Ashok K. Tiwary

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.

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.

Lectins: Sources, Activities, and Applications

ABSTRACT: Lectins are glycoproteins or oligomeric proteins with one or more sugar-binding site(s) per subunit. These molecules are of nonimmune origin and bind reversibly with specific sugars and precipitate polysaccharides, glycoproteins, and glycolipids bearing specific sugars, thus acting as cell recognizers. They play a key role during the initiation of infections in the altered behavior of cells during metastasis and in protection of neonates against environmental antigens. The specificity of lectins for certain sugars has been used as probes to detect cell surface sugars, enzymes, immunoglo-bulins, and to identify tumorogenic cells. Lectin-liposome conjugates have also found applications for targeted drug delivery. In addition, they have been used for flocculation of bacterial suspensions in the industry. This review discusses various sources of lectins and the mechanism behind their potential role in diverse fields of biological interest.

Orally disintegrating systems: innovations in formulation and technology.

Orally disintegrating systems have carved a niche amongst the oral drug delivery systems due to the highest component of compliance they enjoy in patients especially the geriatrics and pediatrics. In addition, patients suffering from dysphagia, motion sickness, repeated emesis and mental disorders prefer these medications because they cannot swallow large quantity of water. Further, drugs exhibiting satisfactory absorption from the oral mucosa or intended for immediate pharmacological action can be advantageously formulated in these dosage forms. However, the requirements of formulating these dosage forms with mechanical strength sufficient to with stand the rigors of handling and capable of disintegrating within a few seconds on contact with saliva are inextricable. Therefore, research in developing orally disintegrating systems has been aimed at investigating different excipients as well as techniques to meet these challenges. A variety of dosage forms like tablets, films, wafers, chewing gums, microparticles, nanoparticles etc. have been developed for enhancing the performance attributes in the orally disintegrating systems. Advancements in the technology arena for manufacturing these systems include the use of freeze drying, cotton candy, melt extrusion, sublimation, direct compression besides the classical wet granulation processes. Taste masking of active ingredients becomes essential in these systems because the drug is entirely released in the mouth. Fluid bed coating, agglomeration, pelletization and infusion methods have proven useful for this purpose. It is important to note that although, freeze dried and effervescent disintegrating systems rapidly disintegrate in contact with fluids, they do not generally exhibit the required mechanical strength. Similarly, the candy process cannot be used for thermolabile drugs. In the light of the paradoxical nature of the attributes desired in orally disintegrating systems (high mechanical strength and rapid disintegration), it becomes essential to study the innovations in this field and understand the intricacies of the different processes used for manufacturing these systems. This article attempts at discussing the patents relating to orally disintegrating systems with respect to the use of different formulation ingredients and technologies.

Percutaneous Permeation Enhancement by Terpenes: Mechanistic View

A popular approach for improving transdermal drug delivery involves the use of penetration enhancers (sorption promoters or accelerants) which penetrate into skin to reversibly reduce the barrier resistance. The potential mechanisms of action of penetration enhancers include disruption of intercellular lipid and/or keratin domains and tight junctions. This results in enhanced drug partitioning into tissue, altered thermodynamic activity/solubility of drug etc. Synthetic chemicals (solvents, azones, pyrrolidones, surfactants etc.) generally used for this purpose are rapidly losing their value in transdermal patches due to reports of their absorption into the systemic circulation and subsequent possible toxic effect upon long term application. Terpenes are included in the list of Generally Recognized As Safe (GRAS) substances and have low irritancy potential. Their mechanism of percutaneous permeation enhancement involves increasing the solubility of drugs in skin lipids, disruption of lipid/protein organization and/or extraction of skin micro constituents that are responsible for maintenance of barrier status. Hence, they appear to offer great promise for use in transdermal formulations. This article is aimed at reviewing the mechanisms responsible for percutaneous permeation enhancement activity of terpenes, which shall foster their rational use in transdermal formulations.

Mannan-coated gelatin nanoparticles for sustained and targeted delivery of didanosine: in vitro and in vivo evaluation.

Mannan-coated gelatin nanoparticles for sustained and targeted delivery of didanosine: In vitro and in vivo evaluation 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. Želatinske nanočestice obložene mananom za polaganu i ciljanu isporuku didanozina: In vitro i in vivo vrednovanje 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.

Modification of crystal habit and its role in dosage form performance.

Crystallization is often employed for purifying a drug substance. Use of different solvents and processing conditions may change the crystal habit, besides altering the polymorphic state. Furthermore, altered habit may result from crystal growth during storage. Hence, there is a need to understand the factors influencing crystal habit and to evaluate critically its role in the performance of dosage forms. Establishing the physicotechnical properties of different habits of a drug will help to recognize lot-to-lot variations in raw materials and to ensure reproducibility of dosage form performance.

Transdermal Delivery of An Analgesic Agent Using Elastic Liposomes: Preparation, Characterization and Performance Evaluation

The aim of the present study was to prepare and characterize novel vesicular carrier elastic liposomes, of most commonly used non-steroidal anti-inflammatory agent diclofenac for its sustained and targeted delivery. Elastic liposomes of diclofenac were prepared and characterized in vitro and in vivo. The effect of different formulation variables like type of surfactant, concentration of surfactant and dose of drug on transdermal flux, amount of drug deposited into the skin, muscle and plasma concentration was investigated. The biological activity of optimized formulation was evaluated using carrageenan induced rat paw edema model and results were compared with commercial hydrogel formulation. The elastic liposomal formulations achieved muscle drug concentration between 2.2+/-0.14 to 5.3+/-0.22 microg/g at 12 hr. The same dose of commercial hydrogel formulation produced drug levels between 0.41+/-0.07 to 1.1+/-0.09 microg/g in the muscle. Plasma concentration study showed regiospecificity of elastic liposomal formulation. The results of in vivo study revealed that incorporation of diclofenac in elastic liposomes increased its biological activity two fold as compared to commercial hydrogel formulation. The results of the present study demonstrated greater effectiveness of dermaly applied diclofenac elastic liposomal formulation in comparison to conventional delivery system. The optimized elastic liposomal formulation offers a promising means for the non-invasive treatment of local pain and inflammation by topical application.

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.

Innovations in Transdermal Drug Delivery: Formulations and Techniques

The transdermal route of drug delivery has attracted researchers due to many biomedical advantages associated with it. However, excellent impervious nature of skin is the greatest challenge that has to be overcome for successfully delivering drug molecules to the systemic circulation by this route. Various formulation approaches used to systemically deliver drug molecules include use of prodrugs/lipophilic analogs, permeation enhancers, sub saturated systems and entrapment into vesicular systems. Further, the adhesive mixture, physical system of the delivery system and release liner influence drug release and its permeation across the skin. In addition, great strides in designing delivery systems for maximizing percutaneous drug permeation without comprising with ease of therapy cannot be neglected in improving functionality of transdermal drug delivery systems. This article deals with the innovations pertaining to formulation and techniques as described in recent patents.