槲皮素前体脂质体的质量考察

目的制备液体型槲皮素前体脂质体,并对制剂质量进行考察。方法采用一种新型前体脂质体制备方法制备液体型槲皮素前体脂质体,将脂质体膜材和药物等以一定比例溶于分散介质中,形成一种无水的澄明溶液。考察其水合后粒子形态、粒径、电位、包封率及自组装速度等理化性质,并评价其体外释药性质。结果槲皮素前体脂质体遇水即可快速自组装成纳米级含药脂质体混悬液,水合后形态多为类球形,平均粒径为228.7nm,Zeta电位为21.2 mV,包封率可达90%以上,体外释药符合Higuchi方程。结论槲皮素口服前体脂质体制备工艺简单可行,包封率高,具有一定的缓释效果。     

Enhancement of dissolution rate and bioavailability of aceclofenac: a chitosan-based solvent change approach

In this study the significant effect of chitosan on improving the dissolution rate and bioavailability of aceclofenac has been demonstrated by simple solvent change method. Chitosan was precipitated on aceclofenac crystals using sodium citrate as the salting out agent. The pure drug and the prepared co-crystals with different concentrations of chitosan (0.05–0.6%) were characterized in terms of solubility, drug content, particle size, thermal behaviour (differential scanning calorimetry, DSC), X-ray diffraction (XRD), morphology (scanning electron microscopy, SEM), in vitro drug release and stability studies. The in vivo performance was assessed by preclinical pharmacodynamic (analgesic and anti-inflammatory activity) and pharmacokinetic studies. The particle size of the prepared co-crystals was drastically reduced during the formulation process. The DSC showed a decrease in the melting enthalpy indicating disorder in the crystalline content. The XRD also revealed a characteristic decrease in crystallinity. The dissolution studies demonstrated a marked increase in the dissolution rate in comparison with pure drug. The considerable improvement in the dissolution rate of aceclofenac from optimized crystal formulation was attributed to the wetting effect of chitosan, decreased drug crystallinity, altered surface morphology and micronization. The optimized co-crystals exhibited excellent stability on storage at accelerated conditions. The in vivo studies revealed that the optimized crystal formulation provided a rapid pharmacological response in mice and rats besides exhibiting improved pharmacokinetic parameters in rats.     

Enhanced bioavailability of exemestane via proliposomes based transdermal delivery

Exemestane, a novel steroidal aromatase inactivator used in the treatment of advanced breast cancer has limited bioavailability (42%) due to poor solubility, extensive first-pass metabolism, and also the absorption is dependent on formulation type and food. The present study is aimed to evaluate the feasibility of proliposomes for transdermal delivery of exemestane. The prepared proliposomes were characterized for size, zeta potential, and entrapment efficiency. The size of the vesicles was found to be between 440 and 700 nm with high entrapment efficiency for the formulation containing greater amounts of phosphatidylcholine. Differential scanning calorimetry and Fourier transform infrared studies were performed to understand the phase transition behavior and mechanism for skin permeation, respectively. The drug release across cellophane membrane follows zero-order kinetics by diffusion. Ex vivo permeation enhancement assessed from flux, permeability coefficient, and enhancement ratio were significantly higher for proliposome gels compared with control. A significant improvement in the bioavailability (2.4-fold) was observed from optimized proliposome gel compared with control (oral suspension). The stability data reveal that the formulations are more stable when stored at 4°C. In conclusion, proliposomal gels offer potential and prove to be efficient carriers for improved and sustained transdermal delivery of exemestane.     

Preparation and Characterization of Ethosomes for Topical delivery of Aceclofenac

The aim of present study was to prepare and characterized ethosomes of aceclofenac which may deliver the drug to targeted site more efficiently than marketed gel preparation and also overcome the problems related with oral administration of drug. The formulations were prepared with varying the quantity of ethanol 10-50% (v/v), lecithin 1-4% (w/v), propylene glycol 5-20% (v/v) and evaluated for their vesicle size, shape and surface morphology, entrapment efficiency and in vitro drug permeation study. Ethosomes of average size of 1.112 μm with a spherical shape bearing smooth surface were observed by transmission electron microscopy and surface electron microscopy. The maximum entrapment of ethosomes was 91.06±0.79%. Cumulative amount of drug permeated through the biological membrane was found to be in the range of 0.26±0.014 to 0.49±0.032 mg/cm(2). Stability profile of prepared system was assessed for 45 days and the results revealed that very less degradation of drug was observed during storage condition.     

Development and evaluation of pharmacosomes of aceclofenac

Pharmacosomes are amphiphilic lipid vesicular systems containing phospholipid complexes with a potential to improve bioavailability of poorly water soluble as well as poorly lipophilic drugs. To improve the water solubility, bioavailability and minimize the gastrointestinal toxicity of aceclofenac, its pharmacosomes were prepared. Aceclofenac was complexed with phosphatidylcholine (80%) in two different ratios (1:1 and 2:1) using conventional solvent evaporation technique. Pharmacosomes thus prepared were subjected to solubility and drug content evaluation, scanning electron microscopy, differential scanning calorimetry, X ray powder diffraction and in vitro dissolution study. Pharmacosomes of aceclofenac were found to be disc shaped with rough surface in scanning electron microscopy. Drug content was found to be 91.88% (w/w) for aceclofenac phospholipid complex (1:1) and 89.03% (w/w) aceclofenac-phospholipid complex (2:1). Differential scanning calorimetric thermograms and X ray powder diffraction datas confirmed the formation of phospholipid complex. Solubility and dissolution profile of the prepared complex was found to be much better than aceclofenac.     

A novel formulation of [6]-gingerol: Proliposomes with enhanced oral bioavailability and antitumor effect

[6]-Gingerol, one of the components of the rhizome of Ginger, has a variety of biological activities such as anticoagulant, antioxidative, antitumor, anti-inflammatory, antihypertensive, and so forth. However, as one of the homologous phenolic ketones, [6]-gingerol is insoluble in water which limits its applications. Herein, we prepared [6]-gingerol proliposomes through modified thin-film dispersion method, which was spherical or oval, and physicochemically stable with narrow size distribution. Surprisingly, in vitro release of [6]-gingerol loaded proliposome compared with the free [6]-gingerol was significantly higher and its oral bioavailability increased 5-fold in vivo. Intriguingly, its antitumor effect was enhanced in the liposome formulation. Thus, our prepared [6]-gingerol proliposome proved to be a novel formulation for [6]-gingerol, which significantly improved its antitumor effect.     

Bioavailability enhancement of zaleplon via proliposomes: Role of surface charge

The present systematic study focused to investigate the combined advantage of proliposomes and surface charge for improved oral delivery of zaleplon. The zaleplon loaded proliposomes were prepared using hydrogenated soyphosphatidylcholine (HSPC) and cholesterol (CHOL) in varying ratios, and the optimized formulation was tailored with dicetyl phosphate and stearylamine to obtain negative and positive charged vesicles, respectively. The formulations were characterized for micromeritics, size, zeta potential, and entrapment efficiency. Further, in vitro release and dissolution study carried out provide an insight on the stability and enhanced dissolution of zaleplon from proliposome formulations. The solid state characterization (SEM, DSC, and PXRD) studies unravel the transformation of zaleplon to amorphous or molecular state from the native crystalline form. To depict the conclusions, in situ single-pass perfusion and bioavailability studies were carried out in rats. The significant increase in effective permeability coefficient (Peff) and rate and extent of absorption from cationic vesicles indicate the importance of surface charge for effective uptake across the gastrointestinal tract. Overall a two- to fivefold enhancement in bioavailability in comparison with control confers the potential of proliposomes as suitable carriers for improved oral delivery of zaleplon.     

Proniosomes as a carrier system for transdermal delivery of tenoxicam

Tenoxicam is a non steroidal anti-inflammatory drug (NSAID) widely used in the treatment of rheumatic diseases and characterized by its good efficacy and less side effects compared to other NSAIDs. Its oral administration is associated with severe side effects in the gastrointestinal tract. Transdermal drug delivery has been recognized as an alternative route to oral delivery. Proniosomes offer a versatile vesicle delivery concept with the potential for drug delivery via the transdermal route. In this study, different proniosomal gel bases were prepared, characterized by light microscopy, revealing vesicular structures, and assessed for their drug entrapment efficiency, stability, their effect on in vitro drug release and ex vivo drug permeation. The lecithin-free proniosomes prepared from Tween 20:cholesterol (9:1) proved to be stable with high entrapment and release efficiencies. The in vivo behaviour of this formula was studied on male rats and compared to that of the oral market product. The investigated tenoxicam loaded proniosomal formula proved to be non-irritant, with significantly higher anti-inflammatory and analgesic effects compared to that of the oral market tenoxicam tablets.     

Proliposomes for oral delivery of dehydrosilymarin: preparation and evaluation in vitro and in vivo

Aim:

To formulate proliposomes with a polyphase dispersed system composed of soybean phospholipids, cholesterol, isopropyl myristate and sodium cholate to improve the oral bioavailability of dehydrosilymarin, an oxidized form of herbal drug silymarin.

Methods:

Dehydrosilymarin was synthesized from air oxidation of silymarin in the presence of pyridine, and proliposomes were prepared by a film dispersion-freeze drying method. Morphological characterization of proliposomes was observed using a transmission electron microscope. Particle size and encapsulation efficiency of proliposomes were measured. The in vitro release of dehydrosilymarin from suspension and proliposomes was evaluated. The oral bioavailability of dehydrosilymarin suspension and proliposomes was investigated in rabbits.

Results:

The proliposomes prepared under the optimum conditions were spherical and smooth with a mean particle size in the range of 7 to 50 nm. Encapsulation efficiency was 81.59%±0.24%. The in vitro accumulative release percent of dehydrosilymarinloaded proliposomes was stable, which was slow in pH 1.2, and increased continuously in pH 6.8, and finally reached 86.41% at 12 h. After oral administration in rabbits, the relative bioavailability of proliposomes versus suspension in rabbits was 228.85%.

Conclusion:

Proliposomes may be a useful vehicle for oral delivery of dehydrosilymarin, a drug poorly soluble in water.     

Chitosan microspheres of aceclofenac: In vitro and in vivo evaluation

The objective of this investigation was to achieve controlled drug release of Aceclofenac (ACE) microspheres and to minimize local side-effects in the gastrointestinal tract (GIT). Sustained release chitosan microspheres containing ACE were prepared using double-emulsion solvent evaporation method (O/W/O). Chitosan microspheres were prepared by varying drug to polymer ratio (1:3, 1:4, 1:5 and 1:6). Microspheres were characterized for morphology, swelling behavior, mucoadhesive properties, FTIR and DSC study, drug loading efficiency, in vitro release, release kinetics, and in vivo study was performed on rat model. ACE-loaded microspheres were successfully prepared having production yield, 57–70% w/w. Drug encapsulation efficiency was ranging from 53–72% w/w, Scanning electron microscopy (SEM) revealed particle size of microspheres was between 39 and 55 μm. FTIR spectra and DSC thermograms demonstrated no interaction between drug and polymer. The in vitro release profiles of drug from chitosan microspheres showed sustained-release pattern of the drug in phosphate buffer, pH 6.8. In vitro release data showed correlation (r² > 0.98), good fit with Higuchi/Korsmeyer-Peppas models, and exhibited Fickian diffusion. ACE microspheres demonstrated controlled delivery of aceclofenac and apparently, no G.I.T. erosion was noticed.     

Floating microspheres of cimetidine: formulation, characterization and in vitro evaluation

The present study involves preparation and evaluation of floating microspheres with cimetidine as model drug for prolongation of gastric residence time. The microspheres were prepared by the solvent evaporation method using polymers hydroxypropylmethyl cellulose and ethyl cellulose. The shape and surface morphology of prepared microspheres were characterized by optical and scanning electron microscopy, respectively. In vitro drug release studies were performed and drug release kinetics was evaluated using the linear regression method. Effects of the stirring rate during preparation, polymer concentration, solvent composition and dissolution medium on the size of microspheres and drug release were also observed. The prepared microspheres exhibited prolonged drug release (approximately 8 h) and remained buoyant for > 10 h. The mean particle size increased and the drug release rate decreased at higher polymer concentration. No significant effect of the stirring rate during preparation on drug release was observed. In vitro studies demonstrated diffusion-controlled drug release from the microspheres.     

Vesicular aceclofenac systems: a comparative study between liposomes and niosomes

Vesicular delivery systems have been reported to serve as local depot for sustained drug release. Aceclofenac multilamellar liposomes and niosomes were prepared and a comparative study was done between them through evaluation of entrapment efficiency, particle size, shape, differential scanning calorimetry and in vitro drug release. A stability study was carried out by investigating the leakage of aceclofenac and the change in the vesicles particle size when stored at (2-8 degrees C) for 3 months. The anti-inflammatory effect of aceclofenac vesicles was assessed by the rat paw oedema technique. Results showed that the entrapment efficiency and the in vitro release of aceclofenac from the vesicles can be manipulated by varying the cholesterol content, the type of surfactant as well as the type of charge. Niosomes showed better stability than liposomes. Both vesicular systems showed significant sustained anti-inflammatory activity compared to the marketed product, with niosomes being superior to liposomes as manifested by both oedema rate and inhibition rate percentages suggesting their effectiveness as topical anti-inflammatory delivery systems.     

Spray dried Eudragit microparticles as encapsulation devices for vitamin C

The aim of the present paper was to study production of methacrylate microparticles for the delivery (administration) of ascorbic acid via the oral route. Vitamin C is an important antioxidant that may be involved in the reduction of the risk of certain types of cancer, such as colorectal cancer. As polymers different acrylic compounds were considered, namely Eudragit RL, L and RS. Spray-drying was used as preparation method of vitamin C/Eudragit microspheres. Microspheres were first characterized by size and morphology by scanning electron microscopy, then in vitro release kinetics by mean of dialysis method were studied. Although the produced microparticles were unable to slow down the release of the drug with respect to the free form of ascorbic acid, these microspheres showed a good morphology and size distribution that permit to propose them as candidate for the delivery of vitamin C as associated therapy in the treatment of colorectal cancer by oral route.     

水飞蓟素前体脂质体的制备和大鼠药代动力学的研究水飞蓟素前体脂质体的制备和大鼠药代动力学的研究

目的为了提高水飞蓟素的口服生物利用度，研制水飞蓟素前体脂质体并对其理化性质进行考察；研究水飞蓟素前体脂质体的大鼠体内生物利用度。方法采用薄膜载体沉积法制备水飞蓟素前体脂质体，通过研究水合后脂质体的包封率、粒径、稳定性来考察其理化性质；将水飞蓟素前体脂质体在体外进行水合，再给予大鼠灌胃，用RP-HPLC法测定不同时间血浆中总的和游离的水飞蓟素的浓度，通过3P97程序计算药代动力学参数。结果用该法制得的前体脂质体包封率可达90%以上，平均粒径为238.8 nm，稳定性较好；药代动力学研究表明水飞蓟素脂质体在体内吸收较快，生物利用度较高。结论采用薄膜载体沉积法制备水飞蓟素前体脂质体，制备工艺简单，易于工业化生产；将水飞蓟素制备成前体脂质体提高了水飞蓟素的生物利用度。     

奥扎格雷纳米结构脂质载体的制备及体外评价

目的:制备奥扎格雷纳米结构脂质载体(ozagrel-loaded nanostructured lipid carriers,OZ-NLC),并考察其理化性质及体外释放。方法:采用熔融-超声乳化法制备OZ-NLC,通过正交设计法优化处方与制备工艺,使用透射电镜(TEM)、激光粒度测定仪、差示扫描量热仪(DSC)及X-射线衍射仪(XRD)考察OZ-NLC的理化性质,通过溶出试验评价其体外释放效果。结果:所制备的OZ-NLC呈球形或类球形;平均粒径为(115±10)nm;Zeta电位为(-37.6±8.9)mV;平均包封率为(61.3±5.2)%;XRD与DSC表明药物以无定形形式分散于OZ-NLC中。与奥扎格雷混悬液相比,OZ-NLC的体外溶出量明显提高且具有很好的缓释效果。结论:熔融-超声乳化法制备的OZ-NLC对促进难溶性药物奥扎格雷的口服吸收具有一定的指导价值。     

他克莫司纳米微球的制备及其体外释药性能

目的采用甲氧基聚乙二醇-聚乳酸聚合物（PEG—PLA）制备他克莫司微球（PPT），研究其体外释药特性。方法考察PPT的载药量、包封率、粒径大小、粒径分布和药物体外释放实验。结果PPT的制备工艺稳定、重复性好，微球外形圆整，表面光滑，分布均匀，平均粒径为（545．1±0．9）nm，平均载药量为（18．90±3．22）％，平均包封率为（25．0±1．6）％，35d的药物累积释放率为67．21％。结论他克莫司微球缓释时间长达35d，能够满足临床治疗的要求。     

Physicochemical characterization and dissolution enhancement of aceclofenac-hydroxypropyl beta-cyclodextrin binary systems

The aim of this study is to prepare and characterize binary systems of aceclofenac (AC) with hydroxypropyl beta-cyclodextrin (HPbetaCD) in equimolar ratio. Solid binary systems of aceclofenac with HPbetaCD were prepared using cogrinding, kneading, and coevaporating methods, and a physical mixture was prepared for comparison. The binary systems were characterized by differential scanning calorimetry, thermogravimetric analysis, mass spectroscopy, 1H nuclear magnetic resonance (NMR) spectroscopy, scanning electron microscopy, and in vitro dissolution studies. 1H NMR studies showed that AC partially fits into the HPbetaCD torus cavity with a preferential inclusion of the phenyl ring of the drug. All the binary systems showed superior dissolution and lower dose:solubility ratio (D:S ratio) as compared to pure AC, but the kneaded product exhibited the best dissolution, with complete drug release within 10 min and a D:S ratio of 5 mL. Hence, it was suggested that complexation of aceclofenac with HPbetaCD may be used as an approach to change the drug from Biopharmaceutics Classification System BCS Class II to BCS Class I without changing its intrinsic permeability.     

A novel method to prepare liposomes containing amikacin.

This work describes a novel method to prepare liposomal amikacin composed of soyabean lecithin and cholesterol; these were also prepared using two other methods (cast film method and proliposome method). Encapsulation efficiency was evaluated. Liposomes prepared by the new method, which combines the method of preparing proliposomes with freeze-drying, had the highest encapsulation efficiency. The influence of drug to lipid ratio on the encapsulation efficiency was investigated. The in vitro efflux of amikacin from liposomes with different lecithin: cholesterol ratios was also investigated.     

Steam sterilisation of vesicular phospholipid gels

Vesicular phospholipid gels (VPGs), highly concentrated phospholipid dispersions of semisolid consistency and vesicular morphology are under investigation as potential implantable depots for sustained release of drugs and as intermediates for subsequent dilution into 'conventional' liposome dispersions. It was investigated here if VPGs can be steam sterilised. VPGs prepared from 400 mg/g egg-phosphatidylcholine by high-pressure homogenisation retained their vesicular structure but showed a slight increase in vesicle size (freeze-fracture electron microscopy). However, autoclaving slowed down both, the in vitro release of the hydrophilic marker carboxyfluorescein and vesicles from VPGs. This was assumed to be due to bigger vesicle sizes and corresponding increase in packing density of the vesicular matrix. Upon dilution into a liposome dispersion both negative staining electron microscopy and dynamic laser light scattering analysis confirmed a distinct increase in liposome size, mainly due to fusion of small (20 nm) vesicles with unfavourable curvature. This was consistent with the observed increase in encapsulation efficiency of carboxyfluorescein. Phospholipid hydrolysis during autoclaving was negligible with lysophosphatidylcholine formation of less than 2% (thin layer chromatography). Despite significant change of their morphological and functional properties during autoclaving VPGs retained their main characteristics, such as vesicular structure, sustained release and dilutability to liposome dispersions, and are, therefore, considered as autoclavable.     

Preparation, characterization and in vitro cytotoxicity of indomethacin-loaded PLLA/PLGA microparticles using supercritical CO(2) technique.

In this work, indomethacin-loaded poly(l-lactic acid)/poly(lactide-co-glycolide) (IDMC-PLLA/PLGA) microparticles were prepared using solution-enhanced dispersion by supercritical fluids (SEDS) technique in an effort to obtain alternative IDMC formulation for drug delivery system. Surface morphology, particle size and particle size distribution, drug encapsulation efficiency, drug release kinetics, in vitro cytotoxicity and the cellular uptake of drug-loaded microparticles were investigated. The drug-loaded microparticles exhibited sphere-like shape and small particle size with narrow particle size distribution. IDMC was amorphously dispersed within the PLLA/PLGA matrix after the SEDS process. In vitro release studies revealed that the drug-loaded microparticles substantially enhanced the dissolution rate of IDMC compared to the free IDMC, and demonstrated a biphasic drug release profile. In vitro cytotoxicity assays indicated that drug-loaded microparticles possessed longer sustained inhibition activity on proliferation of the non-small-cell lung cancer A549 cell lines than did free IDMC. Fluorescence microscopy and transmission electron microscopy identified the phagocytosis of drug-loaded microparticles into the A549 cells and characteristic morphology of cell apoptosis such as the nuclear aberrations, condensation of chromatin, and swelling damage in mitochondria. These results collectively suggested that IDMC-PLLA/PLGA microparticles prepared using SEDS would have potentials in anti-tumor applications as a controlled drug release dosage form without harmful organic solvent residue.