Mohali, Punjab — , India. E-mail: ni. Aggarwal Received Aug 1; Accepted Aug This article has been cited by other articles in PMC.
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Mohali, Punjab — , India. E-mail: ni. Aggarwal Received Aug 1; Accepted Aug This article has been cited by other articles in PMC. Abstract The aim of the present study was to investigate transfersomes as a transdermal delivery system for the poorly soluble drug, sertraline, in order to overcome the troubles associated with its oral delivery.
Different transfersomal formulations were prepared with non-ionic surfactant span 80 , soya lecithin, and carbopol by the rotary evaporation sonication method. The prepared formulations were characterized for light microscopy, particle size analysis, drug entrapment, turbidity, drug content, rheological studies, in vitro release, ex vivo permeation, and stability studies.
The optimized formulation was evaluated for in vivo studies using the modified forced swim model test. FTIR studies showed compatibility of the drug with excipients. The result revealed that sertraline in all of the formulations was successfully entrapped with uniform drug content.
Transfersomal gel containing 1. The ex vivo permeation profile of EL-SP4 was compared with the transfersomal suspension, control gel, and drug solution. It also owed to better applicability due to the higher viscosity imparted by the gel rather than the transfersomal suspension, and no skin irritation was observed. The modified forced swim test in mice revealed that the transfersomal gel had better antidepressant activity as compared to the control gel. Thus, the study substantiated that the transfersomal gel can be used as a feasible alternative to the conventional formulations of sertraline with advanced permeation characteristics for transdermal application.
Keywords: Sertraline, Transfersomes, Transdermal, Permeation studies, In vivo study Introduction Depression is one of the most common psychiatric disorders and is characterized by feelings of intense sadness, helplessness, worthlessness, and impaired functioning [ 1 ].
Sertraline, an antidepressant drug, is a selective serotonin reuptake inhibitor SSRI administered orally alone or in combination with hydrochloride in a daily oral dose of 50 mg.
But various problems are associated with its oral delivery such as extensive first-pass metabolism, gastrointestinal disturbances such as nausea, dry mouth, diarrhea, decreased appetite etc. Transdermal delivery of sertraline is a better-suited alternative to surmount the problems associated with its oral delivery. The transdermal route, besides being convenient and safe, offers several advantages over conventional ones, such as avoidance of GI incompatibility, variable GI absorption, avoidance of first-pass metabolism, improved bioavailability, reduced frequency of administration, improved patient compliance, and rapid termination of drug input [ 3 ].
Despite decades of research, the barrier function of the stratum corneum still remains a problem, which makes the development of new transdermal drug delivery systems an interesting challenge. Vesicular systems have been widely explored as surrogate vehicles for topical and transdermal drug delivery.
Their benefits in enhancing drug permeation have been well established [ 4 ]. Despite the strong rationale for the use of vesicles in transdermal drug delivery, the major problem in the development of vesicular systems at industrial and clinical levels is their poor stability.
Different approaches have been proposed to enhance the stability of the vesicular system. Transfersomes transfersomes offer a versatile delivery concept for improving the stability as well as the potential to be used with a wide range of active compounds. They are quasi metastable, which makes the vesicle membrane ultra-flexible, and thus, the vesicles are highly deformable that squeeze through pores in the stratum corneum less than one-tenth of their own diameter when applied under non-occlusive conditions.
Thus, even sizes up to — nm can penetrate intact skin. It is primarily due to the remarkable strong membrane adaptability that allows the transfersomal vesicles to lodge in a confining pore, and thus permeate that pore [ 3 , 5 , 6 ].
But the low viscosity of transfersomal suspensions constrains its application in transdermal delivery due to its cumbersome use. Biocompatible gels having weak interactions with surfactants have already been explored to modify the rheological behavior of the transfersomal suspension. Thus, the incorporation of the transfersomal suspension into the gel matrix can result in a transfersomal gel which may be more relevant for transdermal application. This study is aimed to incorporate sertraline in the transfersomal gel system for transdermal administration to avoid problems associated with its oral delivery, and to enhance the permeation of the drug through the skin and ultimately enhance the bioavailability.
The prepared system was optimized and evaluated for in vitro release studies. An ex vivo permeation study was also conducted to assess the transdermal ability of this system to deliver sertraline.
Furthermore, skin irritation studies and an in vivo study of the optimized transfersomal formulation was also conducted using the modified forced swim model test in mice.
Span 80 and soya lecithin were obtained from S. Fine chemicals Ltd. All other chemicals used in this study were of analytical grade.
Formulation of sertraline transfersomes The transfersomes were formulated by the conventional rotary evaporation sonication method [ 7 , 8 ]. Transfersomes containing phospholipids soya lecithin , surfactant span 80 , and the drug sertraline were formulated. The drug concentration varied from 0. The phospholipids and surfactant were taken in a clean, dry, round-bottom flask and this lipid mixture was dissolved in a small quantity of ethanol.
Final traces of solvents were removed under vacuum overnight. The resulting vesicles were kept for 2 h at ambient temperature to swell and form into large multilamellar vesicles. These were sonicated in a bath for 10 min to achieve smaller vesicles.
The varied amounts of the drug were added 0. All of the drug-loaded vesicular formulations were examined for maximum entrapment efficiency and for the appearance of drug crystals over a period of 14 days using an optical microscope.
Also, the UV spectra of the pure drug and drug with excipients were also observed. Characterization of elastic liposomal formulations Entrapment efficiency Percentage entrapment efficiency was conducted by the centrifuge method.
The clear fraction supernatant was used for the determination of free drug. The drug concentration in the resulting solution was assayed by a UV spectrophotometer Shimadzu- , Japan at nm [ 9 ].
Transfersomal formulations were diluted with water. Vesicles without sonication were also visualized by using an optical microscope Leica digital microscope, Germany. A thin film of transfersomes was spread on a slide and a cover slip was placed over it and then observed under the optical microscope [ 10 ]. Vesicle size and size distribution Analysis of the transfersome vesicle size before sonication was determined by optical microscopy using a stage eyepiece micrometer calibrated using a micrometer scale.
All samples were subjected to sonication prior to PDI determination [ 11 ]. Turbidity measurements The transfersomes were diluted with distilled water to give a total lipid concentration of 0. After rapid mixing by sonication for 5 min, the turbidity was measured as the absorbance at nm with a UV- visible spectrophotometer Shimadzu, Japan.
Development of a secondary topical vehicle All of the formulations EL-SP1 to EL-SP5 were found to be in the nano size range and were therefore incorporated into the gel matrix resulting in transfersomal gel. Carbopol was selected as the gel matrix base.
Carbopol was swelled in a small amount of water for 24 h and a high viscous solution was obtained, and the transfersomal suspension was slowly added to the viscous solution of carbopol under magnetic stirring.
The pH values were subsequently regulated to 6—9 by using triethanolamine. Drug content determination The amount of drug contained in the transfersomal gel was determined by dissolving mg of the formulation in 10 mL of ethanol. The mixture was analysed by a UV-Visible spectrophotometer at nm against ethanol as a blank [ 12 ].
Viscosity measurement and rheological behavior of transfersomal gel The viscosity of the prepared formulations was determined at different angular velocities at The transfersomal gel formulations were evaluated for their rheological behavior using cone and plate configuration 40 mm cone with 2. Rheology studies were conducted in the shear rate range of In vitro drug release studies through cellophane membrane The in vitro permeation behaviour of sertraline from all transfersomal gel formulations and the control gel formulation containing drug, lecithin, and span 80 were investigated using cellophane membrane Molecular weight cut of —, HI Media Ltd, Mumbai, India.
The vertical type of the Franz Diffusion cell was designed, fabricated, and validated prior to the permeation study. The cellophane membrane was mounted on a diffusion cell assembly with an effective diffusion area of 2. The receptor compartment consisted of a The prepared formulation was applied to the membrane in the donor compartment. An aliquot of 2 mL sample was withdrawn at suitable time intervals and replaced immediately with an equal volume of fresh diffusion medium.
The cumulative amount that permeated across the cellophane membrane was calculated and plotted against time. Release kinetics To study the release kinetics, data obtained from in vitro permeation studies were fitted in various kinetic models: zero order as the cumulative percent of drug permeated vs.
To determine the mechanism of drug release, the data were fitted into the Korsmeyer- Peppas model as the log cumulative percentage of drug released vs. For the slab matrix, if the exponent is 0. Ex vivo drug permeation using a diffusion cell Preparation of Wistar rat skin for permeation studies Hairless animal skin was used for the permeation studies.
Hair on the dorsal skin of the sacrificed animal was removed with an animal hair clipper, subcutaneous tissue was surgically removed, and the dermis side was wiped with isopropyl alcohol to remove residual adhering fat. The skin was washed with PBS pH 6. The skin was defrosted at room temperature when required. Skin permeation studies The selected formulations on the basis of entrapment efficiency, drug content, and permeation through the cellophane membrane were subjected to permeation studies through rat skin using the Franz Diffusion cell in a similar manner as through the cellophane membrane.
The cumulative amount of drug permeated was compared with the transfersomal suspension, control gel, and drug solution. The cumulative amount of drug permeated across the rat skin was plotted against time and the flux was calculated as drug permeated per cm2 per hour.
Skin irritation studies Skin irritation studies were carried out according to the Ammar technique. Four groups of guinea pigs with three animals each of either sex were used to study the hypersensitivity reaction on the skin.
The first group of animals served as the control group i. The erythema and edema were scored as follows: 0 for none, 1 for slight, 2 for well defined, 3 for moderate, and 4 for scar formation and severe erythema and edema [ 15 ]. The first group served as the control group, i. The FST included two phases: an initial 15min pretest followed by a 5min test 24 h later.
After each session, the mice were removed from the cylinders, dried with towels, and placed into heated cages for 10min, and then returned to their home cages.
The total duration of immobility, struggling, and swimming were measured during a 5 min test. A mouse was judged to be immobile whenever it remained passively floating in the water in a slightly hunched but upright position, its head just above the surface. Struggling was considered when the mice made active movements with their forepaws in and out of the water along the side of the swim chamber, whereas swimming was considered when the mice made active swimming or circular movements [ 16 ].
Stability Studies Stability of the product may be defined as the capability of a particular formulation to remain within the physical, chemical, therapeutic, and toxicological specifications.
Parameters like morpholgy, drug leakage, and drug entrapment were evaluated at pre-determined time intervals i. Statistical analysis All of the studies were carried out in triplicates. The steady-state flux was determined from the slope of the linear portion of the cumulative amount permeated versus time plot.
Chirag Patel has published various Books, Research and Review articles. Recently, various strategies have been used to augment the transdermal delivery of bioactives. Mainly, they include electrophoresis, iontophoresis, chemical permeation enhancers, microneedles, sonophoresis, and vesicular system like liposomes, niosomes, elastic liposomes such as ethosomes and transfersomes. Among these strategies transferosomes appear promising. A novel vesicular drug carrier system called transfersomes, which is composed of phospholipid, surfactant, and water for enhanced transdermal delivery.
Transfersomes – A Review
TRANSFERSOMES: A NOVEL TECHNIQUE FOR TRANSDERMAL DRUG DELIVERY