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。     

Interaction of flavonoids with 1,1-diphenyl-2-picrylhydrazyl free radical, liposomal membranes and soybean lipoxygenase-1

The interaction of the antiperoxidative flavonoids namely, quercetin, quercetrin, rutin, myricetin, phloretin, phloridzin, catechin, morin and taxifolin with the 1,1,-diphenyl-2-picrylhydrazyl (DPPH) free radical was demonstrated. Flavonoid-DPPH interaction was looked at in the absence and presence of liposomes so as to reveal some information on bilayers. Perturbations in the lipid bilayers were monitored with the fluorescent probe, dansylhexadecylamine (DSHA). It was observed that the interaction of the flavonoids on the lipid bilayer occurred in the polar zone of the lipid bilayers. The flavonoids were able to scavenge free radicals and could do so in biomembranes. It is suggested that the DPPH free radical abstracts the phenolic hydrogen of the flavonoid molecule and that this could be the general mechanism of the scavenging action of the antiperoxidative flavonoids. The effects of the flavonoids on soybean lipoxygenase-1 were investigated both in buffer and also in liposomal suspension. All the flavonoids studied showed inhibition of the enzyme in both systems but the inhibition was greater in the liposomal suspension. Quercetin was the most potent and it inhibited the lipoxygenase in the liposomal suspension by about 42% while the other flavonoids inhibited the enzyme by about 14-23%. We observed that the effect of myricetin and quercetin on the enzyme was pH dependent.     

Development and characterization of dutasteride bearing liposomal systems for topical use

Dutasteride loaded liposomal system were developed for topical application in order to avoid the side effects associated with the oral administration of the drug. Drug-loaded multilamellar liposomes were prepared using thin-film hydration method followed by sonication and optimized with respect to entrapment efficiency, drug payload, size and lamellarity. The vesicular systems consisting of egg phosphatidylcholine (100 mg), cholesterol (50 mg), and dutasteride (5 mg) showed highest drug entrapment efficiency (94.6%) and drug payload (31.5 μg/mg of total lipids). Mean vesicle size of these liposomes was noted to be 1.82 ± 0.15 μm. Significantly higher skin permeation of dutasteride through excised abdominal mouse skin was achieved via the developed liposomal formulations as compared to hydro-alcoholic solution and conventional gels. The formulation exhibited about seven fold higher deposition of drug in skin. Stability studies indicated that the liposomal formulations were quite stable in the refrigerated conditions for 10 weeks with negligible drug leakage or vesicle size alteration. Results of the current studies exhibited improved and localized drug action in the skin and thus could be formulated as a better option to cure androgenetic alopecia.     

Effects of quercetin treatment on vascular function in deoxycorticosterone acetate-salt hypertensive rats. Comparative study with verapamil

This study analysed and compared the effects of chronic oral treatment with quercetin or verapamil on systolic blood pressure and vascular function in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Quercetin and verapamil inhibited the development of DOCA-salt-induced hypertension in a similar manner. DOCA-salt-hypertensive rats showed potassium depletion and oxidative stress, prevented only by concomitant quercetin administration. Quercetin and verapamil treatments reduced the endothelium-independent hyper-reactivity to KCl observed in the aorta of DOCA-salt-hypertensive rats, but only quercetin increased the contractile responses to angiotensin II, improved endothelial dysfunction and restored basal aortic Cu/Zn SOD expression, altered in DOCA-salt-treated rats. In conclusion, quercetin and verapamil show similar antihypertensive effects in mineralocorticoid hypertension, but quercetin was superior to verapamil in improving endothelial-dependent aortic dilatation, suggesting a better vascular protection in this volume expansion hypertension model.     

Effects of quercetin on the bioavailability of doxorubicin in rats: Role of CYP3A4 and P-gp inhibition by quercetin

Quercetin, a flavonoid, is an inhibitor of P-glycoprotein-mediated efflux transport, and its oxidative metabolism is catalyzed by CYP enzymes. Thus, it is expected that the pharmacokinetics of both intravenous and oral doxorubicin can be changed by quercetin. The purpose of this study was to investigate the effect of oral quercetin on the bioavailability and pharmacokinetics of orally and intravenously administered doxorubicin in rats. The effects of quercetin on the P-glycoprotein (P-gp) and CYP3A4 activities were also evaluated. Quercetin inhibited CYP3A4 enzyme activity in a concentration-dependent manner with a 50% inhibition concentration (IC₅₀) of 1.97 μM. In addition, quercetin significantly enhanced the intracellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. The pharmacokinetic parameters of doxorubicin were determined in rats after oral (50 mg/kg) or intravenous (10 mg/kg) administration of doxorubicin to rats in the presence and absence of quercetin (0.6, 3 or 15 mg/kg). Compared to control, quercetin significantly (p < 0.05 for 0.6 mg/kg, p < 0.01 for 3 and 15 mg/kg) increased the area under the plasma concentration-time curve (AUC_0−∞, 31.2-136.0% greater) of oral doxorubicin. Quercetin also significantly increased the peak plasma concentration (C_max) of doxorubicin, while there was no significant change in T_max and T_1/2 of doxorubicin. Consequently, the absolute bioavailability of doxorubicin was increased by quercetin compared to control, and the relative bioavailability of oral doxorubicin was increased by 1.32 to 2.36 fold. In contrast, the pharmacokinetics of intravenous doxorubicin were not affected by quercetin. These results suggest that the quercetin-induced increase in bioavailability of oral doxorubicin can be attributed to enhanced doxorubicin absorption in the gastrointestinal tract via quercetin-induced inhibition of P-gp and reduced first-pass metabolism of doxorubicin due to quercetin-induced inhibition of CYP3A in the small intestine and/or in the liver rather than reduced renal and/or hepatic elimination of doxorubicin. Therefore, it appears that the development of oral doxorubicin preparations is possible, which will be more convenient than the intravenous dosage forms. Therefore, concurrent use of quercetin provides a therapeutic benefit — it increases the bioavailability of doxorubicin administered orally.     

Antimicrobial effectiveness of liposomal polymyxin B against resistant Gram-negative bacterial strains

Polymyxin B is a polycationic antibiotic effective in the treatment of Gram-negative bacterial infections. Systemic use of polymyxin B has been limited due to its toxicity, most notably nephrotoxicity, ototoxicity, and neuromuscular blockade. Entrapment of antibiotics in liposomes is known to enhance their antimicrobial activities while minimizing their toxic effects. In the present study, polymyxin B was incorporated into liposomes composed of either 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and cholesterol (Chol) or 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and Chol. The entrapment efficiency of sonicated liposomes containing DPPC/Chol (32.1+/-2.43%) was six-fold higher than that of liposomes containing POPC/Chol (5.35+/-0.32%). On the other hand, the entrapment efficiency of extruded DPPC/Chol liposomes (3.23+/-0.46%) was about 30% less than that of liposomes composed of POPC/Chol (5.10+/-0.37%). Incubation of extruded DPPC/Chol liposomes containing polymyxin B in serum at 37 degrees C resulted in a complete release of the antibiotic into the supernatant after 3h as compared to 6h in the case of POPC/Chol liposomes. Spontaneous release of polymyxin B from DPPC/Chol liposomes incubated in saline was significantly higher (66%) than that from POPC/Chol liposomes (24%) after 48h at 37 degrees C. With respect to the antimicrobial activities of the liposomal polymyxin B formulations, the MICs of sonicated DPPC/Chol liposomes against Gram-negative strains were generally lower when compared to free polymyxin B. Immunocytochemistry and electron transmission microscopic studies revealed that the penetration of polymyxin B into a resistant strain of Pseudomonas aeruginosa was higher following its administration as a liposomal formulation as compared to its conventional form. The combination of free drug and plain liposomes had an antibacterial activity similar to that of free antibiotic. These data suggest that incorporation of polymyxin B in liposomes could be useful in the management of Gram-negative infections induced by these microorganisms.     

Quercetin along with piperine prevents cognitive dysfunction,oxidative stress and neuro-inflammation associated with mouse model of chronic unpredictable stress

Stress occurs in everyday life and persistence of it causes memory loss. Bioflavonoids like quercetin are reported to have poor bioavailability and limited therapeutic potential against stress induced neurological disorders. Therefore, the present study is an attempt to elucidate the therapeutic potency of combination of quercetin with piperine; a bioavailability enhancer against chronic unpredictable stress (CUS)-induced behavioral and biochemical alterations. Laca mice were subjected to a series of stressful events for a period of 28 days. Quercetin (20, 40 and 80 mg/kg, p.o.), piperine (20 mg/kg, p.o.) and their combinations were administered daily 30 min before CUS procedure. Piracetam (100 mg/kg, i.p.) served as a standard control. CUS caused impaired spatial navigation in Morris water maze test and poor retention in elevated plus maze task. Further, there was significant increase in brain oxidative stress markers and neuro-inflammation (TNF-α). This was coupled with marked rise in acetylcholinesterase and serum corticosterone levels. Co-administration of piperine with quercetin significantly elevated their potential to restore these behavioral, biochemical and molecular changes associated with mouse model of CUS. These results suggest that piperine enhances the neuroprotective effects of quercetin against CUS-induced oxidative stress, neuro-inflammation and memory deficits.     

Quercetin,a bioflavonoid,reverses development of tolerance and dependence to morphine

Quercetin, a bioflavonoid (25 and 50 mg/kg), when chronically administered for 9 days, failed to produce any significant change in tail flick latency as compared to control mice. However, repeated administration of quercetin (25 and 50 mg/kg) for 9 days attenuated the development of tolerance to the analgesic effect of morphine (10 mg/kg). Quercetin (25 and 50 mg/kg) also suppressed naloxone (2 mg/kg)‐precipitated withdrawal jumps on day 10 in morphine‐tolerant mice. Pretreatment of mice with quercetin (10–50, ip) significantly reversed the morphine (5 mg/kg)‐induced delay in gastric transit, whereas a higher dose of quercetin (100 mg/kg) did not have any significant effect on morphine‐induced delay in gastric transit. Quercetin per se had no effect on gastric transit. In conclusion, the results of the present study suggest potential use of quercetin in alleviating the adverse effects of opioid treatment. Drug Dev. Res. 57:167–172, 2002. © 2003 Wiley‐Liss, Inc.     

Liposomal formulations of serratiopeptidase: in vitro studies using PAMPA and Caco-2 models

The feasibility of using liposomes as a potential oral delivery system for the systemic delivery of other peptides and protein-based pharmaceuticals has been studied. Serratiopeptidase, a proteolytic enzyme, was used as a model drug. Liposomes were prepared by a thin film hydration method using various lipids, namely, soya lecithin, DMPC and DMPE. It was further investigated whether the liposomal formulations of serratiopeptidase altered the permeability/absorption of the drug using PAMPA, a non-cell-based assay, and Caco-2 assay, a cell monolayer system, mimicking in vivo GI epithelium cells. The entrapment efficiency of the formulations was found to be 62%, 84% and 86% for the liposomes of soya lecithin, DMPC and DMPE respectively. The effectiveness of the liposomal formulations against the pure drug in terms of permeability/absorption was compared. The effective permeability (log Pe) values from PAMPA study varied from -7.47 to -6.5 cm/s whereas for the serratiopeptidase it was -7.72 cm/s. The apparent permeability values calculated from Caco-2 assay varied from 1.25 x 10(-6) to 1.61 x 10(-6) cm/s whereas for the serratiopeptidase it was 1.25 x 10(-6) cm/s. The flux was found to be 3.88-4.96 microg/cm (2)/h for the formulations when compared to 3.208 microg/cm(2)/h for serratiopeptidase. The results obtained indicated that in comparison with the pure drug, incorporation of drug into liposomes improved the permeability. Thus it could be concluded that the liposomal formulations would improve the oral absorption of serratiopeptidase.     

A critical evaluation of the Heckel equation

Tropicamide, a mydriatic, cycloplegic drug was entrapped in liposomes. Liposomes were investigated by laser counting studies, transmission electron microscopy and differential scanning calorimetry for characterization. The precorneal clearance of liposomes was compared with solution by gamma-scintigraphy in the rabbit. The neutral liposomes failed to demonstrate significant enhancement in precorneal retention in comparison with aqueous solution. The potential of liposomes as an ophthalmic drug delivery system was investigated by comparing pupil dilatory effect of tropicamide by topical instillation, in the rabbit eye, of the solution and various drug-loaded liposomal forms, i.e. neutral liposomes, positively charged liposomes and neutral liposomes dispersed in 0.25% (w/v) polycarbophil gel. The positively charged liposomal formulation and liposomes dispersed in polycarbophil gel were found to be more effective than neutral liposomal dispersion when data were statistically treated at the 5% level of significance.     

Improved in vitro and in vivo hepatoprotective effects of liposomal silymarin in alcohol-induced hepatotoxicity in Wistar rats

BackgroundSilymarin, a known hepatoprotectant, owing to its poor oral bioavailability, has limited pharmacological effects. The present study was designed to improve its in vitro and in vivo hepatoprotection and increase its oral bioavailability against alcohol intoxication by formulating it in four different liposomal formulations namely conventional, dicetyl phosphate, stearyl amine and PEGylated liposomes.MethodThe liposomes were prepared using phosphatidylcholine, cholesterol, and silymarin in addition to dicetyl phosphate, stearyl amine and DSPE mPEG 2000 by film hydration method with 5% sucrose as a cryo-protectant. The optimized formulations were studied for their release profile at pH 1.2 and 6.8. Liposomes were studied for in vitro protection on Chang liver cells and efficacious liposomes were selected for in vivo hepatoprotection study. Further, conventional liposomes were studied for bioavailability in alcohol intoxicated Wistar rats.ResultsThe conventional liposomes increased in vitro release profile at pH 1.2 and 6.8 and also showed better in vitro protection compared to silymarin alone. Conventional and PEGylated liposomes showed better improvement in liver function, better efficacy in combating inflammatory conditions, better improvement in antioxidant levels and reversal of histological changes compared to silymarin alone. Conventional also showed an almost fourfold increase in area under the curve compared to silymarin suspension.ConclusionConventional and PEGylated liposomes of silymarin were found to be more efficacious as hepatoprotective against alcohol-induced hepatotoxicity by its free radical scavenging and anti-inflammatory effects. Conventional liposomes showed enhanced bioavailability compared to silymarin alone.     

Hypoglycemic efficacy of chitosan-coated insulin liposomes after oral administration in mice

INTRODUCTION In the past two decades the potential usefulnessof liposomes as drug carriers for improving enteral ab-sorption of poorly absorbed drugs including peptidedrugs such as insulin has attracted considerable interest.These phospholipid vesicles are capable of encapsulat-ing both hydrophobic and hydrophilic drugs; they arebiodegradable and are not toxic in vivo. The drugsencapsulated in liposomes are sufficiently protectedfrom enzymatic attack and immune recognition[1]. Li-po…     

Inhalable Liposomes of Low Molecular Weight Heparin for the Treatment of Venous Thromboembolism

This study tests the feasibility of inhalable pegylated liposomal formulations of low molecular weight heparin (LMWH) for treatment of two clinical manifestations of vascular thromboembolism: deep vein thrombosis (DVT) and pulmonary embolism (PE). Conventional distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) and long-circulating pegylated (DSPE–PEG-2000 and DSPE-PEG-5000) liposomes were prepared by hydration method. Formulations were evaluated for particle size, entrapment efficiency, stability, pulmonary absorption, anticoagulant, and thrombolytic effects in rats. Pulmonary absorption was monitored by measuring plasma antifactor Xa activity; anticoagulant and thrombolytic effects were studied by measuring reduction in thrombus weight and amount of dissolved radioactive clot in the blood, respectively. Pegylated liposomal were smaller and showed greater drug entrapment efficiency than conventional liposomes. All formulations produced an increase in pulmonary absorption and circulation time of LMWH upon first dosing. Three repeated dosings of conventional liposomes resulted in decreased half-life and bioavailability; no changes in these parameters were observed with pegylated liposomes. PEG-2000 liposomes were effective in reducing thrombus weight when administered every 48 h over 8 days. In terms of thrombolytic effects and dosing frequency, PEG-2000 liposomes administered via the pulmonary route at a dose of 100U/kg were as effective as 50 U/kg LMWH administered subcutaneously. This paper suggests that inhalable pegylated liposomes of LMWH could be a potential noninvasive approach for DVT and PE treatment. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci99:4554–4564,     

Azelastine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential

Azelastine is an antiallergic agent which demonstrates histamine H1-receptor antagonist activity and also inhibits histamine release from mast cells following antigen and non-antigen stimuli. Azelastine antagonises histamine- and leukotriene-induced bronchospasm in animal studies and reduces airway responsiveness to inhaled antigen or distilled water, and exercise challenge. In comparative studies, orally administered azelastine in doses up to 4 mg/day consistently relieved symptoms in patients with seasonal or perennial rhinitis - comparable to inhaled sodium cromoglycate (cromolyn sodium) 80 mg/day, oral chlorpheniramine (chlorphenamine) and oral terfenadine 120 mg/day. In addition, azelastine administered as an intranasal spray was as effective as oral terfenadine 120 mg/day and intranasal budesonide 0.4 mg/day in alleviating symptoms of rhinitis. Azelastine is also a potent antiasthmatic agent which produces significant and long lasting bronchodilation in patients with bronchial asthma. The drug is superior to placebo and comparable to oral ketotifen 2 mg/day and sustained release theophylline 700 mg/day when administered as a twice daily oral 4 mg dose. Azelastine is generally well tolerated: the most common adverse effects are altered taste perception and drowsiness. Adverse effects are mild and transient and result in withdrawal of treatment in less than 2% of patients. In a comparative study oral azelastine 2 or 4 mg/day produced no more sedation than terfenadine 120 mg/day. Thus, barring unexpected findings with wider clinical use, azelastine offers an effective and well tolerated choice of treatment for patients with allergic rhinitis and/or bronchial asthma, which may be particularly beneficial in patients in whom inhaled drug treatment is contraindicated.     

Quercetin-Containing Self-Nanoemulsifying Drug Delivery System for Improving Oral Bioavailability

Quercetin is a dietary flavonoid with potential chemoprotective effects, but has low bioavailability because of poor aqueous solubility and low intestinal absorption. A quercetin-containing self-nanoemulsifying drug delivery system (Q-SNEDDS) was developed to form oil-in-water nanoemulsions in situ for improving quercetin oral bioavailability. On the basis of the quercetin solubility, emulsifying ability, and stability after dispersion in an aqueous phase, an optimal SNEDDS consisting of castor oil, Tween® 80, Cremophor® RH 40, and PEG 400 (20:16:34:30, w/w) was identified. Upon mixing with water, Q-SNEDDS formed a nanoemulsion having a droplet size of 208.8 ± 4.5 nm and zeta potential of −26.3 ± 1.2 mV. The presence of Tween® 80 and PEG 400 increased quercetin solubility and maintained supersaturated quercetin concentrations (5 mg/mL) for >1 month. The optimized Q-SNEDDS significantly improved quercetin transport across a human colon carcinoma (Caco-2) cell monolayer. Fluorescence imaging demonstrated rapid absorption of the Q-SNEDDS within 40 min of oral ingestion. Following oral administration of Q-SNEDDS in rats (15 mg/kg), the area under the concentration curve and maximum concentration of plasma quercetin after 24 h increased by approximately twofold and threefold compared with the quercetin control suspension. These data suggest that this Q-SNEDDS formulation can enhance the solubility and oral bioavailability of quercetin for appropriate clinical application.     

Enhanced systemic exposure of fexofenadine via the intranasal administration of chitosan-coated liposome

The present study aimed to develop the intranasal delivery system of fexofenadine for the prolonged drug release via the preparation of mucoadhesive liposome. By using thin layer film hydration method, liposome of fexofenadine was prepared with DPPC/DPPG, resulting in the small lipid vesicles (359 ± 5.5 nm) with narrow size distribution (PI<0.1). Subsequently, the surface of anionic liposome was coated by chitosan and in vitro characteristics of liposomes were evaluated along with the pharmacokinetic studies in rats. Chitosan coated liposomes were stable for 6-month storage at 4 °C without any significant size change and drug leakage. Furthermore, it exhibited strong mucoadhesive properties in mucin adsorption test, which was 3-fold higher than uncoated liposomes. Compared to the oral delivery of powder formulation, the intranasal delivery of fexofenadine significantly (p<0.05) increased systemic exposure of fexofenadine in rats. Particularly, the intranasal administration of chitosan coated liposome exhibited approximately 5 fold enhancement of AUC with more sustained drug release in rats compared to the oral delivery. In conclusion, intranasal administration of chitosan coated liposome appeared to be effective to enhance the bioavailability as well as prolonged exposure of fexofenadine in rats.     

Behavioral responses to ethanol in rats perinatally exposed to low lead levels.

Wistar rats were exposed to 220 ppm of lead (Pb) in the drinking water from conception to the end of the nursing period (postnatal day 25). Maternal blood Pb levels at this time were 25 microg/dl. Male offspring were tested at the age of 35 or 70 days. We studied the anxiolytic response to 0.5-2.0 g/kg ethanol in an elevated plus maze test and preference for increasing ethanol solutions (2%, 4%, and 6%, v/v) in a free-choice paradigm; we also determined basal blood levels of corticosterone. Results demonstrated that, at 35 days of age, experimental rats were hypersensitive to the anxiolytic effect of ethanol and showed greater voluntary intake of this drug. In addition, 35-day-old Pb-treated rats exhibited higher basal levels of corticosterone as compared with those of controls. These differences disappeared at 70 days. Our findings are discussed in terms of either Pb-induced alterations in the development of the CNS or higher levels of corticosterone in experimental animals. Possible Pb-ethanol effects interactions are also considered.     

Quercetin impairs learning and memory in normal mice via suppression of hippocampal phosphorylated cyclic AMP response element-binding protein expression

Quercetin is a naturally occurring dietary flavonol and several reports have shown that quercetin substantially affects cognitive function in disease models, which suggests that quercetin might be a useful agent for treatment of memory dysfunction. However, only one report has examined the effects of quercetin on normal cognitive function. In the present study, we investigated the potential deleterious effects of quercetin on normal cognitive function using Western blot assays and the following behavioral tasks: passive avoidance, Y-maze, and Morris water maze. In the passive avoidance task, pre-acquisition administration of quercetin (10, 20, or 40 mg/kg, p.o.) caused significant cognitive impairments in mice (P < 0.05 or P < 0.01). Quercetin-treated groups (10, 20, or 40 mg/kg, p.o.) also showed significant memory impairments compared with the control group in the Y-maze task (P < 0.05). In the Morris water maze task, there were no significant differences among the groups during training trial sessions, but at the probe trial session, the quercetin-treated group (40 mg/kg, p.o.) spent significantly less time in the target quadrant than did the control group (P < 0.05). In Western blot assays of hippocampal tissue, we found that quercetin-treated groups showed decreased expression of phosphorylated Akt (pAkt), phosphorylated calcium-calmodulin kinase II (pCaMKII), and phosphorylated cyclic AMP response element-binding protein (pCREB). These results suggest that acute administration of quercetin impairs cognitive function by suppression of pAkt and pCaMKII, which, in turn, decreases pCREB expression in the hippocampus.     

Ethinylestradiol-loaded ultraflexible liposomes: pharmacokinetics and pharmacodynamics

This study aimed to develop ultraflexible liposomes as an alternative to the oral route, which would enhance the bioavailability and reduce the toxicity of ethinylestradiol. Ultraflexible liposomes of ethinylestradiol using an optimized concentration of surfactants were prepared and characterized in vitro. The effect of surfactant type under non-occlusive conditions on transdermal permeability was assessed. A histopathological study was performed to assess the action of ethinylestradiol on the uterus and ovaries. The pharmacokinetics of free ethinylestradiol (following single oral administration and one day of application to the skin), ultraflexible liposomal ethinylestradiol and non-flexible liposomal ethinylestradiol were studied in female Sprague-Dawley rats. Insignificant differences in size between the ultraflexible liposomal formulations containing optimized concentrations of different surfactants were observed. Ultraflexible liposomes can penetrate through pores much smaller than their own diameter. The transdermal permeability of lipophilic surfactant was greater than that of hydrophilic surfactant. The release of ethinylestradiol from the proposed formulation through rat skin was found to be constant. The histopathological study showed that the ultraflexible liposomal transdermal drug delivery system for ethinylestradiol provided effective contraception by follicular cell lysis, depletion of zona granulosa and ova, and by increasing the uterine mucosal and endometrial proliferation. Encapsulation of ethinylestradiol in ultraflexible liposomes modified the pharmacodynamics and pharmacokinetics of the contraceptive agent, resulting in a marked improvement in bioavailability and optimized therapy.     

The effect of PEG coating on in vitro cytotoxicity and in vivo disposition of topotecan loaded liposomes in rats

Amphoteric drugs encapsulated in PEGylated liposomes may not show superior therapeutic antitumor activity due to increased leakage rate of these drugs in presence of PEG-lipids. In order to investigate the effect of PEG coating on in vitro and in vivo characteristics of topotecan loaded liposomes, an amphoteric anticancer drug, PEGylated and conventional liposomes were prepared by lipid film hydration method. Various properties of the prepared nanoliposomes such as encapsulation efficiency, size, zeta potential, physical stability as well as the chemical stability of lactone form of topotecan, cytotoxicity and topotecan pharmacokinetics were evaluated. In vitro cytotoxic activity was evaluated on murine Lewis lung carcinoma (LLC) and human mammary adenocarcinoma (BT20) cells. Pharmacokinetic was evaluated in Wistar rats after i.v. injection of topotecan, formulated in PBS pH 7.4 or in conventional or in PEGylated liposomes. The conventional liposome (CL) formulation was composed of DSPC/cholesterol/DSPG (molar ratio; 7:7:3), while for PEGylated liposome the composition was DSPC/cholesterol/DSPG/DSPE-PEG(2000) (molar ratio; 7:7:3:1.28). The size of both liposomes was around 100 nm with polydispersity index of about 0.1. In comparison with free drug, liposomal topotecan showed more stability for topotecan lactone form in vitro. Compared to free topotecan, PEGylated and conventional liposomes improved cytotoxic effect of topotecan against the two cancer cell line studied. The results of pharmacokinetic studies in rats showed that both CL and PEGylated liposomal formulations increased the concentration of total topotecan in plasma, however, initial concentration and the values of AUC, MRT and t(1/2 beta) were much higher (P<0.001) for PEGylated liposomal drug than for conventional one or free drug. PEGylated liposome resulted in a 52-fold and 2-fold increases in AUC(0-infinity) compared with that of free topotecan and CL, respectively. These results indicated that PEG modified liposome might be an effective carrier for topotecan.