Nanosized ethosomes bearing ketoprofen for improved transdermal delivery

This is a post by Urwashi Sharad Naik on the paper:

Nanosized ethosmes bearing ketoprofen for improved transdermal delivery

by

Manish K. Chourasia, Lifeng Kang, Sui Yung Chan

Transdermal delivery of the drug provides excellent route of administration of the drug to enhance the oral absorption of the drug.  Our human skin contains the major barrier called stratum corneum layer which is a greatest challenge for transdermal delivery of drugs. Various approaches have been adopted to pass this major barrier such as micro needles, chemicals, surfactants, iontophoresis, chemicals and lipid based systems. The lipid based systems are of the best mechanism to carry out transdermal drug delivery as the lipids are biocompatible to our skin lipids. Conventional liposomes are used for transdermal drug delivery. However, these conventional liposomes are unable to cross the major stratum corneum barrier due to which the drug is unable to delivery deep inside the skin. These conventional liposomes have been modified by introduction of two novel carriers called as transfersomes and ethosomes. Transfersomes are ultradeformable lipid vesicles which consist of one layer of phospholipid and other layer of surfactants which allows them to squeeze through the stratum corneum layer and enhances the transdermal delivery of the drug. One the other hand, ethosomes are the vesicles contain higher concentration of the ethanol which acts as penetration enhancer allowing them to be more flexible than liposomes. The preparations of ethosomes are similar to liposomes but in liposomal preparation cholesterol and phospholipids are present but in ethosomes higher concentration of ethanol is present in place of cholesterol. As reported by Elsayed et al., ethosomes seems to be more superior than tansferosomes with respect to increase the permeability of entrapped ketotifen.

Ketotifen is non-steroidal anti-inflammatory drug. This drug have been tried to pass through other modes of transdermal delivery such as gels/patches which are available in the market. However, the drug delivery has been poorly observed previously. In this experiment, ketotifen have been entrapped in the ethosomal bilayer and the invitro and invivo transdermal delivery of this drug have been studied using varies techniques of characterization such as laser diffraction, zeta charger, HPLC (for drug entrapment), confocal laser scanning microscopy and micro column centrifugation. The in vivo studies were performed using the skin samples of female adult mice.

For in vitro studies, the experimental procedure was setup by placing the cellophone membrane dialysis tubing with both the ends sealed and suspended into a beaker containing PBS solution (pH 7.4)of 100 ml at 37 ± 1 ᵒC. The buffer of the solution was stirred at 45 mins intervals and sample was collected at 24,6,8,10,12,18 and 24 hr time intervals by replacing with equal quantities of fresh buffer and drug contain was analysed using HPLC. Different ethosomal formutions were evaluated for drug release and compared with hydroaloholic drug solutions.

For in vitro studies, the permeation was checked through diffusion cell system consisting of 16 channel peristaltic cassette pump, a circulating water bath, a fraction collector and flow through diffusion cells. Adult Chinese female skin was used in the experiment, the skin was thawed and hydrated with saline solution containing 1% v/v antibiotic antimitotic solution. For experiment the skin was immersed into water bath (60ᵒC) for 2 mins, peeled off and then stored at -80ᵒC.The receptor solution was pumped into the peristaltic cassette continuously through receptor compartment and drained into sample collection tubes. Sample collection was performed at various time intervals.

Penetration of ethosomes were confirmed using confocal laser scanning microscopy. The formulations were loaded with dye called fluorescent probe Rhodamine 123 insread of ketoprofen. Skin sample was mounted between the donar and the receiver compartment and either 1 ml of either hydroalcoholic probe solution was placed in the donar compartment and covered with paraflim to prevent contamination and evaporation at 37oC. Skin was removed and washed after 4 hours and scanned at different increments through Z- axis of confocal laser scanning microscopy.

Drug quantitative studies was performed using HPLC using C18 column (Agilent, 5µm 4.0 x 250 mm) and using a mobile phase of phosphate buffer (pH 3.5) and acetonitrile in ratio of 50:50 at wavemenght 254 nm. The experiments were statistically performed using ANOVA. at p < 0.05 with mean ± standard deviation. The size of the vesicles were seems to be decrease with increase in concentration of alcohol contained. Higher concentration of ethanol confers net negative charges to the vesicular systems. As the keptoprofen is hydrophobic drug, it was expected to be encapsulated within the non-polar region of the bilayer as the bilayer amount increases the drug holding capacity also increases.

Vesicle

Alcohol Entrapment efficiency
SPC (1%) Ethanol (20%) 42.9 ±3.7 %
(3%) Ethanol (20%) 63.1 ±5.8 % SPC

Entrapment efficiency of vesicles

The above table show that the entrapment efficiency of the vesicles increases with increase in phospholipid concentration even though keeping the concentration of the alcohol constant.

In vitro drug release through cellophane membrane shows that the hydroacoholic drug release was 3-4 hours slower than the drug release from the ethosomal preparation indicating that the drug diffusion in ethosomes is rate limiting step. The increase drug release may be due to increase in alcohol contain within the bilayer membrane.

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