In vitro evaluation of PLA nanoparticles containing a lipophilic drug in water-soluble or insoluble form

Cloricromene (AD6), an anti-ischemic drug, is rapidly metabolised into a stable and active metabolite (cloricromene acid, AD6-acid) poorly soluble in water and less lipophilic than cloricromene. The aim of this study was to evaluate which of the two forms has more possibility to be efficiently encapsulated in nanoparticles based on poly(D,L-lactide) and prepared using the nanoprecipitation method. Increasing the theoretical loading of AD6, an increase in drug actual loading and in the mean particle size occurred, while no formation of nanoparticles was observed when the highest theoretical loading (50 mg) was employed. Changing the pH of the aqueous phase the drug content dramatically increased. However, at a pH value of 11 a more rapid hydrolysis of AD6 occurred. When AD6-acid was embedded in the nanoparticles, suitable results concerning both drug content and encapsulation efficiency were achieved. A good control in the release of AD6 from the AD6-loaded nanoparticles was observed while the liberation of AD6-acid from the AD6-acid-loaded nanoparticles was faster than the dissolution of the AD6-acid free. These results confirm that the most easy encapsulable form in nanoparticles is AD6-acid probably owing to its poor water solubility. Further studies will be carried out in order to evaluate if the increase in the liberation of AD6-acid by nanoencapsulation may have outcomes in its bioavaibility in vivo.     

吡喹酮固体脂质纳米粒的研制

目的采用超声分散法制备吡喹酮固体脂质纳米粒,并考察制备过程中的主要影响因素。方法首先通过试验确定制备工艺参数,然后考察各处方因素对粒径大小和稳定性的影响,最后以包封率为评价指标,采用正交实验设计法确定最优处方。结果透射电镜测得纳米粒为类圆球状,粒径分布较均匀。动态光散射法测得样品的粒径为(100±21)nm,包封率为(79.3±0.69)%,平均zeta电位值为-66.3 mV。结论以山嵛酸甘油酯和乙酸丁酯为脂质材料,豆磷脂、泊洛沙姆188和硬脂酸钠为复配乳化剂,采用超声分散法可以简便、快速制得吡喹酮固体脂质纳米粒。     

Microencapsulation of lipophilic drugs in chitosan-coated alginate microspheres.

Chitosan-coated alginate microspheres containing a lipophilic marker dissolved in an edible oil, were prepared by emulsification/internal gelation and the potential use as an oral controlled release system investigated. Microsphere formation involved dispersing a lipophilic marker dissolved in soybean oil into an alginate solution containing insoluble calcium carbonate microcrystals. The dispersion was then emulsified in silicone oil to form an O/W/O multiple phase emulsion. Addition of an oil soluble acid released calcium from carbonate complex for gelation of the alginate. Chitosan was then applied as a membrane coat to increase the mechanical strength and stabilize the microspheres in simulated intestinal media. Parameters studied included encapsulation yield, alginate concentration, chitosan molecular weight and membrane formation time. Mean diameters ranging from 500 to 800 micron and encapsulation yields ranging from 60 to 80% were obtained. Minimal marker release was observed under simulated gastric conditions, and rapid release was triggered by transfer into simulated intestinal fluid. Higher overall levels of release were obtained with uncoated microspheres, possibly due to binding of marker to the chitosan membrane coat. However the slower rate of release from coated microspheres was felt better suited as a delivery vehicle for oil soluble drugs.     

Solid lipid nanoparticles for parenteral drug delivery

This review describes the use of nanoparticles based on solid lipids for the parenteral application of drugs. Firstly, different types of nanoparticles based on solid lipids such as "solid lipid nanoparticles" (SLN), "nanostructured lipid carriers" (NLC) and "lipid drug conjugate" (LDC) nanoparticles are introduced and structural differences are pointed out. Different production methods including the suitability for large scale production are described. Stability issues and drug incorporation mechanisms into the particles are discussed. In the second part, the biological activity of parenterally applied SLN and biopharmaceutical aspects such as pharmacokinetic profiles as well as toxicity aspects are reviewed.     

Solid lipid nanoparticles for ocular drug delivery

Ocular drug delivery remains challenging because of the complex nature and structure of the eye. Conventional systems, such as eye drops and ointments, are inefficient, whereas systemic administration requires high doses resulting in significant toxicity. There is a need to develop novel drug delivery carriers capable of increasing ocular bioavailability and decreasing both local and systemic cytotoxicity. Nanotechnology is expected to revolutionize ocular drug delivery. Many nano-structured systems have been employed for ocular drug delivery and yielded some promising results. Solid lipid nanoparticles (SLNs) have been looked at as a potential drug carrier system since the 1990s. SLNs do not show biotoxicity as they are prepared from physiological lipids. SLNs are especially useful in ocular drug delivery as they can enhance the corneal absorption of drugs and improve the ocular bioavailability of both hydrophilic and lipophilic drugs. SLNs have another advantage of allowing autoclave sterilization, a necessary step towards formulation of ocular preparations. This review outlines in detail the various production, characterization, sterilization, and stabilization techniques for SLNs. In-vitro and in-vivo methods to study the drug release profile of SLNs have been explained. Special attention has been given to the nature of lipids and surfactants commonly used for SLN production. A summary of previous studies involving the use of SLNs in ocular drug delivery is provided, along with a critical evaluation of SLNs as a potential ocular delivery system.     

Solid lipid nanoparticles as drug delivery systems

For a decade, trials have been made to utilize solid lipid nanoparticles (SLNs) as alternative drug delivery systems to colloidal drug delivery systems such as lipid emulsions, liposomes, and polymeric nanoparticles. Various lipid matrices, surfactants, and other excipients used in formulation, preparation methods, sterilization and lyophilization of SLNs are discussed in this article. Entrapment efficiency of drug carrier and its effect on physical parameters, drug release, and release mechanisms of various compositions are reviewed and discussed. Important points in characterization and stability of SLNs are outlined. Various in vitro studies carried out by different research groups are mentioned in addition to in vivo evaluation. Exploitation potential of SLNs to administer by various routes of administration are covered. Passive and active drug targeting using SLNs are presented.     

Solid lipid nanoparticles for topical drug delivery

Solid lipid nanoparticles (SLN) have shown interesting potential as a drug delivery system for the topical delivery of various drugs. However, their performance when applied to the skin has not been fully investigated because of the complexity of their composition and structure. Theoretically, drug can be targeted systemically to the vasculature in the dermis, locally to the skin strata, or superficially to the surface of the skin. Therefore, the topical delivery vehicle should be designed according to the desired therapeutic purposes. To understand drug permeation behavior, it is essential to elucidate the pattern of drug release from the SLN formulations. A number of different drug release patterns have been outlined in the literature, and these patterns have been found to be related to the manufacturing process of the vehicle. In this paper, we summarize the results of SLN-mediated skin penetration data in the literature and illustrate several theoretical mechanisms of SLN-skin interactions that might take place at the site of action. Substantial research dedicated to the development of this promising drug delivery system is still required.     

Stabilization of all-trans retinol by loading lipophilic antioxidants in solid lipid nanoparticles.

Loading of drugs into the solid matrix of solid lipid nanoparticles (SLNs) can be one of effective means to protect them against chemical degradation. In this study, the SLNs for all-trans retinol (AR) were formulated to improve the stability of AR, whose chemical instability has been a limiting factor in its clinical use. First of all, the physicochemical properties of AR-loaded SLNs, including mean particle diameter and zeta potential, were modulated by changing the total amount of surfactant mixture and the mixing ratio of eggPC and Tween 80 as surfactant mixture. The AR-loaded SLNs formulation was irradiated with a 60-W bulb to investigate the photostability. The extent of photodegradation was measured by high-performance liquid chromatography. The mean particle diameter and zeta potential of the smallest SLNs were 96 nm and -28 mV, respectively. The loading of AR in optimized SLNs formulations rather decelerated the degradation of AR, compared with AR solution dissolved in methanol. Our subsequent study showed that the co-loading of antioxidants greatly enhanced the stability of AR loaded in SLNs, compared with those loaded in SLNs without antioxidant. The photostability at 12 h of AR in SLNs was enhanced folds (43% approximately) higher than that in methanol solution (about 11%). Furthermore, the protecting effect of antioxidants was greatly dependent on the type of antioxidant. Taken together, AR could be effectively stabilized by being loaded in SLNs together with an antioxidant BHT-BHA.     

Application of lipid nanoparticles to ocular drug delivery

ABSTRACT

Introduction: Although eye drops are widely used as drug delivery systems for the anterior segment of the eye, they are also associated with poor drug bioavailability due to transient contact time and rapid washout by tearing. Moreover, effective drug delivery to the posterior segment of the eye is challenging, and alternative routes of administration (periocular and intravitreal) are generally needed, the blood–retinal barrier being the major obstacle to systemic drug delivery.

Areas covered: Nanotechnology, and especially lipid nanoparticles, can improve the therapeutic efficiency, compliance and safety of ocular drugs, administered via different routes, to both the anterior and posterior segment of the eye. This review highlights the main ocular barriers to drug delivery, as well as the most common eye diseases suitable for pharmacological treatment in which lipid nanoparticles have proved efficacious as alternative delivery systems.

Expert opinion: Lipid-based nanocarriers are among the most biocompatible and versatile means for ocular delivery. Mucoadhesion with consequent increase in pre-corneal retention time, and enhanced permeation due to cellular uptake by corneal epithelial cells, are the essential goals for topical lipid nanoparticle delivery. Gene delivery to the retina has shown very promising results after intravitreal administration of lipid nanoparticles as non-viral vectors.     

紫杉醇固体脂质纳米粒大鼠体内药动学

目的研究紫杉醇固体脂质纳米粒在大鼠体内的药动学。方法10只健康大鼠,雌雄各半,分为2组,分别口服给药紫杉醇固体脂质纳米粒和紫杉醇乳剂30 mg.kg-1,在设计的时间点从颈静脉取血,采用RP-HPLC测定紫杉醇在全血中的药物浓度,药动学参数用3P97软件进行处理。结果大鼠口服给药后,紫杉醇固体脂质纳米粒和乳剂的tm ax分别为3.133 h和1.627 h,MRT分别为10.362 h和3.297 h,mρax分别为1.512 2 mg.L-1和0.718 9 mg.L-1。结论固体脂质纳米粒能够显著改善大鼠体内紫杉醇的药动学行为,有利于其更好地发挥抗肿瘤作用。     

Preparation and characterization of solid lipid nanoparticles containing peptide

Solid lipid nanoparticles (SLN) are an alternative colloidal carrier system for controlled drug delivery. However, only a few have been studied regarding the incorporation of peptides into SLN, due to the hydrophilic peptide not easy to enter the lipophilic matrix of SLN. In the present report, peptide-loaded solid lipid nanoparticles were prepared by a novel solvent diffusion method in an aqueous system. The model peptide gonadorelin was incorporated to study the entrapment efficiency, size, zeta potential (charge) and drug delivery characterization. Gonadorelin and monostearin were dissolved in acetone and ethanol at 50 degrees C in water bath, the resultant organic solution was poured into an aqueous containing 1% polyvinyl alcohol (PVA) under mechanical agitation. The peptide-loaded solid lipid nanoparticles were quickly produced and separated by centrifugation. The average volume diameter of gonadorelin-loaded SLN is 421.7 nm and the zeta potential of SLN is -21.1 mV dispersed in distilled water. Up to 69.4% of gonadorelin can be incorporated. In vitro release of gonadorelin from SLN is slow. In the test solution of a 0.1N hydrochloric acid for 2h and then transferred in a pH 6.8 phosphate buffer (simulative gastrointestinal fluid), the drug-release behavior from SLN suspension exhibited a biphasic pattern. After burst drug-release at the first 6h at a percentage of 24.4% of loaded gonadorelin, a distinctly prolonged release over a monitored period of 12 days was observed and nearly 3.81% of drug was released in each day. In the test solution of a pH 6.8 phosphate buffer (simulative intestinal fluid), the drug-release rate from SLN was similar to that in the simulative gastrointestinal fluid. Further, a novel preparation method in the present research for peptide-loaded SLN was established. These results also demonstrate the principle suitability of SLN as a prolonged release formulation for hydrophilic peptide drugs.     

Preparation and characterization of solid lipid nanoparticles containing cloricromene

This article describes the development of solid lipid nanoparticles (SLN) as colloidal carriers for cloricromene. Nanoparticles were prepared by the microemulsion or precipitation technique. In vitro drug release profile from SLN was studied under various experimental conditions mimicking some body fluids. The drug release rate of drug at pH 7.4 and human plasma is high. In plasma, after 15 min, about 70% of drug was released. The cloricromene that was not released within 4 hr was found in the SLN. This result suggests that this colloidal system could be useful for targeted drug delivery to the central nervous system after intravenous administration.     

Preparation and characterization of solid lipid nanoparticles containing silibinin

The study describes the development of stealth solid lipid nanoparticles (SLNs) as colloidal carriers for silibinin, a drug with very low solubility. Stealth SLNs were constituted mainly of bioacceptable and biodegradable lipids, such as stearic acid and surfactant Brij 78 (polyoxyethylene 20 stearyl ether) and can incorporate amounts of silibinin up to 7.55%. Stealth-loaded SLNs were in the nanometer size range. Thermal analysis (differential scanning calorimetry) showed that silibinin was dispersed in the stealth SLNs at an amorphous state. Release of silibinin from stealth SLNs was very slow. Stealth SLNs were stable without precipitation of silibinin on storage conditions and can be proposed for their parenteral administration.     

Microdialysis for evaluating the entrapment and release of a lipophilic drug from nanoparticles

The aim of the study was to evaluate the microdialysis (MD) as a tool to determine entrapment efficiency and drug release of a lipophilic drug model, diclofenac (DIC), from nanocapsules, nanospheres, and nanoemulsions. Factors that could interfere with the MD probe recovery were investigated: perfusion fluid composition, concentration and form of the drug in the perfusate, and recovery method. DIC entrapment efficiency to nanoparticles and the drug release in phosphate buffer pH 7.4 after different dilutions were evaluated by MD and ultrafiltration/centrifugation (UC). DIC recovery for the 5 μL/min flux was concentration and pH dependent. DIC sodium was used for the recoveries determination since it did not differ from the DIC acid recovery for the same media. DIC entrapment efficiency determined applying both techniques were equivalent and close to 100% for all nanoparticles. In pH 7.4 DIC release from the nanoparticles was partial for the dilution rate 1:1 (v/v), around 50–60%. A complete release was observed from 1:10 (v/v) dilution. Only nanocapsules presented a incomplete release for 1:5 (v/v) dilution, around 86%. MD and UC techniques were equivalent for the evaluation of DIC entrapment efficiency and drug release from the nanoparticles.     

Solid lipid nanoparticles (SLN) for topical drug delivery: incorporation of the lipophilic drugs N,N-diethyl-m-toluamide and vitamin K

Solid lipid nanoparticles (SLN) for topical delivery were prepared by high pressure homogenization using solid lipids. The lipophilic agents DEET (N,N-diethyl-m-toluamide) and vitamin K were used as model drugs. These topical agents were incorporated into SLN which were characterized. Differential scanning calorimetry studies were performed in order to detect probable interactions in the SLN dispersions. Physical stability of SLN in aqueous dispersions and the effect of drug incorporation into SLN were investigated by photon correlation spectroscopy and zeta potential measurements. Characterization and short-term stability studies showedthat DEET and vitamin K are good candidates for topical SLN formulations.     

Solid lipid nanoparticles for targeted brain drug delivery

The present review discusses the potential use of solid lipid nanoparticles for brain drug targeting purposes. The state of the art on surfactant-coated poly(alkylcyanoacrylate) nanoparticles specifically designed for brain targeting is given by emphasizing the transfer of this technology to solid lipid matrices. The available literature on solid lipid nanoparticles and related carriers for brain drug targeting is revised as well. The potential advantages of the use of solid lipid nanoparticles over polymeric nanoparticles are accounted on the bases of a lower cytotoxicity, higher drug loading capacity, and best production scalability. Solid lipid nanoparticles physicochemical characteristics are also particularly regarded in order to address the critical issues related to the development of suitable brain targeting formulations. A critical consideration on the potential application of such technology as related to the current status of brain drug development is also given.     

莪术油固体脂质纳米粒的制备

目的研究影响莪术油固体脂质纳米粒制备的主要因素。方法采用高压均质法制备莪术油固体脂质纳米粒混悬液,以单因素考察和正交设计法筛选出比较理想的处方和工艺,并考察其形态、粒径、载药量及包封率。结果所制得的固体脂质纳米粒为圆整的类球形实体粒子,表面光滑,平均粒径为80.3nm,载药量为11.82%,包封率为81.75%。结论高压均质法可用于莪术油类液体药物固体脂质纳米粒的制备。     

固体脂质纳米粒和纳米结构脂质载体在药物传递中的研究进展

基于固体脂质的纳米粒（Solid lipid - based nanoparticles,SLBNs）作为新型药物传递系统比常规的药物传递系统存在优势。通常,基于固体脂质的纳米粒可以分成两种形态,即固体脂质纳米粒（ Solid lipid nanoparticles, SLNs）和纳米结构脂质载体（Nanostructured lipid carriers,NLCs）。但固体脂质纳米粒与纳米结构脂质载体在基质的组成上不同,本文就基于固体脂质的纳米粒的制备技术、表征方法及应用的最新研究进展进行总结,为基于固体脂质的纳米粒进一步研究提供参考依据。