Želatinske nanočestice presvučene mananom za polaganu i ciljanu isporuku didanozina: In vitro i in vivo vrednovanje

Macrophages of the reticuloendothelial system and brain act as major reservoir for HIV because of their long term survival after HIV infection and ability to spread virus particles to bystander CD4 positive lymphocyte cells. The objective of the present study was to investigate mannan-coated nanoparticles for macrophage targeting of didanosine. Different didanosine loaded nanoparticles were prepared using the double desolvation technique and were characterized in vitro, ex-vivo and in vivo. Results of the ex-vivo cellular uptake study indicated 5-fold higher uptake of didanosine from the mannan-coated nanoparticles formulation (62.5 ± 5.4%) by the macrophages in comparison with didanosine solution in phosphate buffer saline (PBS, pH 7.4) (12.1 ± 2.3%). The better cellular uptake from the nanoparticles formulation was further confirmed by fluorescence microscopy using hydrophilic 6-carboxyfluorescein as a marker. Results of the quantitative biodistribution study showed 1.7, 12.6 and 12.4 times higher localization of didanosine in the spleen, lymph nodes and brain, respectively, after administration of mannan-coated nanoparticles compared to that after injection of didanosine solution in PBS (pH 7.4). Results of the present study showed that the mannan-coated nanoparticles targeted didanosine to the macrophage by mannosyl receptor mediated endocytosis.Makrofagi retikuloendotelnog sustava i mozak djeluju kao glavni rezervoari za HIV zbog njihovog dugoročnog preživljavanja nakon infekcije HIV-om i sposobnosti da usmjere virusne čestice u CD4 pozitivne limfocite. Cilj rada bio je ispitati nanočestice obložene mananom za ciljanu isporuku didanozina u makrofage. Koristeći metodu dvostruke desolvatacije pripravljene su različite nanočestice s didanozinom te su zatim karakterizirane in vitro, ex vivo i in vivo. Rezultati ex vivo ispitivanja ukazuju da je unos didanozina u makrofage 5 puta veći iz nanočestica obloženih mananom (62,5 ± 5,4%) u usporedbi s otopinom didanozina u fosfatnom puferu (PBS, pH 7,4) (12,1 ± 2,3%). Bolji celularni unos iz nanočestica potvrđen je fluorescentnom mikroskopijom koristeći hidrofilni 6-karboksifluorescein kao marker. Rezultati kvantitativne biodistribucije pokazuju da je lokalizacija didanozina u slezeni, limfnim čvorovima i mozgu 1,7, 12,6, odnosno 12,4 puta veća nakon primjene nanočestica obloženih mananom nego nakon primjene otopine didanozina u PBS-u (pH 7,4). Nanočestice s mananom usmjeravaju didanozin u makrofage procesom endocitoze u kojoj posreduju receptori za manozu

Antitumour, acute toxicity and molecular modeling studies of 4-(pyridin-4-yl)-6-(thiophen-2-yl) pyrimidin-2(1H)-one against Ehrlich ascites carcinoma and sarcoma-180

In an effort to discover an effective and selective antitumour agent, synthesis and anti-cancer potential of 4-(pyridin-4-yl)-6-(thiophen-2-yl) pyrimidin-2(1H)-one (SK-25), which has been reported earlier by us with significant cytotoxicity towards MiaPaCa-2 malignant cells, with an IC50 value of 1.95 μM and was found to instigate apoptosis. In the present study, the antitumour efficacy of SK-25 was investigated on Ehrlich ascites tumour (EAT, solid), Sarcoma 180 (solid) tumour and Ehrlich ascites carcinoma. The compound was found to inhibit tumour development by 94.71% in Ehrlich ascites carcinoma (EAC), 59.06% in Ehrlich tumour (ET, solid) and 45.68% in Sarcoma-180 (solid) at 30 mg/kg dose. Additionally, SK-25 was established to be non-toxic at a maximum tolerated dose of 1000 mg/kg in acute oral toxicity in Swiss-albino mice. Computer-based predictions also show that the compounds could have an interesting DMPK profile since all 51 computed physicochemical parameters fall within the recommended range for 95% of known drugs. The current study provides insight for further investigation of the antitumour potential of the molecule

Formulation and evaluation of ethosomes for transdermal delivery of lamivudine

The purpose of the present research was to investigate the mechanism for improved intercellular and intracellular drug delivery from ethosomes using visualization techniques and cell line study. Ethosomal formulations were prepared using lamivudine as model drug and characterized in vitro, ex vivo and in vivo. Transmission electron microscopy, scanning electron microscopy, and fluorescence microscopy were employed to determine the effect of ethosome on ultrastructure of skin. Cytotoxicity and cellular uptake of ethosome were determined using T-lymphoid cell line (MT-2). The optimized ethosomal formulation showed 25 times higher transdermal flux (68.4±3.5 µg/cm2/h) across the rat skin as compared with that of lamivudine solution (2.8±0.2 µg/cm2/h). Microscopic studies revealed that ethosomes influenced the ultrastructure of stratum corneum. Distinct regions with lamellar stacks derived from vesicles were observed in intercellular region of deeper skin layers. Results of cellular uptake study showed significantly higher intracellular uptake of ethosomes (85.7%±4.5%) as compared with drug solution (24.9%±1.9%). The results of the characterization studies indicate that lipid perturbation along with elasticity of ethosomes vesicles seems to be the main contributor for improved skin permeation

Proultraflexible lipid vesicles for effective transdermal delivery of levonorgestrel: Development, characterization, and performance evaluation

The present investigation aimed at formulation, performance evaluation, and stability studies of new vesicular drug carrier system protransfersomes for transdermal delivery of the contraceptive agent, levonorgestrel. Protransfersome gel (PTG) formulations of levonorgestrel were prepared and characterized for vesicle shape, size, entrapment efficiency, turbidity, and drug permeation across rat skin and were evaluated for their stability. The system was evaluated in vivo for biological assay of progestational activity including endometrial assay, inhibition of the formation of corpora lutea, and weight gain of uterus. The effects of different formulation variables (type of alcohol, type and concentration of surfactant) on transdermal permeability profile were assessed. The optimized PTG formulation showed enhanced in vitro skin permeation flux of 15.82±0.37 μg/cm2/hr as compared to 0.032±0.01 μg/cm2/hr for plain drug solution. PTG also showed good stability and after 2 months of storage there was no change in liquid crystalline nature, drug content, and other characteristic parameters. The peak plasma concentration of levonorgestrel (0.139±0.05 μg/mL) was achieved within 4 hours and maintained until 48 hours by a single topical application of optimized PTG formulation. In vivo performance of the PTG formulation showed increase in the therapeutic efficacy of drug. Results indicated that the optimized protransfersomal formulation of levonorgestrel had better skin permeation potential, sustained release characteristic, and better stability than proliposomal formulation

Drug-Cyclodextrin-Vesicles Dual Carrier Approach for Skin Targeting of Anti-acne Agent

In the present study attempt was made for preparation of isotretinoin-hydroxypropyl β cyclodextrin (HP-β-CD) inclusion complex and encapsulate this complex in elastic liposomes to study the effect of dual carrier approach on skin targeting of isotretinoin. The isotretinoin HP-β-CD complex was prepared by freeze-drying method and characterized by IR spectroscopy. The drug and drug-CD complex loaded elastic liposomal formulation were prepared and characterized in vitro, ex-vivo and in vivo for shape, size, entrapment efficiency, no. of vesicles per cubic mm, in vitro skin permeation and deposition study, photodegradation and skin toxicity assay. The transdermal flux for different vesicular formulations was observed between 10.5 ± 0.5 to 13.9 ± 1.6 μg/cm2/h. This is about 15-21 folds higher than that obtained from drug solution (0.7 ± 0.1 μg/cm2/h) and 4-5 folds higher than obtained with drug-CD complex solution (2.7 ± 0.1 μg/cm2/h). The amount of drug deposit was found to increase significantly (p < 0.05) by cyclodextrin complexation (30.1 ± 0.1 μg). The encapsulation of this complex in elastic liposomal formulation further increases its skin deposition (262.2 ± 21 μg). The results of skin irritation study using Draize test also showed the significant reduction in skin irritation potential of isotretinoin elastic liposomal formulation in comparison to free drug. The results of the present study demonstrated that isotretinoin elastic liposomal formulation possesses great potential for skin targeting, prolonging drug release, reduction of photodegradation, reducing skin irritation and improving topical delivery of isotretinoin

Formulation and in vitro, in vivo evaluation of extended- release matrix tablet of Zidovudine: Influence of combination of hydrophilic and hydrophobic matrix formers

The aim of the present study was to prepare and characterize extended-release matrix tablets of zidovudine using hydrophilic Eudragit RLPO and RSPO alone or their combination with hydrophobic ethyl cellulose. Release kinetics was evaluated by using United States Pharmacopeia (USP)-22 type I dissolution apparatus. Scanning electron microscopy was used to visualize the effect of dissolution medium on matrix tablet surface. Furthermore, the in vitro and in vivo newly formulated sustained-release zidovudine tablets were compared with conventional marketed tablet (Zidovir, Cipla Ltd, Mumbai, India). The in-vitro drug release study revealed that either Eudragit preparation was able to sustain the drug release only for 6 hours (94.3%±4.5% release). Combining Eudragit with ethyl cellulose sustained the drug release for 12 hours (88.1%±4.1% release). Fitting the in vitro drug release data to Korsmeyer equation indicated that diffusion along with erosion could be the mechanism of drug release. In vivo investigation in rabbits showed sustained-release pharmacokinetic profile of zidovudine from the matrix tablets formulated using combination of Eudragits and ethylcellulose. In conclusion, the results suggest that the developed sustained-release tablets of zidovudine could perform therapeutically better than conventional dosage forms, leading to improve efficacy and better patient compliance