INTERNATIONAL JOURNAL OF PHARMACEUTICAL RESEARCH AND BIO-SCIENCE

Review Article CODEN: IJPRNK Impact Factor: 5.567 Upadhye S. S., IJPRBS, 2016; Volume 5(4): 69-82

ISSN: 2277-8713 IJPRBS

INTERNATIONAL JOURNAL OF PH

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Review Article CODEN: IJPRNK Impact Factor: 5.567 Upadhye S. S., IJPRBS, 2016; Volume 5(4): 69-82

ISSN: 2277-8713 IJPRBS

INTERNATIONAL JOURNAL OF PHARMACEUTICAL RESEARCH AND BIO-SCIENCE A REVIEW ON ETHOSOMES AS A NOVEL DRUG DELIVERY SYSTEM MR. UPADHYE S. S.1, MR. B. K. KOTHALI 2, MRS. A. K. APTE 3, MRS. A.A. PATIL1, MR. A.B. DANOLE1 1. Lecturer, Dr. J.J. Magdum Pharmacy College, Jaysingpur, A/P- Jaysingpur, Tal- Shirol, Dist- Kolhapur-416101, Maharashtra, India. 2. Principal, Dr. J.J. Magdum Pharmacy College, Jaysingpur, A/P- Jaysingpur, Tal- Shirol, Dist- Kolhapur-416101, Maharashtra, India. 3. Vice-Principal, Dr. J.J. Magdum Pharmacy College, Jaysingpur, A/P- Jaysingpur, Tal- Shirol, Dist- Kolhapur-416101, Maharashtra, India.

Accepted Date: 03/08/2016; Published Date: 27/08/2016 Abstract: As the ethosomal systems are conceptually sophisticated, they are characterized by simplicity in their preparation, safety & efficacy a combination that can expand highly their application. The ethosomes are soft, malleable vesicles tailored for the enhanced delivery of the active agents. The ethosomes are noninvasive delivery carriers that enable drugs to reach the deep skin layers or/and the systemic circulation. The ethosomes are gaining popularity in designing the drug delivery systems for the topical & transdermal use for their capability to reach the deep skin layers & systemic circulation. This review article focuses on various aspects of ethosomes like, their method of preparation, mechanism of penetration, characterization, advantages, composition, marketed products & applications of ethosomes. Keywords: Ethosomes, Transdermal, Mechanism of Penetration

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Review Article CODEN: IJPRNK Impact Factor: 5.567 Upadhye S. S., IJPRBS, 2016; Volume 5(4): 69-82

ISSN: 2277-8713 IJPRBS

INTRODUCTION Due to its noninvasive procedure for the administration, the transdermal drug delivery is gaining importance. The transdermal drug delivery overcomes the number of limitations of the oral drug delivery such as the irritation of gastrointestinal mucosa, degradation of drugs by digestive enzymes & the first pass effect. The Patients also highly prefer transdermal route due the pain on administration associated with the parenteral route. The transdermal dosage forms enjoy being the most patient compliant mode of delivery of the drug. [1, 2] CHALLENGES WHILE DESIGNING THE TRANSDERMAL DOSAGE FORMS The skin is the multi-layered structure made up of the stratum corneum, the outermost layer, under which lies the epidermis & dermis. Within these layers of the skin are interspersed fibroblasts, hair follicles & the sweat glands that originate in the blood supply of dermis. The almost unsurmountable nature of the stratum corneum is the major challenge for the systemic delivery of the percutaneously applied drugs. The Obrick & the mortaro arrangement of the corneocytes, the flattened mononucleated keratinocytes, with the interspersed lipids & the proteins makes the stratum corneum approximately 1000 times less permeable than the other biological membranes. It is even more difficult for anything to penetrate to the deeper strata of the skin. [3-5] NEED FOR TRANSDERMAL DRUG DELIVERY Transdermal Drug delivery offers the several unique advantages including relatively large & readily accessible surface area for the absorption, the ease of application & termination of the therapy, despite the different challenges. For delivering of the drug molecules, the evolution of the better technologies, the use of vesicular carriers, safe penetration enhancers have rejuvenated the interest for designing the transdermal drug delivery system for the drugs that were thought to be unfit for the transdermal delivery of drug. ETHOSOMES Ethosomes are the vesicular carrier consisting of the hydroalcoholic or the hydro / alcoholic/ glycolic phospholipids in which the alcohols concentration or their combination is high relatively. With various chemical structures like the hydrogenated PC, phosphatidylcholine [PC], phosphatidylserine [PS], phosphatidic acid [PA], phosphatidylinositol [PI], phosphatidylethanolamine [PE], alcohol [ethanol or isopropyl alcohol], phosphatidylglycerol [PPG], the water & the propylene glycol [or other glycols] the ethosomes may contain phospholipids. A composition like this enables the delivery of the high concentration of the active ingredients through the skin. The change in the alcohol: water or alcoholpolyol: water ratio alters the delivery of drug. The soya phospholipids such as PL-90 [Phospholipon 90] in Available Online at www.ijprbs.com

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Review Article CODEN: IJPRNK Impact Factor: 5.567 Upadhye S. S., IJPRBS, 2016; Volume 5(4): 69-82

ISSN: 2277-8713 IJPRBS

concentration range of 0.5-10% w/w, is the phospholipids generally used. The cholesterol at the concentrations ranging between the 0.1-1% can also be used in the preparation to increase the stability of the ethosomes. Alcohols like isopropyl alcohol & ethanol & the glycols like the Transcutol & the propylene glycol are generally used. Sometimes the non-ionic surfactants [PEG-alkyl ethers] in the combination with the phospholipids are used in these preparations. Cationic lipids like dodecylamine, cetrimide, POE alkyl amines, cocoamide, etc. can also be included. In the final product the concentration of the alcohol may range from 20 - 50%. The non-aqueous phase [alcohol & glycol combination] concentration may range between 22- 70%. [6] COMPOSITION OF ETHOSOMES The ethosomes are mainly composed of the high concentration of hydroalcohols or hydroalcohols, phosphatidylcholine, glycols & water. The Phosphatidylcholine can be, phosphatidyl soya phosphatidylcholine, dipalmityl phosphatidyl choline, egg phosphatidylcholine, hydrogenated phosphatidylcholine. As the alcohols, we can use ethanol or the isopropyl alcohol & as poliglicols propylene glycol & transcutol [7] Table 1: Different Additives Employed In Formulation of Ethosomes. [6] Class Phospholipid

Uses Vesicles forming component

Alcohol

For providing the softness for vesicle membrane As a penetration enhancer For characterization study

Dye

Polyglycol

As a skin Penetration enhancer

Cholesterol

For providing the

Example Soya phosphatidyl choline Dipalmitylphosphatidyl choline Egg phosphatidyl choline Distearylphosphatidyl choline Ethanol

Isopropyl alcohol Rhodamine-123 Rhodamine red FluoresceneIsothiocynate (FITC) 6- Carboxy fluorescence Propylene glycol Transcutol RTM Cholesterol

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Review Article CODEN: IJPRNK Impact Factor: 5.567 Upadhye S. S., IJPRBS, 2016; Volume 5(4): 69-82

Vehicle

stability to vesicle membrane As a gel former

ISSN: 2277-8713 IJPRBS

Carbopol D934

ETHANOL- AS PENETRATION ENHANCER The substances that reduce reversibly the barrier resistance of the stratum corneum are known as the chemical penetration enhancers. One of the most commonly used permeation enhancers is the ethanol. Several numbers of mechanisms have been proposed for the permeation enhancing action of the ethanol. To enhance the solubility of the drug the ethanol can be included in the formulation as the solvent. For poorly soluble permeants this is particularly important as they are prone to depletion in the donor vehicle. The ethanol is the relatively volatile solvent & will rapidly evaporate at the skin temperature. The loss of ethanol from the formulation may lead to the drug becoming supersaturated, which will influence drug flux across the membrane. In addition the ethanol is thought to alter the solubility properties of the stratum corneum facilitating improved drug partitioning. The ethanol has been employed in vitro to enhance the transdermal delivery of the levonorgesterol, hydrocortisone & the 5fluorouracil across rodent skin & estradiol across the human skin in vivo. the enhancement effect of ethanol was concentration dependent was noted by the Megrab & the collaborators. The effect of ethanol on skin water content was investigated by the authors & concluded that the formulations containing high levels of the alcohol were capable of the dehydrating the skin which may explain the concentration dependant action of the ethanol.[8,9] METHOD OF PREPARTION There are two methods which can be used for the formulation & preparation of the ethosomes. These two methods are very convenient & simple & do not involve any sophisticated instrument or the complicated process. The formulation of ethosomes is done by following two methods THE HOT METHOD The phospholipid is dispersed in water by heating in the water bath at 40 ⁰C until the colloidal solution is obtained in this method. Mix properly ethanol & propylene glycol & heat upto 400C in the separate vessel. Then add the organic phase into the aqueous phase. Depending on its solubility, dissolve the drug in the ethanol or water. To the desire extent by using the probe sonication or the extrusion method. the vesicle size of the ethosomal formulation can be decreased.

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Review Article CODEN: IJPRNK Impact Factor: 5.567 Upadhye S. S., IJPRBS, 2016; Volume 5(4): 69-82

ISSN: 2277-8713 IJPRBS

Figure 1: Preparation of Ethosomes by Hot Method THE COLD METHOD It is the most widely & commonly used method for the preparation of ethosomes. At room temperature dissolve the phospholipid, drug & other lipid materials in the ethanol in the covered vessel with vigorous stirring. Then during stirring add propylene glycol or the other polyol. Then in the water bath heat the mixture upto 30 ⁰C. Then heat the water upto 300C in the separate vessel & then add to the mixture & then stir it for 5 min in the covered vessel. By using sonication or extrusion method the vesicle size of the ethosomal formulation can be decreased to the desire extend. Lastly, the formulation should be properly stored under the refrigeration. [1,4]

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Review Article CODEN: IJPRNK Impact Factor: 5.567 Upadhye S. S., IJPRBS, 2016; Volume 5(4): 69-82

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Figure 2: Preparation of Ethosomes by Cold Method MECHANISM OF DRUG PENETRATION The first part of the mechanism is due to the ‘ethanol effect’ whereby the intercalation of the ethanol into a intercellular lipids increasing lipid fluidity & decreases the density of the lipid multilayer. This is followed by the “ethosome effect” which includes permeation & the inter lipid penetration by the opening of new pathways due to the malleability & fusion of the ethosomes with the skin lipids. This Absorption of ethosomes is still not clear. in following two phases the drug absorption probably occurs, 1. The Ethanol effect 2. The Ethosomes effect THE ETHANOL EFFECT The ethanol is the major ingredient & acts as the penetration enhancer during the skin. The mechanism of its penetration enhancing effect is also well known. The ethanol interacts with the lipid molecules in the polar hard group region resulting in the reducing the rigidity of the stratum corneum lipids, increasing their fluidity. The intercalation of the ethanol into the polar head group environment can result in the increase in the membrane permeability. In addition, to the effect of the ethanol on the stratum corneum structure, with the stratum corneum barrier, the ethosome itself may interact. Available Online at www.ijprbs.com

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Review Article CODEN: IJPRNK Impact Factor: 5.567 Upadhye S. S., IJPRBS, 2016; Volume 5(4): 69-82

ISSN: 2277-8713 IJPRBS

THE ETHOSOMES EFFECT The Increased cell membrane lipid fluidity caused by the ethanol of the ethosomes results in increased skin permeability. In the case of the drugs encapsulating ethosomes, the higher positive zeta potential imparted by the drug can improve skin attachment of the vesicles. While the encapsulated drug in the classic liposomes remained primarily at the surface of the skin. The ethosomal system was showed to be the highly efficient carrier for the enhanced drug delivery through the skin due to the increased fluidity of the lipids. [10]

Figure 3: Flow chart showing action of Ethosomes ADVANTAGES OF ETHOSOMAL DRUG DELIVERY In comparison to other transdermal & dermal delivery systems 1] The ethosomal drug delivery system can be applied widely in Veterinary, Pharmaceutical & the Cosmetic fields.

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2] Patient compliance is High‐The ethosomal drug is administrated in the semisolid form [cream or gel] hence it produces high patient compliance. 3] It is simple method for the drug delivery in comparison to the iontophoresis & the phosphophoresis & the other complicated methods. 4] The delivery of the large molecules [protein molecules, peptides] is possible. 5] This Ethosomal system is non‐invasive, passive & is available for immediate commercialization. 6] The enhanced permeation of the drug through the skin for transdermal drug delivery. 7] It contains non‐toxic raw material in the formulation. [11-13] Table 3: Methods for the Characterization of Ethosomal Formulation Methods Confocal laser scanning microscopy Fluorescence microscopy Transmission electron microscopy Eosin-Hematoxylin staining Extrusion method

Parameters Vesicle Skin interaction study

Degree of deformability Franz diffusion cell Drug deposition study Mini column centrifugation Entrapment efficiency method Fluorescence spectrophotometry Dynamic light scattering Stability study method Transmission electron Vesicle shape microscopy (morphology) Scanning electron microscopy Nephalometer Turbidity Zeta meter Zeta potential Franz diffusion cell with Invitro drug release study artificial or biological membrane, Dialysis bag diffusion Transmission electron Vesicle size and size microscopy (TEM) distribution

References [14,15]

[16, 17] [16,17] [18]

[10] [19,20]

[21] [21] [19,21]

[21,22]

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Review Article CODEN: IJPRNK Impact Factor: 5.567 Upadhye S. S., IJPRBS, 2016; Volume 5(4): 69-82 Scanning electron microscopy (SEM) 31P NMR Phospholipid-ethanol Differential scanning interaction calorimeter

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[10,23]

APPLICATIONS OF ETHOSOMES 1. The Delivery of Anti-Viral Drugs A potent antiviral agent zidovudine is acting on the acquired immunodeficiency virus. The oral administration of the zidovudine is associated with the strong side effects. Hence, an adequate zero order delivery of the zidovudine is desired to maintain the expected anti-AIDS effect [24]. The Jain et al. [25] concluded that ethosomes could the increase the transdermal flux, prolong the release & present an attractive route for the sustained delivery of the zidovudine. Another anti-viral drug acyclovir is topically used widely for the treatment of the Herpes labialis [26]. With poor skin penetration of the hydrophilic acyclovir to dermal layer resulting in weak therapeutic efficiency the conventional marketed acyclovir external formulation is associated. The replication of virus takes place at the basal dermis has been reported. [27]. Horwitz et al. formulated the acyclovir ethosomal formulation for dermal delivery, to overcome the problem associated with the conventional topical preparation of the acyclovir The results showed that higher percentage of abortive lesions & shorter healing time were observed when into ethosomes the acyclovir was loaded. 2. The Topical Delivery of DNA Several environmental pathogens attempt to enter the body through the skin. The skin therefore has evolved into an excellent protective barrier which is also active immunologically & able to express the gene [28]. Another important application of ethosomes is to use them for topical delivery of DNA molecules to express genes in skin cells on the basis of the above facts. The Touitou et al. in their study encapsulated the GFP-CMV-driven transfecting construct into the formulation of ethosome. They applied this formulation to the dorsal skin of the 5-week male CD-1 nude mice for the 48 hour. After the 48 hr the treated skin was removed & the penetration of the GFP [Green Fluorescent Protein] formulation was observed by the CLSM. Topically applied ethosomes-GFP-CMV-driven transfecting construct enabled efficient delivery & the expression of the genes in skin cells, was observed. It was suggested that the ethosomes could be used as the carriers for the gene therapy applications that require the transient expression of the genes. These results also showed that the possibility of using the ethosomes for the effective transdermal immunization. The Gupta et al. recently reported immunization

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ISSN: 2277-8713 IJPRBS

potential using the transfersomal formulation. Hence, the better skin permeation ability of the ethosomes opens the possibility of using these dosage forms for delivery of the immunizing agents [29]. 3. The Transdermal Delivery of Hormones The oral administration of the hormones is associated with the problems like the high first pass metabolism, low oral bioavailability & several dose dependent side effects. With each pill missed the risk of failure of treatment is known to increase [30]. The Touitou et al. compared the skin permeation potential of the testosterone ethosomes [Testosome] across the rabbit pinna skin with the marketed transdermal patch of the testosterone [Testoderm patch, Alza]. They observed nearly 30-times higher the skin permeation of the testosterone from the ethosomal formulation as compared to that of the marketed formulation. 4. The Delivery of anti-parkinsonism agent The Dayan & Touitou prepared the ethosomal formulation of the psychoactive drug THP [trihexyphenidyl hydrochloride] & compared its delivery with that from the classical liposomal formulation. THP is the M1 muscarinic receptors antagonist & is used in the treatment of the parkinson disease. The results indicated that the better skin permeation potential of the ethosomal-THP formulation & its use for better management of the parkinson disease [29]. 5. The Transcellular Delivery The Touitou et al. in their study demonstrated the better intracellular uptake of the DNA, bacitracin, & erythromycin using the CLSM & FACS techniques in different cell lines. The better cellular uptake of the anti-HIV drug zidovudine & lamivudine in MT-2 cell line from the ethosomes as compared to the marketed formulations suggested ethosomes to be an attractive clinical alternative for the anti-HIV therapy [7, 31]. 6. The Delivery of Anti-Arthritis Drug The delivery of anti-arthritis drug by topical route is the better option for its site-specific delivery & overcomes the problem associated with the conventional oral therapy. For treating the rheumatoid arthritis, the CBD [Cannabidol] is the recently developed drug candidate. The Lodzki et al. prepared cannabidol ethosomal formulation for the transdermal delivery. When tested by the carrageenan induced rat paw edema model, the results shows significantly increase in the biological antiinflammatory activity of the CBD-ethosomal formulation was observed. It was concluded that encapsulation of cannabidol in ethosomes significantly increased its accumulation, skin permeation & hence it’s biological activity [29].

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7. The Delivery of Problematic drug molecules It is difficult for the oral delivery of the large biogenic molecules such as the proteins or peptides because in the GI tract they are completely degraded. For overcoming the problems associated with the oral delivery the non-invasive delivery of the proteins is the better option [25]. The effect of ethosomal insulin delivery in lowering blood glucose levels (BGL) in vivo in normal and diabetic SDI rats is investigated by the Dkeidek & Touitou. In this study the Hill Top patch containing insulin ethosomes was applied on the abdominal area of an overnight fated rat. The result shows that the insulin delivered from this patch produced the significant decrease [up to 60%] in the BGL in both normal & diabetic rats. The insulin application from the control formulation was not able to reduce the BGL On the other hand. For the treatment of inflammatory skin disease like psoriasis, atopic dermatitis and disease of hair follicle like alopecia areata etc Verma and Fahr [8] reported the cyclosporin A ethosomal formulation. The potential application of ethosomes for dermal delivery of ammonium glycyrrhizinate is investigated by Paolino et al. [33] The Ammonium glycyrrhizinate is naturally occurring triterpenes obtained from Glycyrrhizinate Glabra & useful for the treatment of the various inflammatory based skin diseases [34]. 8. The Delivery of Antibiotics For increasing the therapeutic efficacy of these agents the topical delivery of antibiotics is the better choice. The conventional oral therapy causes several allergic reactions along with the several side effects. The conventional external preparations possess the low permeability to the deep skin layers & subdermal tissues. By delivering sufficient quantity of antibiotic into deeper layers of skin the ethosomes can circumvent this problem. The ethosomes penetrate rapidly through the epidermis & bring appreciable amount of drugs into the deeper layer of the skin & suppress the infection at their root. With this purpose in mind the Godin & Touitou prepared the bacitracin & erythromycin loaded ethosomal formulation for the dermal & intracellular delivery. The results of this study showed that the ethosomal formulation of the antibiotic could be highly efficient & the problems associated with conventional therapy would overcome. [28] PATENTED AND MARKETED FORMULATION OF ETHOSOME The ethosome was invented & patented by the Prof. Elka Touitou along with her students of the department of Pharmaceutics at the Hebrew University School of Pharmacy. The NTT [Novel Therapeutic Technologies] Inc of the Hebrew University have been succeeded in bringing the number of products to the market based on ethosome delivery system. The Noicellex TM an

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anti-cellulite formulation of the ethosome is currently marketed in Japan. Another formulation, Lipoduction TM is currently used in the treatment of cellulite containing pure grape seed extracts [antioxidant] is marketed in USA. Similarly the Physonics is marketing anti-cellulite gel Skin Genuity in London. Nanominox© containing monoxidil is used as hair tonic to promote hair the growth is marketed by the Sinere. [35, 36] CONCLUSION The main limitation of transdermal drug delivery system i.e. the epidermal barrier can be overcomed by the ethosomes to significant extent. The ethosomes are soft, malleable vesicles & possible carrier for the transportation of the drugs. The ethosomes are characterized by the simplicity in their safety, efficacy & preparation & can be tailored for the enhanced skin permeation of the active drugs. It can be concluded that ethosomes can provide better skin permeation than the liposomes. The ethosomes have been tested to encapsulate the cationic drugs, hydrophilic drugs, proteins & the peptides. For the development of the novel improved therapies the ethosomal carrier has opened new opportunities. REFERENCES 1. Godin B, Tauitou Elka; Erythromycin Ethosomal Systems: Physicochemical Characterization and Enhanced Antibacterial Activity, Current Drug Delivery; 2005; 2: 269‐275. 2. Akiladev D, Basak S; ETHOSOMES- A noninvasive approach for transdermal drug delivery; International Journal of Current pharmaceutical research; 2010; 2(4): 1-4. 3. Dave V, Kumar D, Lewis S, Paliwal S; Ethosome for Enhanced Transdermal Drug Delivery of Aceclofenac. International Journal of Drug Delivery 2010; 2:81-92. 4. Hadgraft J, Guy R. Transdermal Drug Delivery, Developmental Issues and Research Initiatives. New York: Marcel Dekker 1989. 5. Chourasia MK; Nanosized ethosomes bearing ketoprofen for improved transdermal delivery, Results in Pharma Sciences; 2011, (1); 60–67. 6. Michaels AS, Chandrasekaran SK, Shaw JW; Drug permeation through human skin: theory and in vitro ex-perimental measurement. AlChE; 1975; 21: 985-96. 7. Touitou E., Godin B., Dayan N., Piliponsky A., Levi-Schaffer F., Weiss C., Intracellular delivery mediated by an ethosomal carrier, Biomaterials, 2001; 22, 3053-3059 8. Verma DD, Fahr A. Synergistic penetration effect of ethanol and phospholipids on the topical delivery of Cyclosporin A. J Control Rel 2004; 97: 55-66. 9. Touitou E, inventor; Composition of applying active substance to or through the skin. US patent 5 540 934, July 30, 1996.

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10. Touitou E, Dayan N, Bergelson L, Godin B and Eliaz M. Ethosomes novel vesicular carriers for enhanced delivery: characterization and skin penetration properties. J. Control. Release2000; 65:403-418 11. Ainley Wade, Paul J. Hand book of pharmaceutical excipents, The Pharmaceutical Press London; Second edition; 1994; 383-384, 392-399. 37. 12. Bhaskaran S, harsh NS. Effect of permeation enhancer and iontophoresis on permeation of atenolol from transdermal gels, Ind J of Pharm Sci. 2001; 6:424-426. 13. Guyot M, Fawaz F. Design and in vitro evaluation of adhesive matrix for transdermal delivery of propranolol, Int J of Pharm 2000; 204(172):171-182. 14. Simonetti O, Hoogstraate J, Bodde HE. Arch. Dermatol. Res.1995;287, 465. 15. Honeywell-Nguyen, PL, Graaff D, Anko M, Groenink HW and Bouwstra JA. Biochim. Biophys. Acta. 2002:1573, 130-138. 16. Jain S, Jain P and Jain NK. Drug Dev. Ind Pharm. 2003;29(90):1013-1026 17. Jain S, Jain N, Bhadra D, Tiwary AK and Jain NK. Current Drug Delivery 2005;2(3): 222-233. 18. Fry DW, White JC and Goldman ID. J. Anal. Biochem. 1978;90: 809. 19. Jain S, Umamaheswari RB, Tripathi, P and Jain NK. Ind. J. Pharm. Sci. 2003; 65(3): 223-231. 20. Touitou E, Godin B and Weiss C. Drug Develop Research 2000; 50: 406-415. 21. Touitou E and Nava Dayan. Carriers for skin delivery of Trihexyphenidyl HCl: ethosomes vs liposomes. Biomaterials. 2000;21:1879-1885. 22. Bhalaria MK, Naik S and Misra AN. Ethosomes: A novel delivery system for antifungal drugs in the treatment of topical fungal diseases, Indian Journal of Experimental Biology 2009; 47: 368-375. 23. Maghraby E, William AC GMM and Barry BW; Int J Pharm 2000; 196: 63- 74. 24. Kim S, Chien YW, “Toxicity of cationic lipids and cationic polymers in gene delivery”, J. Control. Release, 1996, 40, 67-76. 25. Jain S, Umamaheshwari RB, Bhadra D, Jain NK, “Ethosomes: a novel vesicular carrier for enhanced transdermal delivery of an anti-HIV agent”, Ind J Pharma Sci, 2004, 66, 72-81. 26. Spruance SL, Semin, “The natural history of recurrent oral facial herpes simplex virus infec tion”, Dermatol, 1992, 11, 200-206. 27. Fiddan AP, Yeo JM, Strubbings R, Dean D, “Vesicular Approach for Drug Delivery into or Across the Skin”, Br. Med. J;1983, 286, 1699. 28. Fang J, Hong C, Chiu W, Wang Y, “Effect of liposomes and niosomes on skin permeation of enoxacin”, Int. J. Pharm., 2001, 219, 61-72. 29. Kumar KP, Radhika PR, Sivakumar T, “Ethosomes-A Priority in Transdermal Drug Delivery”, International Journal of Advances in Pharmaceutical Sciences, 2010, 1, 111-121. 30. Johnsen SG, Bennett EP, Jensen, VG Lance, “Therapeutic effectiveness of oral testosterone” 1974, 2, 1473-1475

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31. Verma P, Pathak K, “Therapeutic and cosmeceutical potential of ethosomes: An overview”, J Adv Pharm Tech Res, 2010, 1, 274-82. 32. Chetty DJ, Chien YW, “Transdermal Delivery of CaCO3-Nanoparticles Containing Insulin”, Crit Rev Ther Drug Carrier Syst., 1998, 15, 629-670. 33. Paolino D, Lucania G, Mardente D, Alhaique F, Fresta M, “Innovative Drug Delivery Systems for the Administration of Natural Compounds”, J. Control. Release, 2005, 106, 99-110. 34. Fu Y, Hsieh J, Guo J, Kunicki J, Lee MY, Darzynkiewicz Z, Wu JM, Licochalcone A, “Antiinflammatory efficacy of Licochalcone A: correlation of clinical potency and in vitro effects”, Biochem. Biophys. Res. Commun., 2004, 322, 263-270. 35. Touitou E. Composition of applying active substance to or through the skin. US Patent: 5716638, 1996. 36. Touitou E. Composition of applying active substance to or through the skin. US Patent: 5540934, 1998.

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