Development and in vivo evaluation of functionalized ritonavir proliposomes for lymphatic targeting.

AIMS: The aim of the present work was to prepare, characterize, and evaluate proliposomes containing lipophilic prodrug ritonavir for targeting towards CD4+ T cells in the lymphatic system. MATERIALS AND METHODS: The liposomes were prepared by lipid thin film hydration method and lyophilized in the presence of cryoprotectant mannitol to obtain proliposomes. The optimized proliposomes by Central Composite Design, were surface modified with biotin. The proliposomes were evaluated for particle size, zeta potential, polydispersity index (PDI), entrapment efficiency, in vitro drug release, in vivo pharmacokinetics and biodistribution studies. KEY FINDINGS: The mean particle size was found to be in the range of 126.6 to 306.2nm with PDI of 0.340-1.00. The entrapment efficiency was found to be in the range of 18.9 to 86.2%. The formulations showed a zeta potential in the range of -18.1 to -20.2mv. Biotinylated proliposomes (LIP-5B) were in the size of 149.8±6.8nm with entrapment efficiency 61.6%. The % CDR of pure drug, conventional, biotinylated proliposome in 3h was found to be 58.3, 82.04, and 95.9% respectively. In vitro drug release and in vivo pharmacokinetics of the pure drug, optimized conventional proliposomes (LIP-5) and biotin proliposomes (LIP-5B) were executed. SIGNIFICANCE: The AUC for the liposomes were found to be much higher in the spleen and thymus compared to that in the plasma which indicated that the developed formulations enhance the bioavailability and target specificity compared to that of the pure drug thereby enhancing bioavailability at target site.

Development of risperidone liposomes for brain targeting through intranasal route.

The present paper is aimed at development of functionalized risperidone liposomes for brain targeting through nasal route for effective therapeutic management of schizophrenia. The risperidone liposomes were prepared by thin film hydration method. Various parameters such as lipid ratio and lipid to drug ratio were optimized by using Design-Expert(®) Software to obtain high entrapment with minimum vesicle size. The surface of the optimized liposomes was modified by coating stearylamine and MPEG-DSPE for enhanced penetration to the brain. The formulations were evaluated for vesicle size, zeta potential, and entrapment efficiency. The morphology was studied by Transmission Electron Microscopy (TEM). In vivo efficacy was assessed by performing pharmacokinetic study in Wistar albino rats following intranasal administration of the formulations in comparison to intravenous bolus administration of pure drug. The mean vesicle size of optimized liposomes ranged from 90 to 100nm with low polydispersity index (<0.5). The entrapment efficiency of optimized liposomes was between 50 and 60%, functionalized liposomes showed maximum entrapment. The TEM images showed predominantly spherical vesicles with smooth bilayered surface. All formulations showed prolonged diffusion controlled drug release. The in vivo results showed that liposomal formulations provided enhanced brain exposure. Among the formulations studied, PEGylated liposomes (LP-16) had shown greater uptake of risperidone into the brain than plasma. High brain targeting efficiency index for LP-16 indicating preferential transport of the drug to brain. The study demonstrated successful formulation of surface modified risperidone liposomes for nasal delivery with brain targeting potential.

Sustained release optimized formulation of anastrozole-loaded chitosan microspheres: in vitro and in vivo evaluation.

The purpose of this study was to develop sustained release formulation of anastrozole-loaded chitosan microspheres for treatment of breast cancer. Chitosan microspheres cross-linked with two different cross-linking agents viz, tripolyphosphate (TPP) and glutaraldehyde (GA) were prepared using single emulsion (w/o) method. A reverse phase HPLC method was developed and used for quantification of drug in microspheres and rat plasma. Influence of cross-linking agents on the properties of chitosan microspheres was extensively investigated. Formulations were characterized for encapsulation efficiency (EE), compatibility of drug with excipients, particle size, surface morphology, swelling capacity, erosion and drug release profile in phosphate buffer pH 7.4. EE varied from 30.4 ± 1.2 to 69.2 ± 3.2% and mean particle size distribution ranged from 72.5 ± 0.5 to 157.9 ± 1.5 µm. SEM analysis revealed smooth and spherical nature of microspheres. TPP microspheres exhibited higher swelling capacity, percentage erosion and drug release compared to GA microspheres. Release of anastrozole (ANS) was rapid up to 4 h followed by slow release status. FTIR analysis revealed no chemical interaction between drug and polymer. DSC analysis indicated ANS trapped in the microspheres existed in amorphous form in polymer matrix. The highest correlation coefficients (R (2)) were obtained for Higuchi model, suggesting a diffusion controlled mechanism. There was significant difference in the pharmacokinetic parameters (AUC(0-∞), Kel and t(1/2)) when ANS was formulated in the form of microspheres compared to pure drug. This may be attributed to slow release rate of ANS from chitosan microspheres and was detectable in rat plasma up to 48 h which correlates well with the in vitro release data.

Erythrocytes as carrier for prednisolone: in vitro and in vivo evaluation.

Resealed erythrocytes, as drug delivery system has tremendous potential to achieve site specificity and prolonged release of drug thereby enhancing therapeutic index and patient compliance. In the present investigation erythrocytes obtained from healthy volunteers were loaded with prednisolone using preswell dilution and dilution technique with two different cross-linking agents, glutaraldehyde and dimethylsulphoxide. Carrier erythrocytes, having acceptable loading parameters showed increased percentage drug content with the addition of cross-linking agents. In vitro drug release followed zero-order kinetics, haemoglobin content was found to be satisfactory and osmotic fragility study indicated that increased drug entrapment efficiency was found at 0.3%w/v concentration of sodium chloride (hypotonic solution). In vivo tissue distribution studies were carried out for optimized formulation and order of distribution was found to be Liver>Lung>Kidney> Spleen. The developed drug delivery system is endowed with several exclusive advantages and hence holds potential for further research and clinical application.

Gender differences in the pharmacokinetics of rivastigmine in rats.

The effect of gender on the pharmacokinetics of rivastigmine (CAS 123441-03-2) was studied in male and female Wistar rats following intravenous bolus administration. The area under the plasma concentration-time curve (AUC), apparent volume of distribution (Vd), systemic clearance (CL), and terminal plasma halflife (t1/2) of rivastigmine were compared between male and female rats. Compared to male rats, female rats exhibited higher plasma rivastigmine levels showing significantly (p < 0.05) larger AUC (226.77 vs. 149.68 ng h/ml), Vd (6.70 vs. 4.13 L), t1/2 (0.84 vs. 0.34 h) and a lower CL (5.51 vs. 8.35 L/h). The male rats had a 2.5 fold greater elimination rate constant than female rats (2.02 vs. 0.82 h(-1)). Gender had a significant effect on the pharmacokinetics of rivastigmine. Gender differences were reported due to gonadal hormones, and the observed difference in pharmacokinetics of rivastigmine might be attributed to testosterone in male rats.