Nanostructured liquid-crystalline particles for drug delivery

Introduction: Nanostructured lyotropic liquid crystal particles (LLC NPs) have proven to be extremely useful tools for applications in drug delivery. These structured nanoparticles are formed by amphiphilic molecules and contain internal water channels, which are not in contact with external water, and where polar drugs can situate; on the other hand, apolar drugs can be loaded in the lipophilic part of the structure and the amphiphilic drugs can locate at the polar/apolar interfaces.

Areas covered: A revision of the most relevant results published in the field of LLC NPs has been made. The first section discusses the most common compounds used in these nanoparticles and their preparation and characterization. A summary of recent and relevant results including the composition and type of nanoparticles used, the illness treated, the administration via and some special features in each case have been summarized in a table.

Expert opinion: LLC NPs are highly versatile drug delivery systems, which can be applied by topical, oral and intravenous treatments. Especially relevant is their use for the release of anticancer drugs, biomolecules and vaccines. Nevertheless a number of critical points need to be solved in order to attain practical applications.     

Effect of new curcumin‐containing nanostructured lipid dispersions on human keratinocytes proliferative responses

This study describes the production and characterization of nanostructured lipid dispersions (NLDs) containing curcumin (CUR) as new tools for curcumin topical delivery. Four types of NLDs based on monoolein in association with different emulsifiers were produced: Na cholate and poloxamer 407 (NLD1), poloxamer alone (NLD2), the mixture of Na cholate and Na caseinate (NLD3) and Na cholate alone (NLD4). Morphology and dimensional distribution of lipid dispersions were investigated by cryo‐TEM and photon correlation spectroscopy (PCS). In vitro studies based on Franz cell, membrane nylon and stratum corneum–epidermis (SCE) were carried out to compare the four NLDs in terms of cytotoxicity in human keratinocytes and CUR diffusion. Our PCS studies showed differences in particles diameter among the different NLDs. In addition, cytotoxicity results in HaCaT cells evidenced that NLD1 and NLD2 were toxic at doses over 1 μm . Therefore, cryo‐TEM was determined only for NLD3 and NLD4 showing that CUR did not affect their structure. Diffusion measurement in SCE and nylon membrane evidenced that CUR had a time‐delayed release for NLD4. The ‘wound healing’ effect of NLD3 and NLD4 with and without CUR analysed keratinocytes in vitro, and a clear inhibition of cell proliferation/migration by CUR was observed. This effect was mediated by the inhibition of cyclin D1 expression as a consequence of the impaired NFkB activation. This study confirms the antiproliferative properties of CUR and evidenced a new possible model of CUR topical delivery for hyperproliferative cutaneous diseases such as psoriasis.     

Interest of glycolipids in drug delivery: from physicochemical properties to drug targeting

Importance of the field: The need for new products derived from natural sources for the replacement of the commonly used non-ionic surfactants containing ethylene oxide units with degradable carbohydrate headgroups has become an important area of research. Glycolipids offer a wide range of applications in the pharmaceutical and cosmetic fields and can compete with the most commonly used surfactants. Involved in molecular recognition mechanisms at the surface of cells, glycolipids are also used for drug targeting.

Areas covered in this review: The structure and pharmaceutical applications of the main glycolipid categories are summarized. The review focuses on marketed glycolipids, biosurfactants and compounds developed at laboratory scale for applications such as self-assembly or drug targeting.

What the reader will gain: This article aims to provide an overview of the different sugar-based surfactant classes and their potential uses.

Take home message: Beside their use as surfactants or absorption enhancers in basic formulations, glycolipids can build gels, niosomes, hexosomes and cubosomes, whose structure is directly related to lyotropic properties. These systems allow solubilization and entrapment of drugs. In innovative delivery systems, glycolipids are also used for drug targeting because their sugar moieties can be specifically recognized by carbohydrate-binding proteins exposed at the surface of cells.     

Cubosome Dispersions as Delivery Systems for Percutaneous Administration of Indomethacin

Purpose The present study concerns the production and characterization of monooleine (MO) dispersions as drug delivery systems for indomethacin, taken as model anti-inflammatory drug. Methods Dispersions were produced by emulsification and homogenization of MO and poloxamer in water. Morphology and dimensional distribution of the disperse phase have been characterized by cryo-transmission electron microscopy and photon correlation spectroscopy, respectively. X-ray diffraction has been performed to determine the structural organization of the disperse phase. Sedimentation field flow fractionation (SdFFF) has been performed to investigate drug distribution in the dispersion. An in vitro diffusion study was conducted by Franz cell associated to stratum corneum epidermis membrane on cubosome dispersions viscosized by carbomer. In vivo studies based on skin reflectance spectrophotometry and tape stripping were performed to better investigate the performance of cubosome as indomethacin delivery system. Results Microscopy studies showed the coexistence of vesicles and cubosomes. X-ray diffraction revealed the presence of a bicontinuous cubic phase of spatial symmetry Im3m (Q²²⁹). SdFFF demonstrated that no free drug was present in the dispersion. Indomethacin incorporated in viscosized MO dispersions exhibited a lower flux with respect to the analogous formulation containing the free drug in the aqueous phase and to the control formulation based on carbomer gel. Reflectance spectroscopy demonstrated that indomethacin incorporated into MO dispersions can be released in a prolonged fashion. Tape-stripping experiments corroborated this finding. Conclusions MO dispersions can be proposed as nanoparticulate systems able to control the percutaneous absorption of indomethacin.     

基于pH梯度法的盐酸普萘洛尔立方液晶纳米粒的制备

目的 制备具有较高包封率的盐酸普萘洛尔立方液晶纳米粒（PPL- Cubs）。方法 采用pH梯度法制备PPL-Cubs;以粒径、多分散指数为评价指标,优化空白立方液晶纳米粒（B-Cubs）制备的高压均质压力、高压均质次数、单油酸甘油酯用量及泊洛沙姆407用量;以包封率等为评价指标,优化外水相pH值、内水相pH值、载体/药物比、载药温度、载药时间、B-Cubs粒径和多分散指数、药物浓度等。结果 高压均质压力为900 bar、均质次数为7次、单油酸甘油酯用量为25%、泊洛沙姆407用量为5%时,制得的B-Cubs具有较小的粒径和多分散指数。外水相pH值为8.5、内水相pH值为3.0、载体/药物比为6∶1、载药温度为20 ℃、载药时间为15 min、药物浓度为1%时,制得的PPL-Cubs包封率较高;B-Cubs粒径和多分散指数对制得的PPL-Cubs包封率无明显影响。结论 pH梯度法能制得较高包封率的盐酸普萘洛尔立方液晶纳米粒。     

Comparative study of liposomes,transfersomes, ethosomes and cubosomes for transcutaneous immunisation: characterisation and in vitro skin penetration

Objectives Lipid colloidal vaccines, including liposomes, transfersomes, ethosomes and cubosomes, were formulated, characterised and investigated for their ability to enhance penetration of a peptide vaccine through stillborn piglet skin in vitro. Methods Liposomes and transfersomes were formulated using a film‐hydration method, ethosomes using a modified reverse phase method and cubosomes using a lipid precursor method. The size, zeta potential, peptide loading and interfacial behaviour of the formulations were characterised. Skin penetration studies were performed using Franz diffusion cells with piglet skin as the membrane. The localization of peptide in the skin was examined using confocal laser scanning microscopy. Key finding The various formulations contained negatively charged particles of similar size (range: 134–200 nm). Addition of the saponin adjuvant Quil A to the formulations destabilised the monolayers and reduced peptide loading. Cubosomes and ethosomes showed superior skin retention compared with the other systems. Confocal laser scanning microscopy showed greater peptide penetration and accumulation in the skin treated with cubosomes and ethosomes. With the other systems peptide was only located in the vicinity of the hair follicles and within the hair shaft. Conclusions We conclude from the in‐vitro studies that cubosomes and ethosomes are promising lipid carriers for transcutaneous immunisation.     

立方晶及其在药剂学中的研究进展

立方晶是两亲性脂质和表面活性剂在水中自发形成的立方液晶的纳米分散体系。立方晶属于自稳定体系,是双连续的水相和脂相形成的类似“蜂窝”状的结构,在其中表面活性剂插入脂质双分子层,晶胞在三维方向上以无限循环方式排列,形成极小曲面的紧密结构。立方晶独特的脂水双连续相立方液晶结构,能够同时增溶亲水、亲脂及两亲性分子,具有生物可降解性、高生物黏附性、制备工艺简单等诸多优点使之在药物载体领域展现较大的优势。本文结合近年文献报道,阐述了立方晶的结构、制备、表征和药物载体的研究进展。     

Novel vehicle based on cubosomes for ophthalmic delivery of flurbiprofen with low irritancy and high bioavailability

Aim:

To develop a novel vehicle based on cubosomes as an ophthalmic drug delivery system for flurbiprofen (FB) to reduce ocular irritancy and improve bioavailability.

Methods:

FB-loaded cubosomes were prepared using hot and high-pressure homogenization. Cubosomes were then characterized by particle size, zeta potential, encapsulation efficiency, particle morphology, inner cubic structure and in vitro release. Corneal permeation was evaluated using modified Franz-type cells. Ocular irritation was then evaluated using both the Draize method and histological examination. The ocular pharmacokinetics of FB was determined using microdialysis.

Results:

The particle size of each cubosome formulation was about 150 nm. A bicontinuous cubic phase of cubic P-type was determined using cryo-transmission electron microscopy (cryo-TEM) observation and small angle X-ray scattering (SAXS) analysis. In vitro corneal permeation study revealed that FB formulated in cubosomes exhibited 2.5-fold (F1) and 2.0-fold (F2) increase in P_app compared with FB PBS. In the ocular irritation test, irritation scores for each group were less than 2, indicating that all formulations exhibited excellent ocular tolerance. Histological examination revealed that neither the structure nor the integrity of the cornea was visibly affected after incubation with FB cubosomes. The AUC of FB administered as FB cubosome F2 was 486.36±38.93 ng·mL⁻¹·min·μg⁻¹, which was significantly higher than that of FB Na eye drops (P<0.01). Compared with FB Na eye drops, the T_max of FB cubosome F2 was about 1.6-fold higher and the MRT was also significantly longer (P<0.001).

Conclusion:

This novel low-irritant vehicle based on cubosomes might be a promising system for effective ocular drug delivery.     

Novel in situ gelling vaginal sponges of sildenafil citrate-based cubosomes for uterine targeting

Sildenafil citrate (SIL), a type 5-specific phosphodiesterase inhibitor, demonstrates valuable results in the management of infertility in women; however, the absence of vaginal dosage form in addition to the associated oral adverse effects minimize its clinical performance. The present study is concerned with SIL uterine targeting following intravaginal administration via optimization of cubosomal in situ gelling sponges (CIS). An emulsification method was employed for preparation of cubosomal dispersions incorporating glyceryl monooleate as a lipid phase and poloxamer 407 as a surfactant with or without polyvinyl alcohol as a stabilizer. Cubosomes were estimated regarding entrapment efficiency (EE%), particle size, and in vitro drug release. Chitosan (2% w/w) was incorporated into the optimum formulation and then lyophilized into small sponges. For the CIS, in vivo histopathological and pharmacokinetic studies were conducted on female Wistar rats and compared with intravaginal free SIL sponges (FIS) and oral SIL solution. SIL-loaded cubosomes showed EE% ranging between 32.15 and 72.01%, particle size in the range of 150.81–446.02?nm and sustained drug release over 8?h. Histopathological study revealed a significant enlargement in endometrial thickness with congestion and dilatation of endometrial blood vessels in intravaginal CIS compared to intravaginal FIS and oral-treated groups. The pharmacokinetic study demonstrated higher AUC_0–∞ and C_max with oral administration compared to intravaginal CIS or intravaginal FIS indicating potential involvement of first uterine pass effect after intravaginal administration. Finally, intravaginal CIS could be considered as a promising platform for SIL uterine targeting with minimized systemic exposure and side effects.     

Superiority of liquid crystalline cubic nanocarriers as hormonal transdermal vehicle: comparative human skin permeation-supported evidence

ABSTRACT

Objectives: The aim of this investigation was to explore the feasibility of various nanocarriers to enhance progesterone penetration via the human abdominal skin.

Methods: Four progesterone-loaded nanocarriers; cubosomes, nanoliposomes, nanoemulsions and nanomicelles were formulated and characterized regarding particle size, zeta potential, % drug encapsulation and in vitro release. Structural elucidation of each nanoplatform was performed using transmission electron microscopy. Ex vivo skin permeation, deposition ability and histopathological examination were evaluated using Franz diffusion cells.

Results: Each nanocarrier was fabricated with a negative surface, nanometric size (≤ 270 nm), narrow size distribution and reasonable encapsulation efficiency. In vitro progesterone release showed a sustained release pattern for 24 h following a non-Fickian transport diffusion mechanism. All nanocarriers exhibited higher transdermal flux relative to free progesterone. Cubosomes revealed a higher skin penetration with transdermal steady flux of 48.57.10^–2 ± 0.7 µg/cm² h. Nanoliposomes offered a higher percentage of skin progesterone deposition compared to other nanocarriers. Based on the histopathological examination, cubosomes and nanoliposomes were found to be biocompatible for transdermal application. Confocal laser scanning microscopy confirmed the ability of fluoro-labeled cubosomes to penetrate through the whole skin layers.

Conclusion: The elaborated cubosomes proved to be a promising non-invasive nanocarrier for transdermal hormonal delivery.