Puneet Utreja

Poly propyl ether imine (PETIM) dendrimer: a novel non-toxic dendrimer for sustained drug delivery.

In the present study, an attempt was made to study the acute and sub-acute toxicity profile of G3-COOH Poly (propyl ether imine) [PETIM] dendrimer and its use as a carrier for sustained delivery of model drug ketoprofen. Drug-dendrimer complex was prepared and characterized by FTIR, solubility and in vitro drug release study. PETIM dendrimer was found to have significantly less toxicity in A541 cells compared to Poly amido amine (PAMAM) dendrimer. Further, acute and 28 days sub-acute toxicity measurement in mice showed no mortality, hematological, biochemical or histopathological changes up to 80 mg/kg dose of PETIM dendrimer. The results of study demonstrated that G3-COOH PETIM dendrimer can be used as a safe and efficient vehicle for sustained drug delivery.

Novel Drug Delivery Systems for Sustained and Targeted Delivery of Anti-Cancer Drugs: Current Status and Future Prospects

In the past years, alternative pharmaceutical formulations of anti-cancer agents have been investigated in order to improve conventional chemotherapy treatment. In conventional/current therapy oral tablet, capsule and injectable formulations are used for anti-cancer drugs delivery. These formulations associated with problems like severe toxic side effects on healthy organs, difficulties in clinical administration, drug resistance and limited access of the drug to the tumor sites suggested the need to focus on site specific controlled drug delivery systems. Novel drug delivery systems are capable of controlling the rate of drug delivery, sustaining the duration of therapeutic activity and targeting the drug to the disease tissue leading to better therapeutic effect with minimum side effects. In this review, we have explored the literature related to recent development in delivery of anti-cancer drugs identify problems in present conventional chemotherapy and detailed newer approaches and future development in the delivery of anti-cancer drugs.

Localized delivery of paclitaxel using elastic liposomes: formulation development and evaluation.

In the present study an elastic liposomes-based paclitaxel formulation was developed with the objective to remove Cremophor EL. Cremophor EL is currently used for solubilizing paclitaxel in the marketed formulation and is known to produce toxic effects. Elastic liposomal paclitaxel formulation was extensively characterized in vitro, ex-vivo, and in vivo. The results obtained were compared against the marketed paclitaxel formulation. The maximum amount of paclitaxel loaded in the elastic liposomal formulation was found to be 6.0 mg/ml, which is similar to the commercial strength of marketed paclitaxel formulation. In vitro skin permeation and deposition studies showed 10.8-fold enhanced steady state transdermal flux and 15.0-fold enhanced drug deposition in comparison to drug solution. These results further confirmed with the vesicle–skin interaction study using FTIR technique. Results of the hemolytic toxicity assay indicate that elastic liposomal formulation induced only 11.2 ± 0.2% hemolysis in comparison to the commercial formulation which showed 38 ± 3.0%. Further, results of the Draize test showed no skin irritation of paclitaxel elastic liposomal formulation. Findings of the study demonstrate that elastic liposomes as a carrier is an attractive approach for localized delivery of paclitaxel.

Evaluation of biosafety and intracellular uptake of Cremophor EL free paclitaxel elastic liposomal formulation.

The present study examines the acute, sub-acute toxicity, and cytotoxicity of paclitaxel elastic liposomal formulation in comparison to a marketed Cremophor EL (polyoxyethylated castor oil):ethanol (1:1, v/v) based formulation. In the previous study, Cremophor EL free paclitaxel elastic liposomal formulation was developed and characterized. Cytotoxicity of formulation was evaluated by MTT assay using A549 cell lines. Percentage intracellular uptake of paclitaxel elastic liposomal and marketed formulation was determined using a fluorescence activating cell sorting assay (FACS) and fluorescence microscopy techniques. Single and repeated dose toxicity measurement showed no mortality, hematological, biochemical, or histopathological changes up to a dose of 120 mg/kg for paclitaxel elastic liposomal formulation, in comparison the marketed formulation showed toxicity at a dose of 40 mg/kg. Maximum tolerated dose (MTD) for paclitaxel elastic liposomal and marketed formulation was found to be 160 mg/kg and 40 mg/kg, respectively. Results of FACS analysis showed a 94.6 ± 2.5% intracellular uptake of fluorescence marker acridine orange (AO) loaded in elastic liposomes; in comparison the AO solution showed only a 19.8 ± 1.1% uptake. Paclitaxel elastic liposomal formulation seems to be a better alternative for safe and effective delivery of paclitaxel. This study proves the safety and higher intracellular uptake of paclitaxel elastic liposomal formulation.

Efficacy and Toxicological Studies of Cremophor EL Free Alternative Paclitaxel Formulation

PURPOSE In the present study, Cremophor EL free paclitaxel elastic liposomal formulation consisting of soya phosphatidylcholine and biosurfactant sodium deoxycholate was developed and optimized. The toxicological profile, antitumor efficacy and hemolytic toxicity of paclitaxel elastic liposomal formulation in comparison to Cremophor EL based marketed formulation were evaluated. METHODS Paclitaxel elastic liposomal formulations were prepared and characterized in vitro, ex-vivo and in vivo. Single dose toxicity study of paclitaxel elastic liposomal and marketed formulation was carried out in dose range of 10, 20, 40, 80, 120, 160 and 200 mg/kg. Cytotoxicity of developed formulation was evaluated using small cell lung cancer cell line (A549). Antitumor activity of developed formulation was compared with the marketed formulation using Cytoselect™ 96-well cell transformation assay. RESULTS In vivo administration of paclitaxel elastic liposomal formulation into mice showed 6 fold increase in Maximum Tolerated Dose (MTD) in comparison to the marketed formulation. Similarly, LD50 (141.6 mg/kg) was also found to increase significantly than the marketed formulation (16.7 mg/kg). Result of antitumor assay revealed a high reduction of tumor density with paclitaxel elastic liposomal formulation. Reduction in hemolytic toxicity was also observed with paclitaxel elastic liposomal formulation in comparison to the marketed formulation. CONCLUSION The carrier based approach for paclitaxel delivery demonstrated significant reduction in toxicity as compared to the Cremophor EL based marketed formulation following intra-peritoneal administration in mice model. The reduced toxicity and enhanced anti-cancer activity of elastic liposomal formulation strongly indicate its potential for safe and effective delivery of paclitaxel.

Nanostructured Lipid Carriers and their application in drug delivery

Since a decade, trials are being made to utilise Solid Lipid Nanoparticles (SLN) as a drug delivery system. However, the major limitation of SLN is limited drug payload and drug expulsion during storage. Recently, areas of research have focused on the carrier system based on mixtures of solid and liquid lipids known as Nanostructured Lipid Carriers (NLC). The aim of developing NLC is to overcome the limitation of SLN. This paper provides an overview of NLC technology and describes the different types of NLC, its production, characterisation and potential applications for the administration of drug molecules.

Recent Advances in Drug Delivery Systems for Anti-Diabetic Drugs: A Review

Almost 200 million people worldwide are found to be affected by Diabetes mellitus (DM). DM is a metabolic disorder which occurs due to reduced insulin action and/or insulin secretion in the body. Reduced or inactive insulin results in imbalanced food metabolism. With the progression of disease, pathological changes like nephropathy, retinopathy and cardiovascular complications start occurring in the body. DM is mainly categorized into 2 types: type 1 DM and type 2 DM. Type 1 is generally treated through insulin replacement therapy. Type 2 DM is treated with oral hypoglycemics. Oral hypoglycemics are classified into 5 types: sulfonylureas, biguanides, α-glucosidase inhibitors, meglitinide analogues and thiazolidinediones. Conventional dosage forms of most of these drugs bear some drawbacks such as frequent dosing, short half live, and low bioavailability. Therefore, to alleviate the drawbacks associated with conventional dosage forms, efforts have been made in the area of novel and controlled drug delivery system for oral hypoglycemics. Present review highlights various novel and controlled drug delivery systems that have been investigated by different researchers for achieving sustained and controlled drug delivery of oral hypoglycemics and for overcoming the limitations related with the conventional dosage forms of oral hypoglycemics.

Emerging Strategies and Challenges for Controlled Delivery of Taxanes: A Comprehensive Review.

Taxanes introduction in the mid 90 s leads to significant advancement as well as superlative improvement in the treatment of cancer. Since then, several strategies have been designed to enhance therapeutic potential of these agents by overcoming the limitations in drug delivery and pharmacokinetic constraints associated with conventional delivery. In this regard, controlled drug delivery systems for taxanes have contributed enormously by altering the pharmacokinetic profile, thus ultimately enhancing their therapeutic response. With their conferred stellar merits, controlled drug delivery systems have been able to surmount many of the challenges associated with conventional drug delivery systems. The altered absorption, resistance, low toxicity and cellular uptake profiles that lead to better safety from variegated carrier systems like nanocarriers, liposomes, solid lipid nanoparticles, nanoemulsions, nanocapsules, hydrogels and micelles for controlled delivery of taxanes call for an exhaustive review for future progressive work. Therefore, this review focuses on the altered pharmacokinetic, pharmacodynamic and toxicity patterns achieved from various controlled drug delivery approaches, with the latter half highlighting the clinical profile set ups and commercial aspects of controlled release drug delivery systems.

Paclitaxel Loaded Nanoliposomes in Thermosensitive Hydrogel: A Dual Approach for Sustained and Localized Delivery

In an attempt to improve the localized paclitaxel delivery, carrier based thermoresponsive chitosan hydrogel was exploited in the present study. Nanoliposomes as carrier for paclitaxel were prepared and optimized in strength of 6 mg/ml similar to marketed paclitaxel formulation. The chitosan solution (2% w/v) mixed with different concentrations of dibasic sodium phosphate (DSP) was evaluated as thermoresponsive systems in terms of gelling temperature and time. Finally, the drug loaded nanoliposomes were incorporated in optimized chitosan- DSP hydrogel base to form nanoliposomal in situ thermosensitive hydrogel formulations having dual mechanism of protection and release. The optimal formulation containing DSP was selected on the basis of minimal gelation temperature (37±0.8 ºC) and time (6.7±0.3 min). In vitro drug release experiment illustrated that developed formulation manifested sustained release action in which drug release was extended for more than 72 h compared to marketed formulation. In addition, optimized nanoliposomal hydrogel demonstrated enhanced biological half-life of 15.7±1.5h, depicting maintenance of constant plasma concentration in contrast to marketed formulation that showed the half-life (t1/2) of 3.6±0.4h. The in vivo anti tumor activity tested using EAC model also corroborated the above findings that developed formulation was having significant higher anti-tumor activity and reduced toxicity than the marketed formulation. Tumor volume was found to reduce upto 89.1±3.5% by treatment with in situ hydrogel formulation. The histopathological study of tumor also demonstrated the better safety and efficacy of developed formulation in comparison to marketed paclitaxel formulation. Our results suggest that carrier based chitosan hydrogel could be an efficacious vehicle for sustained and localized delivery of paclitaxel.

Anti-cancer, pharmacokinetic and biodistribution studies of cremophor el free alternative paclitaxel formulation.

PURPOSE The aim of the present investigation is to determine the in vivo potential of previously developed and optimized Cremophor EL free paclitaxel (CF-PTX) formulation consisting of soya phosphatidylcholine and biosurfactant sodium deoxycholate. CF-PTX was found to have drug loading of 6 mg/ml similar to Cremophor EL based marketed paclitaxel formulation. In the present study, intracellular uptake, repeated dose 28 days sub-acute toxicity, anti-cancer activity, biodistribution and pharmacokinetic studies were conducted to determine in vivo performance of CF-PTX formulation in comparison to marketed paclitaxel formulation. METHODS Intracellular uptake of CF-PTX was studied using A549 cells by fluorescence activated cell sorting assay (FACS) and fluorescence microscopy. In vivo anti-cancer activity of CF-PTX was evaluated using Ehrlich ascites carcinoma (EAC) model in mice followed by biodistribution and pharmacokinetic studies. RESULTS FACS investigation showed that fluorescence marker acridine orange (AO) solution showed only 19.8±1.1% intracellular uptake where as significantly higher uptake was observed in the case of AO loaded CF-PTX formulation (85.4±2.3%). The percentage reduction in tumor volume for CF-PTX (72.5±2.3%) in EAC bearing mice was found to be significantly (p<0.05) higher than marketed formulation (58.6±2.8%) on 14th day of treatment. Pharmacokinetic and biodistribution studies showed sustained plasma concentration of paclitaxel depicted by higher mean residence time (MRT; 18.2±1.8 h) and elimination half life (12.8±0.6 h) with CF-PTX formulation as compared to marketed formulation which showed 4.4±0.2 h MRT and 3.6±0.4 h half life. The results of the present study demonstrated better in vivo performance of CF-PTX and this formulation appears to be a promising carrier for sustained and targeted delivery of paclitaxel.