Bharti Sapra

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.

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.

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.

Niosomal Gel for Site-Specific Sustained Delivery of Anti-Arthritic Drug: In Vitro-In Vivo Evaluation

Celecoxib, a selective COX-2 inhibitor is commonly used in the treatment of arthritis. Recently, cardiotoxic effects associated with conventional modes of delivery of celecoxib have made it pertinent to develop alternate dosage forms capable of selectively delivering the drug topically to affected joints. The aim of the present study was to prepare and characterize niosomal gel formulation for sustained and site-specific delivery of celecoxib. Celecoxib loaded niosomes were prepared and characterized in vitro, ex-vivo and in vivo. The results of organ localization (deep skin layer + muscle) study showed that niosomal gel provided 6.5 times higher drug deposition as compared to carbopol gel (195.2+/-8.7 and 30.0+/-1.5 microg, respectively). The muscle to plasma concentration ratio for niosomal gel formulation was six (2.16+/-0.12 microg/g vs. 0.34+/-0.01 microg/ml) and for carbopol gel it was one (0.36+/-0.01 microg/g vs. 0.43+/-0.02 microg/ml). Biological effectiveness of optimized formulation was evaluated using carrageenan induced rat paw edema model. The application of niosomal gel produced significant reduction of rat paw edema as compared to that after application of conventional gel indicating better skin permeation and deposition of celecoxib from niosomes. The results of the present study demonstrated niosomal gel formulation possess great potential for enhanced skin accumulation, prolonging drug release and improving the site specificity of celecoxib.

Transdermal Delivery of Carvedilol Containing Glycyrrhizin and Chitosan as Permeation Enhancers: Biochemical, Biophysical, Microscopic and Pharmacodynamic Evaluation

The present study was aimed at unveiling the influence of glycyrrhizin and chitosan on rat epidermis and to correlate these effects with percutaneous permeation characteristics of carvedilol. The permeation of carvedilol across excised rat epidermis was significantly higher (p < 0.05) when glycyrrhizin, chitosan, or glycyrrhizin–chitosan mixture was used as a donor vehicle as compared to propylene glycol:ethanol (7:3) mixture. Epidermis obtained after 12 hr treatment of viable rat skin with a glycyrrhizin–chitosan mixture showed significantly higher (p < 0.05) permeability to carvedilol as compared to that after treatment with glycyrrhizin or chitosan alone. Further, the application of patches containing glycyrrhizin–chitosan mixture resulted in sustained release of carvedilol, which was able to control the hypertension in deoxycorticosterone acetate induced hypertensive rats through 28 hr. Estimation of microconstituents in rat epidermis revealed maximum extraction of cholesterol, sphingosine, and triglycerides after treatment with glycyrrhizin–chitosan mixture. This was manifested in altered lipid and protein-specific thermotropic transitions. Further, increase in intercellular space, disordered lipid structure and corneocyte detachment as observed in SEM and TEM suggests great potential of glycyrrhizin for use as a percutaneous permeation enhancer.

Transdermal delivery of carvedilol in rats: probing the percutaneous permeation enhancement mechanism of soybean extract-chitosan mixture.

Background: This study was designed for investigating the effect of soybean (SS) extract and chitosan (CTN) in facilitating the permeation of carvedilol (CDL) across rat epidermis. Method: Transdermal flux of carvedilol through heat-separated rat epidermis was investigated in vitro using vertical Keshary–Chien diffusion cells. Biophysical and microscopic manifestations of epidermis treated with SS-extract, CTN, and SS extract–CTN mixture were investigated by using DSC, TEWL, SEM, and TEM. Biochemical estimations of cholesterol, sphingosine, and triglycerides were carried out for treated excised as well as viable rat epidermis. The antihypertensive activity of the patches in comparison to that after oral administration of carvedilol was studied in deoxycorticosterone acetate-induced hypertensive rats. Results: The solubility of CDL was found to be maximum in the presence of 1% (w/v) SS extract. The KIPM/PB of CDL decreased with increase in concentration of SS extract. The in vitro permeation of CDL across rat epidermis increased and was maximum with combination of SS extract and chitosan (CTN). Biochemical and microscopic studies revealed the initiation of reversal of barrier integrity after 12 hours. Furthermore, the application of patches containing SS extract–CTN mixture resulted in sustained release of carvedilol, which was able to control the hypertension in deoxycorticosterone acetate (DOCA) induced hypertensive rats through 24 hours. CTN was found to potentiate the permeation enhancing activity of SS extract. Conclusion: The developed transdermal patches of CDL containing SS extract–CTN mixture exhibited better performance as compared to oral administration in controlling hypertension in rats.

A critical appraisal of microemulsions for drug delivery: part II

Microemulsions are thermodynamically stable, optically transparent isotropic solutions of oil and water successfully formulated by using a combination of suitable surfactant and cosurfactant. The solubilization power of microemulsions for lipophilic, hydrophilic and amphiphilic solutes form a viable approach for enhancing the bioavailability of hydrophobic drugs and percutaneous permeation of poorly permeable drugs, mainly due to the large area per volume ratio available for mass transfer. Microemulsions have emerged as novel vehicles for drug delivery due to their versatile applications. They allow sustained release for topical, oral, nasal, intravenous, ocular, parenteral and other administration routes of drugs. They also offer a relevant application platform for improving target specificity, therapeutic activity, and reducing toxicity of drugs.

Tamarindus indica pectin blend film composition for coating tablets with enhanced adhesive force strength.

Tablet coating is the most useful method to improve tablet texture, odour and mask taste. Thus, the present investigation was aimed at developing an industrially acceptable aqueous tablet coating material. The physico-chemical, electrical and SEM investigations ensures that blending of Tamarindus indica (Linn.) pectin (TP) with chitosan gives water resistant film texture. Therefore, CH-TP (60:40) spray coated tablets were prepared. The evaluation of CH-TP coated tablets showed enhanced adhesive force strength (between tablet surface to coat) and negligible cohesive force strength (between two tablets) both evaluated using texture analyzer. The comparison of CH-TP coated tablets with Eudragit coated tablets further supported superiority of the former material. Thus, the findings pointed towards the potential of CH-TP for use as a tablet coating material in food as well as pharmaceutical industry.

Understanding pharmaceutical polymorphic transformations I: influence of process variables and storage conditions

The active pharmaceutical ingredient (API) of a dosage form is affected by number of mechanical and environmental factors which have a tendency to alter its crystalline state. Polymorphic transitions have been observed to occur during various unit operations like granulation, milling and compression. Forces of pressure, shear and temperature have an ability to induce alterations in crystal habit. A conversion in polymorphic form during a unit operation is very likely to affect the handling of API in the subsequent unit operation. Transitions have also been observed during storage of formulations where the relative humidity and temperature play a major role. An increase in temperature during storage can dehydrate or desolvate the crystal and hence produce crystal defects, whilst, high humidity conditions produce higher molecular mobility leading to either crystallization of API or alteration of its crystalline form.

Microemulsion Transdermal Formulation for Simultaneous Delivery of Valsartan and Nifedipine: Formulation by Design

The objective of the study was to optimize the proportion of different components for formulating oil in water microemulsion formulation meant for simultaneous transdermal delivery of two poorly soluble antihypertensive drugs. Surface response methodology of Box-Behnken design was utilized to evaluate the effect of two oils (Captex 500 - x1 and Capmul MCM - x2) and surfactant (Acrysol EL135 - x3) on response y1 (particle size), y2 (solubility of valsartan), and y3 (solubility of nifedipine). The important factors which significantly affected the responses were identified and validated using ANOVA. The model was diagnosed using normal plot of residuals and Box-Cox plot. The design revealed an inverse correlation between particle size and concentration of Capmul MCM and Acrysol EL 135. However, an increase in concentration of Captex 500 led to an increase in particle size of microemulsion. Solubility of valsartan decreased while that of nifedipine increased with increase in concentration of Captex 500. Capmul MCM played a significant role in increasing the solubility of valsartan. The effect of Acrysol EL 135 on solubility of both drugs, although significant, was only marginal as compared to that of Captex 500 and Capmul MCM. The optimized microemulsion was able to provide an enhancement ratio of 27.21 and 63.57-fold for valsartan and nifedipine, respectively, with respect to drug dispersion in aqueous surfactant system when evaluated for permeation studies. The current studies candidly suggest the scope of microemulsion systems for solubilizing as well as promoting the transport of both drugs across rat skin at an enhanced permeation rate.