils, based on the desired function of antimicrobials in the food, cosmetics, and agrochemical industries.     

Investigation of true nanoemulsions for transdermal potential of indomethacin: characterization,rheological characteristics,and ex vivo skin permeation studies

The aim of the present study was to investigate the potential of true nanoemulsions for transdermal delivery of indomethacin. Thermodynamically stable true nanoemulsions were characterized for morphology using transmission electron microscopy (TEM), droplet size, rheological characteristics, and refractive index. The rheological behavior for all true nanoemulsions was found to be Newtonian as viscosity was unchanged by increasing the rate of shear. The ex vivo skin permeation studies were performed using Franz diffusion cell with rat skin as permeation membrane. The ex vivo skin permeation profile of optimized formulation was compared with marketed Indobene gel and nanoemulsion gel. Significant increase in permeability parameters was observed in nanoemulsion formulations (P?<?0.05). The steady-state flux (J_ss) and permeability coefficient (K_p) for optimized nanoemulsion formulation were found to be 73.96?±?2.89?μg/cm²/h and 1.479?×?10^?2?±?0.289?×?10^??2?cm/h, respectively, which were significant compared with Indobene gel and nanoemulsion gel (P?<?0.05). Enhancement ratio (E_r) was found to be 7.88 in optimized formulation F6 compared with other formulations. These results suggested that nanoemulsions can be used as potential vehicles for improved transdermal delivery of indomethacin.