ETHOSOMES AS ELASTIC VESICLES IN TRANSDERMAL DRUG DELIVERY: AN OVERVIEWHTML Full Text
ETHOSOMES AS ELASTIC VESICLES IN TRANSDERMAL DRUG DELIVERY: AN OVERVIEW
N. B. Gupta*, S. Loona and M. U. Khan
Department of Pharmaceutics, Sri Sai College of Pharmacy, Badhani, Pathankot (Punjab)- 145001
ABSTRACT:Ethosomes are as novel vesicles in transdermal drug delivery show significant effects of drug penetration through the biological membrane with slight modification of well established drug carrier liposomes. Ethosomes are soft, malleable vesicles composed mainly of phospholipids, ethanol and water. The size of ethosome vesicles can be modulated from tens of nanometer to microns. The ethosomes can be prepared by Hot as well as Cold method. The evaluation parameters of ethosomes include visualization, vesicle size and zeta potential, transition temperature, surface tension activity measurement, vesicle stability, drug content, penetration and permeation studies. Ethosomes have been found to be much more efficient at delivering drug to the skin than either liposomes or hydroalcoholic solution. Thus, it can be a logical conclusion that ethosomal formulation possesses promising future in effective dermal/transdermal delivery of bioactive agents.
Transdermal drug delivery
INTRODUCTION: Transdermal administration of drugs is generally limited by the barrier function of the skin. Vesicular systems are one of the most controversial methods for transdermal delivery of active substances 1. The interest in designing transdermal delivery systems was relaunched after the discovery of elastic vesicles: Ethosomes. Ethosomes are novel carrier system used for delivery of drugs having low penetration through the biological membrane mainly skin. Ethosomes are the slight modification of well established drug carrier liposomes 2.
Ethosomes: Ethosomes are lipid vesicles containing phospholipids, alcohol (ethanol and isopropyl alcohol) in relatively high concentration and water3.Ethosomes are soft vesicles made of phospholipids and ethanol (in higher quantity) and water. The size range of ethosomes may vary from tens of nanometers to microns (μ) 4. Ethosomes permeate through the skin layers more rapidly and possess significantly higher transdermal flux in comparison to conventional liposomes 4, 5. Visualization of ethosomes is shown in Figure 1. Although, the exact mechanism for better permeation into deeper skin layers from ethosomes is still not clear. The synergistic effects of combination of phospholipids and high concentration of ethanol in vesicular formulations have been suggested to be responsible for deeper distribution and penetration in the skin lipid bi-layers.
VISUALIAZATION OF ETHOSOME (TEM MAGNIFICATION: 315000)
VISUALIAZATION OF ETHOSOME
(SEM X 100, 000)
FIGURE 1: VISUALIZATION OF ETHOSOMAL VESICLES
Composition: The ethosomes are vesicular carrier comprise of hydroalcoholic or hydro/alcoholic/glycolic phospholipid in which the concentration of alcohols or their combination is relatively high. Typically, ethosomes may contain phospholipids with various chemical structures like phosphatidylcholine (PC), hydrogenated PC, phosphatidic acid (PA), phosphatidylserine (PS), phosphatidylethanolamine (PE), phosphatidylglycerol (PPG), phosphatidylinositol (PI), hydrogenated PC, alcohol (ethanol or isopropyl alcohol), water and and propylene glycol (or other glycols) 6, 7.
Such a composition enables delivery of high concentration of active ingredients through skin. Drug delivery can be modulated by altering alcohol: water or alcohol-polyol: water ratio. Some preferred phospholipids are soya phospholipids such as Phospholipon 90 (PL-90). It is usually employed in a range of 0.5-10% w/w. Cholesterol at concentrations ranging between 0.1-1 percent can also be added to the preparation1. Examples of alcohols, which can be used, include ethanol and isopropyl alcohol. Among glycols, propylene glycol and Transcutol are generally used.
In addition, non-ionic surfactants (PEG-alkyl ethers) can be combined with the phospholipids in these preparations. Cationic lipids like cocoamide, POE alkyl amines, dodecylamine, cetrimide etc. can be added too. The concentration of alcohol in the final product may range from 20 to 50%. The concentration of the non-aqueous phase (alcohol and glycol combination) may range between 22 to 70% 8, 9. Different additives used in the ethosomal formulation are presented in the table 1.
TABLE 1: TABULAR FORM REPRESENTS DIFFERENT ADDITIVES USED IN THE ETHOSOMAL FORMULATION
|Phospholopids||Soya phosphatidyl choline; Egg phosphatidyl choline; Diestearyl phopshatidyl choline||Vesicle forming components|
|Polyglcerol||Propylene glycol; Transcutol RTM||As a skin penetration enhancer|
|Alcohol||Ethanol; Isopropyl alcohol||For providing the softness for vesicle membrane; As a skin penetration enhancer|
|Cholesterol||Cholesterol||For providing the stability for vesicle membrane|
|Dyes||Rhodamine 123; Rhodamine red||For characterization studies|
|Vehicles||Carbopol D934||As a gel former|
Advantages of Ethosomal Drug Delivery 3, 10, 11: In comparison to other transdermal & dermal delivery system;
- Ethosomes have enhanced permeation of drug through skin for transdermal drug delivery.
- The delivery of large molecules (peptides, protein molecule) is possible.
- It contains non-toxic raw material in formulation.
- High patient compliance- The ethosomal drug is administrated in semisolid form (gel or cream) hence producing high patient compliance.
- The Ethosomal system is passive, non-invasive and is available for immediate commercialization.
- Ethosomal drug delivery system can be applied widely in Pharmaceutical, Veterinary, Cosmetic fields.
- Simple method for drug delivery in comparison to Iontophoresis and Phonophoresis and other complicated methods.
Mechanism of Drug Penetration 12: The main advantage of ethosomes over liposomes is the increased permeation of the drug. The mechanism of the drug absorption from ethosomes is not clear. The drug absorption probably occurs in following two phases 13, 14 (Figure 2):
- Ethanol Effect: Ethanol acts as a penetration enhancer through the skin. The mechanism of its penetration enhancing effect is well known. Ethanol penetrates into intercellular lipids and increases the fluidity of cell membrane lipids and decrease the density of lipid multilayer of cell membrane.
- Ethosomal Effect: Increased cell membrane lipid fluidity caused by the ethanol of ethosomes results increased skin permeability. So the ethosomes permeates very easily inside the deep skin layers, where it got fused with skin lipids and releases the drugs into deep layer of skin.
FIGURE 2: DIAGRAMMATICALLY REPRESENTATION OF MECHANISM OF ACTION OF ETHOSOMES
Method of Preparation 4, 8, 15: There are two methods which can be used for the formulation and preparation of ethosomes. Both of the methods are very simple and convenient and do not involve any sophisticated instrument or complicated process.
Ethosomes can be formulated by following two methods: The formulation of ethosomes involves hot and cold method (see table 2)
- Hot Method: In this method disperse phospholipid in water by heating in a water bath at 400°C until a colloidal solution is obtained. In a separate vessel properly mix ethanol and propylene glycol and heat up to 400°C. Add the organic phase into the aqueous phase. Dissolve the drug in water or ethanol depending on its solubility.The vesicle size of ethosomal formulation can be decreased to the desire extent using probe sonication or extrusion method.
- Cold Method: This is the most common and widely used method for the ethosomal preparation. Dissolve phospholipids, drug and other lipid materials in ethanol in a covered vessel at room temperature with vigorous stirring. Add propylene glycol or other polyglycol during stirring. Heat the mixture up to 300°C in a water bath. Heat the water up to 300°C in a separate vessel and add to the mixture and then stir it for 5 min in a covered vessel. The vesicle size of ethosomal formulation can be decreased to desire extend using sonication or extrusion method. Finally, the formulation should be properly stored under refrigeration.
TABLE 2: FLOW CHART REPRESENTATION OF HOT METHOD AND COLD METHOD
Evaluation: The methods of evaluation for ethosomes are discussed below:
- Vesicle Shape 16: Ethosomes can be easily visualized by using transmission electron microscopy (TEM) and by scanning electron microscopy (SEM).
- Vesicle Size and Zeta Potential 15: Particle size of the ethosomes can be determined by dynamic light scattering (DLS) and photon correlation spectroscopy (PCS). Zeta potential of the formulation can be measured by Zeta meter.
- Transition Temperature 14: The transition temperature of the vesicular lipid systems can be determined by using differential scanning calorimetry (DSC).
- Drug Entrapment 17: The entrapment efficiency of ethosomes can be measured by the ultracentrifugation technique.
- Drug Content 18: Drug content of the ethosomes can be determined using UV spectrophotometer. This can also be quantified by a modified high performance liquid chromatographic method.
- Surface Tension Measurement 19: The surface tension activity of drug in aqueous solution can be measured by the ring method in a Du Nouy ring tensiometer.
- Stability Studies 20: The stability of vesicles can be determined by assessing the size and structure of the vesicles over time. Mean size is measured by DLS and structure changes are observed by TEM.
- Skin Permeation Studies 13: The ability of the ethosomal preparation to penetrate into the skin layers can be determined by using confocal laser scanning microscopy (CLSM).
Evaluation parameters and instrument/methods used in Ethosomes are shown in table 3.
TABLE 3: EVALUATION PARAMETERS AND INSTRUMENT/METHODS USED IN ETHOSOMES
|Vesicle Shape||Transmission Electron Microscopy (TEM)Scanning Electron Microscopy (SEM)||Determines skin penetration|
|Vesicle Size and Zeta Potential||Dynamic Light Scattering (DLS), Photon Correlation Spectroscopy (PCS) and Zeta Meter||Determines skin penetration and stability of vesicles|
|Transition Temperature||Differential Scanning Calorimetry (DSC)||Determines transition temperature of lipid vesicles|
|Drug Entrapment||Ultracentrifugation Technique||Suitability of method|
|Drug Content||UV Spectrophotometer, High Performance Liquid Chromatographic Method (HPLC)||Important in deciding the amount of vesicle preparation to be used|
|Surface Tension Measurement||Ring Method in a Du Nouy ring tensiometer||Determines surface tension activity of drug in aqueous solution|
|Stability Studies||Dynamic Light Scattering (DLS), Transmission Electron Microscopy (TEM)||To determine the shelf-life of vesicle formulation|
|Skin Permeation Studies||Confocal Laser Scanning Microscopy (CLSM)||Determines rate of drug transport through skin|
|In-vitro dissolution||Franz diffusion cell||Determines the drug release rate from vesicle|
Ethosomes as a Drug Carrier: Ethosomes can be used for many purposes in drug delivery. Ethosomes are mainly used as replacement of liposomes. Ethosomes can be used for transdermal delivery of hydrophilic and impermeable drugs through the skin. Following drugs have been used with ethosomal carrier (see Table 4).
TABLE 4: DRUG INCORPORATED IN ETHOSOMAL CARRIER
|NAME OF DRUG||DRUG INCORPORATED IN ETHOSOMAL CARRIER||USES|
|Acyclovir21||Improved skin permeation. Improved in pharmacodynamics profile.Improved in biological activity two to three times.||Treatmentof Herpes labialis|
|Anti-HIV agents22(Zidovudine, Lamivudine)||Reduced drug toxicity. Prolonging drug action. Improved transdermal flux.Affected the normal histology of skin. Improved in biological activity two to three times.||Anti-HIV|
|Azelaic acid23Ammonium glycyrrhizinate24||Prolong drug release. Improved in biological anti-inflammatory activity.Improved dermal deposition exhibiting sustained release.||Treatment of various inflammatory based skin diseases|
|Bacitracin25||Increased bioavailability. Improved dermal deposition. Improved intracellular delivery.||Anti-bacterial|
|Cannabidol26||Improve bioavailability. Increased skin permeation. Improved GIT degradation.||Treatment of Rhematoid arthritis|
|Cyclosporin A6||Prolong drug action. Improved bioavailability. Improved skin deposition.||Treatment of inflammatory skin diseases|
|DNA9||Better expression of genes. Selective targeting to dermal cells.||Treatment of genetic disorders|
|Erythromycin27||Better cellular uptake||Anti-microbial|
|Fluconazole7||Better skin permeation||Treatment of Candidiasis|
|Insulin8||Provide control release. Significant decrease in blood glucose level.||Treatment of diabetes|
|Minoxidol28||Pilocebaceous targeting. Accumulation in skin increased significantly.||Treatment of baldness|
|Methotrexate9||Better skin permeation||Treatment of Proriasis|
|NSAIDs9 (Diclofenac)||Selective delivery of drug to described side for prolong period of time||Analgesic and anti-inflammatory|
|Testosterone29||Improved oral bioavailability. Reduced side effects.||Steroidal hormone|
|Trihexyphenidyl hydrochloride18||Provide control release. Improved transdermal flux. Improved patient compliance.||Treatment of Parkineonis disease|
|Salbutamol Sulfate5||Enhanced drug delivery through skin||Anti-asthmatic|
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N. B. Gupta*, S. Loona and M. U. Khan
Assistant Professor, Department of Pharmaceutics, Sri Sai College of Pharmacy, Badhani, Pathankot, Punjab , India
06 November, 2011
20 February, 2012
25 February, 2012