Lipospheres as Carriers for Topical Delivery of Aceclofenac: Preparation,Characterization and <Emphasis Type="BoldItalic">In Vivo</Emphasis> Evaluation

The purpose of this study was to prepare lipospheres containing aceclofenac intended for topical skin delivery with the aim of exploiting the favorable properties of this carrier system and developing a sustained release formula to overcome the side effects resulting from aceclofenac oral administration. Lipospheres were prepared using different lipid cores and phospholipid coats adopting melt and solvent techniques. Characterization was carried out through photomicroscopy, scanning electron microscopy, particle size analysis, DSC, In vitro drug release and storage study. The anti-inflammatory effect of liposphere systems was assessed by the rat paw edema technique and compared to the marketed product. Results revealed that liposphere systems were able to entrap aceclofenac at very high levels (93.1%). The particle size of liposphere systems was well suited for topical drug delivery. DSC revealed the molecular dispersion of aceclofenac when incorporated in lipospheres. Both entrapment efficiency and release were affected by the technique of preparation, core and coat types, core to coat ratio and drug loading. Lipospheres were very stable after 3 months storage at 2–8°C manifested by low leakage rate (less than 7%) and no major changes in particle size. Finally, liposphere systems were found to possess superior anti-inflammatory activity compared to the marketed product in both lotion and paste consistencies. Liposphere systems proved to be a promising topical system for the delivery of aceclofenac as they possessed the ability to entrap the drug at very high levels and high stability, and to sustain the anti-inflammatory effect of the drug.     

Controllable microfluidic synthesis of multiphase drug‐carrying lipospheres for site‐targeted therapy

We report the production of micrometer‐sized gas‐filled lipospheres using digital (droplet‐based) microfluidics technology for chemotherapeutic drug delivery. Advantages of on‐chip synthesis include a monodisperse size distribution (polydispersity index (σ) values of <5%) with consistent stability and uniform drug loading. Photolithography techniques are applied to fabricate novel PDMS‐based microfluidic devices that feature a combined dual hydrodynamic flow‐focusing region and expanding nozzle geometry with a narrow orifice. Spherical vehicles are formed through flow‐focusing by the self‐assembly of phospholipids to a lipid layer around the gas core, followed by a shear‐induced break off at the orifice. The encapsulation of an extra oil layer between the outer lipid shell and inner bubble gaseous core allows the transport of highly hydrophobic and toxic drugs at high concentrations. Doxorubicin (Dox) entrapment is estimated at 15 mg mL^?1 of particles packed in a single ordered layer. In addition, the attachment of targeting ligands to the lipid shell allows for direct vehicle binding to cancer cells. Preliminary acoustic studies of these monodisperse gas lipospheres reveal a highly uniform echo correlation of greater than 95%. The potential exists for localized drug concentration and release with ultrasound energy. © 2009 American Institute of Chemical Engineers Biotechnol. Prog., 2009     

Bio-shielding <Emphasis Type="Italic">In Situ</Emphasis> Forming Gels (BSIFG) Loaded With Lipospheres for Depot Injection of Quetiapine Fumarate: <Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> Evaluation

Quetiapine fumarate (QF), an anti-schizophrenic drug, suffers from rapid elimination and poor bioavailability due to extensive first-pass effect. Intramuscularly (IM) injected lipospheres were designed to enhance the drug’s bioavailability and extend its release. A central composite design was applied to optimize the liposphere preparation by a melt dispersion technique using Compritol® 888 ATO or glyceryl tristearate as lipid component and polyvinyl alcohol as surfactant. Lipospheres were evaluated for their particle size, entrapment efficiency, and in vitro release. The optimized QF lipospheres were prepared using a Compritol® 888 ATO fraction of 18.88% in the drug/lipid mixture under a stirring rate of 3979 rpm. The optimized lipospheres were loaded into a thermoresponsive in situ forming gel (TRIFG) and a liquid crystalline in situ forming gel (LCIFG) to prevent in vivo degradation by lipases. The loaded gels were re-evaluated for their in vitro release and injectability. Bioavailability of QF from liposphere suspension and bio-shielding in situ gels loaded with QF lipospheres were assessed in rabbits compared to drug suspension. Results revealed that the AUC_0–72 obtained from the liposphere-loaded TRIFG was ～3-fold higher than that obtained from the aqueous drug suspension indicating the bio-shielding effect of Poloxamer® 407 gel to inhibit the biodegradation of the lipospheres prolonging the residence of the drug in the muscle for higher absorption. Our results propose that bio-shielding in situ Poloxamer® 407 gels loaded with lipospheres is promising for the development of IM depot injection of drugs having extensive first-pass metabolism and rapid elimination.     

Recent Advances in Lipid Nanoparticle Formulations with Solid Matrix for Oral Drug Delivery

Lipid nanoparticles based on solid matrix have emerged as potential drug carriers to improve gastrointestinal (GI) absorption and oral bioavailability of several drugs, especially lipophilic compounds. These formulations may also be used for sustained drug release. Solid lipid nanoparticle (SLN) and the newer generation lipid nanoparticle, nanostructured lipid carrier (NLC), have been studied for their capability as oral drug carriers. Biodegradable, biocompatible, and physiological lipids are generally used to prepare these nanoparticles. Hence, toxicity problems related with the polymeric nanoparticles can be minimized. Furthermore, stability of the formulations might increase than other liquid nano-carriers due to the solid matrix of these lipid nanoparticles. These nanoparticles can be produced by different formulation techniques. Scaling up of the production process from lab scale to industrial scale can be easily achieved. Reasonably high drug encapsulation efficiency of the nanoparticles was documented. Oral absorption and bioavailability of several drugs were improved after oral administration of the drug-loaded SLNs or NLCs. In this review, pros and cons, different formulation and characterization techniques, drug incorporation models, GI absorption and oral bioavailability enhancement mechanisms, stability and storage condition of the formulations, and recent advances in oral delivery of the lipid nanoparticles based on solid matrix will be discussed.     

综述——纳米材料与药物输递：脂质纳米粒在口服给药系统中的应用

脂质纳米粒是由固体脂肪酸或其酯类制成的一类纳米制剂,其生物相容性好、安全性好,所以在药物递送领域受到广泛关注．难溶性药物、多肽及蛋白质药物由于溶解度、跨膜能力以及稳定性等问题,导致口服生物利用度低,而利用脂质纳米粒作为其载体,口服给药后能显著改善药物的生物利用度,这使得脂质纳米粒在口服给药系统中得到了广泛的应用与研究．本文从口服脂质纳米粒的处方、制备工艺、吸收机制以及应用四个方面对其进行了详细的综述．     

Preparation and Characterization of Fenofibrate-Loaded Nanostructured Lipid Carriers for Oral Bioavailability Enhancement

The aim of this study is to investigate the potential of nanostructured lipid carriers (NLCs) in improving the oral bioavailability of a lipid lowering agent, fenofibrate (FEN). FEN-loaded NLCs (FEN-NLCs) were prepared by hot homogenization followed by an ultrasonication method using Compritol 888 ATO as a solid lipid, Labrafil M 1944CS as a liquid lipid, and soya lecithin and Tween 80 as emulsifiers. NLCs were characterized in terms of particle size and zeta pote\ntial, surface morphology, encapsulation efficiency, and physical state properties. Bioavailability studies were carried out in rats by oral administration of FEN-NLC. NLCs exhibited a spherical shape with a small particle size (84.9 ± 4.9 nm). The drug entrapment efficiency was 99% with a loading capacity of 9.93 ± 0.01% (w/w). Biphasic drug release manner with a burst release initially, followed by prolonged release was depicted for in vitro drug release studies. After oral administration of the FEN-NLC, drug concentration in plasma and AUC_t-∞ was fourfold higher, respectively, compared to the free FEN suspension. According to these results, FEN-NLC could be a potential delivery system for improvement of loading capacity and control of drug release, thus prolonging drug action time in the body and enhancing the bioavailability.KEY WORDS: bioavailability, fenofibrate, nanoparticles, nanostructured lipid carriers     

A lipid based depot (DepoFoam technology) for sustained release drug delivery

Encapsulation of drugs into multivesicular liposomes (DepoFoam) offers a novel approach to sustained-release drug delivery. While encapsulation of drugs into unilamellar and multilamellar liposomes, and complexation of drugs with lipids, resulted in products with better performance over a period lasting several hours to a few days after intravascular administration, DepoFoam-encapsulation has been shown to result in sustained-release lasting over several days to weeks after non-vascular administration. The routes of administration most viable for delivery of drugs via DepoFoam formulations include intrathecal, epidural, subcutaneous, intramuscular, intra-atricular, and intraocular. DepoFoam particles are distinguished structurally from unilamellar vesicles, multilamellar vesicles, and neosomes in that each particle comprises a set of closely packed non-concentric vesicles. The particles are tens of microns in diameter and have large trapped volume, thereby affording delivery of large quantities of drugs in the encapsulated form in a small volume of injection. A number of methods based on a manipulation of the lipid and aqueous composition can be used to control the rate of sustained-release from a few days to several weeks.     

Development of Lipid-Based Nanoparticles for Enhancing the Oral Bioavailability of Paclitaxel

The current research work investigates the potential of solid lipid nanoparticles (SLNs) in improving the oral bioavailability of paclitaxel. Paclitaxel-loaded SLNs (PTX-SLNs) were prepared by modified solvent injection method using stearylamine as lipid, soya lecithin and poloxamer 188 as emulsifiers. SLNs were characterized in terms of surface morphology, size and size distribution, surface chemistry and encapsulation efficiency. Pharmacokinetics and bioavailability studies were conducted in male Swiss albino mice after oral administration of PTX-SLNs. SLNs exhibited spherical shape with smooth surface as analyzed by transmission electron microscopy (TEM). The mean particle size of SLNs was 96 ± 4.4 nm with a low polydispersity index of 0.162 ± 0.04 and zeta potential of 39.1 ± 0.8 mV. The drug entrapment efficiency was found to be 75.42 ± 1.5% with a loading capacity of 31.5 ± 2.1% (w/w). Paclitaxel showed a slow and sustained in vitro release profile and followed Higuchi kinetic equations. After oral administration of the PTX-SLNs, drug exposure in plasma and tissues was ten- and twofold higher, respectively, when compared with free paclitaxel solution. PTX-SLNs produced a high mean C _max (10,274 ng/ml) compared with that of free paclitaxel solution (3,087 ng/ml). The absorbed drug was found to be distributed in liver, lungs, kidneys, spleen, and brain. The results suggested that PTX-SLNs dispersed in an aqueous environment are promising novel formulations that enhanced the oral bioavailability of hydrophobic drugs, like paclitaxel and were quite safe for oral delivery of paclitaxel as observed by in vivo toxicity studies.     

Characterization and Evaluation of 5-Fluorouracil-Loaded Solid Lipid Nanoparticles Prepared via a Temperature-Modulated Solidification Technique

The aim of this research was to advance solid lipid nanoparticle (SLN) preparation methodology by preparing glyceryl monostearate (GMS) nanoparticles using a temperature-modulated solidification process. The technique was reproducible and prepared nanoparticles without the need of organic solvents. An anticancer agent, 5-fluorouracil (5-FU), was incorporated in the SLNs. The SLNs were characterized by particle size analysis, zeta potential analysis, differential scanning calorimetry (DSC), infrared spectroscopy, atomic force microscopy (AFM), transmission electron microscopy (TEM), drug encapsulation efficiency, in vitro drug release, and in vitro cell viability studies. Particle size of the SLN dispersion was below 100 nm, and that of redispersed lyophilizates was ~500 nm. DSC and infrared spectroscopy suggested that the degree of crystallinity did not decrease appreciably when compared to GMS. TEM and AFM images showed well-defined spherical to oval particles. The drug encapsulation efficiency was found to be approximately 46%. In vitro drug release studies showed that 80% of the encapsulated drug was released within 1 h. In vitro cell cultures were biocompatible with blank SLNs but demonstrated concentration-dependent changes in cell viability to 5-FU-loaded SLNs. The 5-FU-loaded SLNs can potentially be utilized in an anticancer drug delivery system.KEY WORDS: atomic force microscopy, calorimetry (DSC), FTIR, particle size, solid lipid nanoparticles     

Preparation and optimization of rivastigmine-loaded tocopherol succinate-based solid lipid nanoparticles

Rivastigmine hydrogen tartrate (RHT) is a pseudo-irreversible inhibitor of cholinesterase and is used for the treatment of Alzheimer's. However, RHT delivery to the brain is limited by the blood–brain barrier (BBB). The purpose of this study was to improve the brain-targeting delivery of RHT by producing and optimizing rivastigmine hydrogen tartrate-loaded tocopherol succinate-based solid lipid nanoparticles (RHT-SLNs). RHT-SLNs were prepared using the microemulsion technique. The impact of significant variables, such as surfactant concentration and drug/lipid ratio, on the size of RHT-SLNs and their drug loading and encapsulation efficiency was analysed using a five-level central composite design (CCD). The minimum size of particles and the maximum efficiency of loading and encapsulation were defined according to models derived from a statistical analysis performed under optimal predicted conditions. The experimental results of optimized RHT-SLNs showed an appropriate particle size of 15.6?nm, 72.4% drug encapsulation efficiency and 6.8% loading efficiency, which revealed a good correlation between the experimental and predicted values. Furthermore, in vitro release studies showed a sustained release of RHT from RHT-SLNs.     

Development of a pH-responsive particulate drug delivery vehicle for localized biologic therapy in inflammatory bowel disease

The treatment of inflammatory bowel disease (IBD) recently has been revolutionized by the introduction of protein-based biologic therapies. However, biologic therapy is complicated by the requirement for administration with a needle, systemic side effects, and high cost. Particulate drug delivery systems have been shown to deliver drugs locally to the intestinal mucosa via oral administration. However, these systems have been largely unexplored for the delivery of biologics due to harsh particle fabrication conditions and the tendency of many particulate formulations to dissolve in the acidic upper GI tract. We have, therefore, fabricated an inexpensive and non-toxic novel microparticle capable of encapsulating proteins. We establish that the particle retains its contents at acidic pH and releases them at neutral pH. We also demonstrate particulate encapsulation of interleukin-10 (IL-10), a protein relevant to the treatment of IBD, at an encapsulation efficiency of 14.3 percent. Such a vehicle is promising for its oral route of administration and potential to decrease side effects and increase potency of biologics.     

Biophysical aspects of using liposomes as delivery vehicles

Liposomes are used as biocompatible carriers of drugs, peptides, proteins, plasmic DNA, antisense oligonucleotides or ribozymes, for pharmaceutical, cosmetic, and biochemical purposes. The enormous versatility in particle size and in the physical parameters of the lipids affords an attractive potential for constructing tailor-made vehicles for a wide range of applications. Some of the recent literature will be reviewed here and presented from a biophysical point of view, thus providing a background for the more specialized articles in this special issue on liposome technology. Different properties (size, colloidal behavior, phase transitions, and polymorphism) of diverse lipid formulations (liposomes, lipoplexes, cubic phases, emulsions, and solid lipid nanoparticles) for distinct applications (parenteral, transdermal, pulmonary, and oral administration) will be rationalized in terms of common structural, thermodynamic and kinetic parameters of the lipids. This general biophysical basis helps to understand pharmaceutically relevant aspects such as liposome stability during storage and towards serum, the biodistribution and specific targeting of cargo, and how to trigger drug release and membrane fusion. Methods for the preparation and characterization of liposomal formulations in vitro will be outlined, too.     

Modulating Drug Release and Enhancing the Oral Bioavailability of Torcetrapib with Solid Lipid Dispersion Formulations

The development of drug dispersions using solid lipids is a novel formulation strategy that can help address the challenges of poor drug solubility and systemic exposure after oral administration. The highly lipophilic and poorly water-soluble drug torcetrapib could be effectively formulated into solid lipid microparticles (SLMs) using an anti-solvent precipitation strategy. Acoustic milling was subsequently used to obtain solid lipid nanoparticles (SLNs). Torcetrapib was successfully incorporated into the lipid matrix in an amorphous state. Spherical SLMs with mean particle size of approximately 15–18 μm were produced with high drug encapsulation efficiency (>96%) while SLNs were produced with a mean particle size of 155 nm and excellent colloidal stability. The in vitro drug release and the in vivo absorption of the solid lipid micro- and nanoparticles after oral dosing in rats were evaluated against conventional crystalline drug powders as well as a spray dried amorphous polymer dispersion formulation. Interestingly, the in vitro drug release rate from the lipid particles could be tuned for immediate or extended release by controlling either the particle size or the precipitation temperature used when forming the drug-lipid particles. This change in the rate of drug release was manifested in vivo with changes in Tmax as well. In addition, in vivo pharmacokinetic studies revealed a significant increase (∼6 to 11-fold) in oral bioavailability in rats dosed with the SLMs and SLNs compared to conventional drug powders. Importantly, this formulation approach can be performed rapidly on a small scale, making it ideal as a formulation technology for use early in the drug discovery timeframe.Electronic supplementary materialThe online version of this article (doi:10.1208/s12249-015-0299-8) contains supplementary material, which is available to authorized users.KEY WORDS: anti-solvent precipitation, controlled release, formulation, nanoparticles, solid lipid     

青藤碱磷脂复合物纳米结构脂质载体的制备、表征及药动学研究

为制备青藤碱磷脂复合物纳米结构脂质载体,并进行体外和SD大鼠体内评价。实验采用溶剂挥发法制备青藤碱磷脂复合物,乳化超声法制备青藤碱磷脂复合物纳米结构脂质载体。考察其粒径分布、Zeta电位,包封率,载药量及体外释药等基本理化性质。SD大鼠分别灌胃给予青藤碱混悬液和青藤碱磷脂复合物纳米结构脂质载体,比较药动学行为及生物利用度。结果显示,青藤碱磷脂复合物纳米结构脂质载体的平均粒径为201.32±5.05 nm,Zeta电位为-22.2±1.5 mV,包封率为80.31±1.01%,载药量为4.42±0.28%,体外释药具有明显的缓释特征,体外释药模型符合Weibull释药模型,拟合方程为:LnLn(1/1-Mt/M∞)=0.576 6Lnt-1.478 1(r=0.988 8)。体内药动学研究结果表明,磷脂复合物纳米结构脂质载体改变了青藤碱的药动学行为,增强了体内吸收,延长了青藤碱在体内滞留时间,相对生物利用度提高到了1.75倍。因此,青藤碱磷脂复合物纳米结构脂质载体可显著促进青藤碱体内吸收,提高其口服生物利用度。     

Preparation and Enhanced Oral Bioavailability of Cryptotanshinone-Loaded Solid Lipid Nanoparticles

In this study, solid lipid nanoparticles (SLNs) were successfully prepared by an ultrasonic and high-pressure homogenization method to improve the oral bioavailability of the poorly water-soluble drug cryptotanshinone (CTS). The particle size and distribution, drug loading capacity, drug entrapment efficiency, zeta potential, and long-term physical stability of the SLNs were characterized in detail. A pharmacokinetic study was conducted in rats after oral administration of CTS in different SLNs, and it was found that the relative bioavailability of CTS in the SLNs was significantly increased compared with that of a CTS-suspension. The incorporation of CTS in SLNs also markedly changes the metabolism behavior of CTS to tanshinone IIA. These results indicate that CTS absorption is enhanced significantly by employing SLN formulations, and SLNs represent a powerful approach for improving the oral absorption of poorly soluble drugs.     

Nanoparticles incorporated in bilaminated films: a smart drug delivery system for oral formulations

A novel smart drug delivery system (NP-Film) consisting of carboxylation chitosan-grafted nanoparticles (CCGNs) and bilaminated films, which were composed of the mucoadhesive chitosan-ethylenediaminetetraacetic acid hydrogel layer and the hydrophobic ethylcellulose layer, was developed for oral delivery of protein drugs. NP-Film was characterized by electron microscopy and fluorescence microscopy, and the results showed that the solid, spherical nanoparticles dispersed evenly in the porous structures of films. The properties of nanoparticles and films were investigated. The mucoadhesive force, CCGNs released from the NP-Film, and the toxicity of NP-Film were also evaluated. Results showed that the nanoparticles could reversibly open the tight junction of the intestine and inhibit trypsin activity. The release behavior of the nanoparticles from the NP-Film exhibited pH sensitivity. The drug delivery system possessed high mucoadhesive force and low intestinal toxicity. Therefore, the NP-Film would be a promising delivery carrier for protein drugs via oral administration.     

Paliperidone-Loaded Nanolipomer System for Sustained Delivery and Enhanced Intestinal Permeation: Superiority to Polymeric and Solid Lipid Nanoparticles

Paliperidone (PPD) is the most recent second-generation atypical antipsychotic approved for the treatment of schizophrenia. An immediate release dose causes extrapyramidal side effects. In this work, a novel nanolipomer carrier system for PPD with enhanced intestinal permeability and sustained release properties has been developed and optimized. PPD was successfully encapsulated into a lipomer consisting of a specific combination of biocompatible materials including poly-ε-caprolactone as a polymeric core, Lipoid S75, and Gelucire® 50/13 as a lipid shell and polyvinyl alcohol as a stabilizing agent. The lipomer system was characterized by dynamic light scattering, TEM, DSC, and FTIR. An optimized lipomer formulation possessed a particle size of 168 nm, PDI of 0.2, zeta potential of ?23 mV and an encapsulation efficiency of 87.27%?±?0.098. Stability in simulated gastrointestinal fluids investigated in terms of particle size, zeta potential, and encapsulation efficiency measurements ensured the integrity of the nanoparticles upon oral administration. PPD-loaded nanolipomers demonstrated a superior sustained release behavior up to 24 h and better ex vivo intestinal permeation for PPD compared to the corresponding polymeric and solid lipid nanoparticles and drug suspension. The in vitro hemocompatibility test on red blood cells revealed no hemolytic effect of PPD-loaded lipomers which reflects its safety. The elaborated nanohybrid carrier system represents a promising candidate for enhancing the absorption of PPD providing a 2.6-fold increase in the intestinal permeation flux compared to the drug suspension while maintaining a sustained release behavior. It is a convenient alternative to the commercially available dosage form of PPD.     

肠道病原菌侵袭素在药物纳米载体中的应用

口服给药是药物递送系统中的优选途径。然而,在通过胃肠道时,肠细胞的低渗透性经常会阻碍药物的有效递送。包囊药物能够解决这一问题的关键,取决于其中的细胞侵袭性靶向基团包裹的纳米颗粒系统。这种药物递送系统的侵入特性是由细菌侵袭素的关键成分提供,这些成分具有快速调节药物穿越肠细胞的作用,从而促进宿主细胞对药物的有效吸收。此综述重点阐述细菌侵袭系统,对合适的侵袭素分别从功能和分子结构、作为靶向药物的相对价值以及在使用过程中可能存在的误区依次进行探讨。此外,对口服给药方法的改进和未来前景也进行了讨论。     

Synthesis,characterization and preliminary analysis of in vivo biological activity of chitosan/celecoxib microcapsules

The use of chitosan as the wall of microcapsule designed for delivery of encapsulated celecoxib is reported. Microcapsules were characterised with respect to size and encapsulation efficiency of celecoxib. In vivo animals demonstrated that both free celecoxib administration and chitosan/celecoxib microcapsules administration lead to a significant inhibition of cyclooxygenase-2 protein expression in the hepatocytes when compared with vehicle control mice. Interestingly, microcapsule containing celecoxib showed a better inhibition of cyclooxygenase-2 protein expression when compared with a simple oral administration of free celecoxib. Gas-chromatography–mass-spectrometry analysis showed that in mice treated with free celecoxib or chitosan/celecoxib microcapsules, their plasma concentration of celecoxib was similar. Microcapsules-based biomaterials as oral drug delivery vehicles may help to improve the absorption efficiency of therapeutic drugs.     

固体脂质纳米粒的制备及在治疗中的应用研究

固体脂质纳米粒(SLN)是20世纪90年代发展起来的一种性能优异的新型纳米粒给药剂型作为一种新型载体,可有效提高包封药物的稳定性、提高病变部位靶向性、低毒性与组织亲和性,为药物的体内递送提供了一种新的方法。本文主要针对固体脂质纳米粒的制备,发展现状,目前存在的问题及解决思路等作以介绍与总结。并在此基础上,介绍了新的脂质纳米粒,纳米脂质载体(nanostructured lipid carriers,NLC)和药脂结合物纳米粒(Lipid drug conjugate nanoparticles,LDC),以及未来固体脂质纳米粒的发展方向。