Ethosomal nanocarriers: the impact of constituents and formulation techniques on ethosomal properties, in vivo studies, and clinical trials

Figures & data

Figure 1 Ethosomal studies covered by this review, and their annual distribution from July 1996 to November 2015.

Figure 2 Schematic representation of the different types of ethosomal systems.

Table 1 Comparison of classical ethosomes, binary ethosomes, and transethosomes in their initial suspension form

Parameter	Classical ethosomes	Binary ethosomes	Transethosomes
Composition	1. Phospholipids 2. Ethanol 3. Stabilizer 4. Charge inducer 5. Water 6. Drug/agent	1. Phospholipids 2. Ethanol 3. Propylene glycol (PG) or other alcohol 4. Charge inducer 5. Water 6. Drug/agent	1. Phospholipids 2. Ethanol 3. Edge activator (surfactant) or penetration enhancer 4. Charge inducer 5. Water 6. Drug/agent
Morphology	Spherical	Spherical	Regular or irregular spherical shapes
Size	Smaller than the classical liposomes	Equal to or smaller than classical ethosomes	Size based on type and concentration of penetration enhancer or edge activator used
ζ-Potential	Negatively charged	Negatively charged	Positively or negatively charged
Entrapment efficiency	Higher than classical liposomes	Typically higher than classical ethosomes	Typically higher than classical ethosomes
Skin permeation	Typically higher than classical liposomes	Typically equal to or higher than classical ethosomes	Typically higher than classical ethosomes
Stability	Stabler than classical liposomes	Stabler than classical ethosomes	No particular trend determined

Table 2 Phospholipids used in ethosomal formulations

Phospholipid name/brand	Composition and source	Reference(s)
Phospholipon 90G	Phosphatidylcholine from soybean (90%), granules	^Citation37, ^Citation49, ^Citation50
Phospholipon 90H	Hydrogenated phosphatidylcholine from soybean (90%), powder	^Citation51
Phospholipon 80H	Hydrogenated phospholipids from soybean with 70% phosphatidylcholine, powder	^Citation46
NAT 8539	Contained phosphatidylcholine (73%–79%), lysophosphatidylcholine (up to 6%), cephalin (up to 4%), and phosphatidic acid (up to 6%) of the dry residue; natural oils and sterol up to 6%; and ethanol (23%–27%)	^Citation52
Dipalmitoylphosphatidylcholine (DPPC)	1,2-Dipalmitoyl-rac-glycero-3-phosphocholine, ~99%, powder	^Citation53
Lipoid S100	Phosphatidylcholine from soybean, agglomerates	^Citation9, ^Citation17, ^Citation54, ^Citation55
Lipoid S75-3	Phosphatidylcholine content (70%–75%), from soybean	^Citation56
Lipoid S75	Phosphatidylcholine content (68%–73%), from soybean	^Citation16
Lipoid E80	Phosphatidylcholine content (81.7%), from egg yolk, agglomerates	^Citation27, ^Citation57
Phosphatidylethanolamine (PE)	3-sn-Phosphatidylethanolamine, ≥98%, from bovine/sheep brain, lyophilized powder	^Citation58
L-α-Phosphatidylcholine (PC)	1,2-Diacyl-sn-glycero-3-phosphocholine, ≥99%, from soybean/egg yolk, lyophilized powder	^Citation24, ^Citation59, ^Citation60
POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine)	1-Hexadecanoyl-2-(9Z-octadecenoyl)-sn-glycero-3-phosphocholine, >99%, synthetic, powder	^Citation61, ^Citation62
DPPG (1,2-dipalmitoyl-sn-glycero-3-phosphatidylglycerol)	1,2-Dipalmitoyl-sn-glycero-3-phospho-(1′-rac-glycerol) (sodium salt), powder	^Citation48
Coatsome^® FE-6081SU5 POPE-NHS	N-(Succinimidyloxy-glutaryl)-L-α-phosphatidylethanolamine, 1-palmitoyl-2-oleoyl	^Citation21, ^Citation22
DOTAP (1,2-dioleoyl-3-trimethylammonium-propane [chloride salt])	1,2-Dioleoyl-3-trimethylammonium-propane (chloride salt), powder or ethanol solution	^Citation22
Phospholipon 50	Lecithin from soy purified phosphatidylcholine, concentration 45%, rich in linoleic acid (65%) and palmitic acid (~20%), solid wax	^Citation63
SPC50	Phosphatidylcholine content (50.3%), from soybean	^Citation27

Table 3 Edge activators or penetration enhancers used in the preparation of transethosomes

Edge activator/penetration enhancer	Type	Concentration	Reference(s)
N-Decylmethyl sulfoxide	Nonionic surfactant	0.35%–1% of the total ethosomal system	^Citation18
Dimethyl sulfoxide	Penetration enhancer	10% of the total ethosomal system	^Citation18
Tween 80	Nonionic surfactant	10%–50% of the total phospholipid concentration in the ethosomal system	^Citation17, ^Citation19, ^Citation24, ^Citation27, ^Citation70
Tween 60	Nonionic surfactant	Up to 50% of the total phospholipid concentration in the ethosomal system	^Citation27
Tween 20	Nonionic surfactant	15%–50% of the total phospholipid concentration in the ethosomal system	^Citation19, ^Citation27
Oleic acid	Penetration enhancer	0.5%–3% of the total ethosomal system	^Citation17, ^Citation25, ^Citation29
L-Menthol	Penetration enhancer	5% of the total ethosomal system	^Citation25
Sodium stearate	Anionic surfactant	Phosphatidylethanolamine:cholesterol:sodium stearate at a molar ratio of 2:1:2.5	^Citation23
Deoxycholic acid	Bile acid/anionic surfactant	Phosphatidylcholine:cholesterol:deoxycholic acid at molar ratios of 2:1:1 and 6:2:1	^Citation24
Sodium deoxycholate	Bile salt/anionic surfactant	0.8% w/v of the total ethosomal system	^Citation29
Sodium cholate	Bile salt/anionic surfactant	0.66% of the total ethosomal system	^Citation19
Sodium taurocholate	Bile salt/anionic surfactant	0.53% of the total ethosomal system	^Citation17
Polyethylene glycol 4000	Surfactant	Phosphatidylcholine:cholesterol:polyethylene glycol 4000 at molar ratios of 2:1:1 and 6:2:1	^Citation24
Hexadecyltrimethylammonium bromide	Cationic surfactant	1% of the total ethosomal system	^Citation20
Cremophor EL-35	Nonionic surfactant	0.5%–1.5% of the total ethosomal system	^Citation20
Cremophor RH-40	Nonionic surfactant	Up to 50% of the total phospholipid concentration in the ethosomal system	^Citation27
Spans 80, 60, 40, 20	Nonionic surfactant	Up to 50% of the total phospholipid concentration in the ethosomal system	^Citation19, ^Citation27, ^Citation30
Skin-penetrating and cell-entering (SPACE) peptide	Penetration enhancer	2–10 mg/mL	^Citation21, ^Citation22
Sodium dodecyl sulfate	Anionic surfactant	0.8% of the total ethosomal system	^Citation26, ^Citation29

Figure 3 The classical cold method for the preparation of ethosomal systems.

Abbreviations: PG, propylene glycol; IPA, isopropyl alcohol.

Figure 4 The transmembrane pH-gradient method for the preparation of ethosomal systems.

Abbreviations: PG, propylene glycol; IPA, isopropyl alcohol.

Table 4 Types and concentrations of gel-forming agents used in ethosomal gel preparations

Drug/agent	Gel-forming agent		Reference(s)
	Name	Concentration
Amphotericin B	Carbopol 934	1% w/w	^Citation100
Econazole nitrate	Carbopol 934	1% w/w	^Citation40
Ketoconazole	Carbopol 934	2% w/w	^Citation84
Lopinavir	Carbopol 934	0.8% w/v	^Citation35
Losartan	Carbopol 934	0.75% w/v	^Citation96
Meloxicam	Carbopol 934	1% w/w	^Citation101
Testosterone	Carbopol 934	NM	^Citation102
Tretinoin	Carbopol 934	1.5% w/w	^Citation78
Valsartan	Carbopol 934	NM	^Citation51
5-Fluorouracil	Carbopol 934P	1.5% w/w	^Citation32
Aceclofenac	Carbopol 934P	0.75% w/v	^Citation15
Azelaic acid	Carbopol 934P	0.75% w/w	^Citation97
Methoxsalen	Carbopol 934P	2% w/w	^Citation103
Vinpocetine	Carbopol 934P	1% w/w	^Citation104
Clotrimazole	Carbopol 934LR	1% w/v	^Citation14
Psoralen	Carbopol 934LR	1% w/v	^Citation92
Benzocaine	Carbopol 940	0.5% w/w	^Citation66
Black-tea extracts	Carbopol 940	NM	^Citation28
Buspirone hydrochloride	Carbopol 940	0.7% w/w	^Citation72
Capsaicin and capsicum tincture	Carbopol 940	1% w/w	^Citation105
Ligustrazine phosphate	Carbopol 940	1% w/w	^Citation106
Repaglinide	Carbopol 940	1.5% w/w	^Citation53
Valsartan	Carbopol 940	1% w/w	^Citation107
Erythromycin	Carbopol 974	1% w/w	^Citation108
Erythromycin	Carbopol 974	NM	^Citation109
Cetirizine	Carbopol 980 NF	1.25%	^Citation98
Griseofulvin	Carbopol 980 NF	0.5% w/w	^Citation110
5-Fluorouracil	Carbopol ultrez	0.8% w/w	^Citation18
Ibuprofen	Carbopol (grade NM)	NM	^Citation111
Felodipine	Hydroxypropyl cellulose	1.5% w/v	^Citation112
Fluconazole	Hydroxypropyl methyl cellulose K4M	2% w/w	^Citation113
Mitoxantrone	Hydroxypropyl methylcellulose RG4T	10% w/v	^Citation114
Salbutamol sulfate	Pluronic F127	20% w/w	^Citation39
Granisetron hydrochloride	Lutrol F127	20% w/w	^Citation115
Metronidazole	Sodium alginate	8% w/v	^Citation116
Cannabidiol	NM	NM	^Citation117
Diclofenac	NM	NM	^Citation8

Abbreviation: NM, not mentioned.

Figure 5 Proposed mechanism for permeation of molecules from ethosomal system through the skin.

Notes: (A) Normal skin; (B) Skin-lipid perturbation by ethanol effects; (C) Penetration of the soft malleable ethosomal system vesicles.

Table 5 Summary of the in vivo studies

Drug/agent	Subjects/species	Aim	Model/method	Main results	DF	Reference(s)
5-Aminolevulinic acid	Nude mice	Skin penetration	Measurement of protoporphyrin IX (PpIX) by CLSM	Penetration ability of ethosomal systems was greater than that of liposomes	Susp	^Citation23
5-Aminolevulinic acid	Nude mice	Skin-penetration behavior	Hyperproliferative skin murine model/the tape-stripping technique	Significant improvement in the formation of PpIX in both normal and hyperproliferative skin	Susp	^Citation58
5-Fluorouracil	Nude mice	Evaluation of the antitumor effect	Two skin cancer models: 1. Intradermal (ID) injection of TE.354.T cells 2. ID injection of ES2 cells	Significant repression of tumor-development rate in both models compared to the commercial product	Gel	^Citation18
5-Fluorouracil	Albino rats, rabbits	Vesicle–skin interaction and drug-localization index	Fluorescence microscopy, CLSM	Ethosomal gel showed five- and tenfold deeper skin penetration than the lipogel and marker solutions, respectively	Gel	^Citation32
5-Fluorouracil	New Zealand White rabbits	Evaluation of laryngotracheal stenosis treatment	Airway-stenosis rabbit model	Ethosomal system resulted in less stenosis than the 5-fluorouracil solution alone	Susp	^Citation93
Ammonium glycyrrhizinate	Humans	Permeation, toxicity, and anti-inflammatory activity	Model of skin erythema	The ethosomal system showed very good skin tolerability, even when applied for a long period (48 hours)	Susp	^Citation64
Apigenin	SD rats + Kunming mice	Skin deposition, antiultraviolet effects	Ultraviolet B-induced skin inflammation	Ethosomes showed superior skin targeting in reducing COX-2 levels	Susp	^Citation16
Bacitracin	SD rats	Mechanisms of skin permeation	CLSM	The antibiotic delivered from ethosomes entered the skin between the corneocytes through the intercellular lipid domain	Susp	^Citation121
Benzocaine	Albino rabbits	Anesthetic activity	Conjunctival reflex test	The efficacy of ethosomal benzocaine was significantly improved in comparison to benzocaine solution	Gel	^Citation66
Buspirone	Wistar rats, SD rats	Pharmacokinetics, menopause syndromes	Ovariectomized rats	The drug was present in plasma for 12 hours, reaching Cmax after 2 hours. Observed temperature alleviation (1.6°C±0.7°C) to normal values after (3 hours) of administration	Gel	^Citation72
Cannabidiol	ICR mice	Anti-inflammatory effects	Carrageenan-induced inflammation	Significant accumulation of the drug in the skin and in the underlying muscle. Prevented inflammation and edema	Gel	^Citation117
Cetirizine	BALB/c-strain mice	Atopic dermatitis	Oxazolone-induced atopic dermatitis	Enhanced therapeutic performance of the ethosomal system	Gel	^Citation98
Combination of artesunate and febrifugine	Kunming mice	Antimalarial effects	Animals infected with Plasmodium berghei	Ethosomal cataplasm showed better antimalarial activity	Patch	^Citation27
Contact allergens: PD, DCB, and isoeugenol	CBA/Ca mice	Sensitization studies	Mouse local lymph node assay	Ethosomes were able to enhance the sensitizing capacity of the contact allergens	Susp	^Citation62
Contact allergens (isoeugenol and DCB)	CBA/Ca mice	Sensitization studies	Mouse local lymph node assay	Increased sensitizing potency compared with the allergens in solution	Susp	^Citation130
Curcuma longa extract	Humans	Photoprotective effects	Measuring skin hydration (Cutometer) and sebum content (Sebumeter)	Improvement in skin properties such as skin hydration and sebum content	Cream	^Citation79
C. longa extract	Humans	Antiwrinkle effects	Cutometer	The ethosomal cream delivered the antiwrinkle agent to the skin efficiently	Cream	^Citation123
Curcumin	SD rats	Anti-inflammatory effects	Carrageenan-induced paw edema	PG liposomes showed the highest and longest inhibition of the development of paw edema, followed by ethosomes and traditional liposomes	Susp	^Citation70
Diclofenac	SD rats	Anti-inflammatory effects	Carrageenan-induced paw edema	Significant inhibition of paw edema with ethosomal gel in comparison to liposomal and plain gels	Gel	^Citation8
DNA	CD1 nude mice	Gene delivery	CLSM	Good ethosomal gene delivery and expression in skin cells	Susp	^Citation120
Erythromycin	ICR mice	Antibacterial activities	Staphylococcus aureus-infected mouse skin	Therapy with ethosomal erythromycin was as effective as systemically administered drug	Gel	^Citation109
Erythromycin	ICR mice	Antibacterial efficiency	S. aureus-infected mice skin	Ethosomal system inhibited of the infection and stopped its development	Gel	^Citation108
Felodipine	Wistar albino rats	Drug release through the skin	Measuring drug plasma concentration	Enhanced transdermal delivery. Improved drug bioavailability	Gel	^Citation112
Fraxinus angustifolia leaf and bark extracts	CD1 mice	Antioxidant, anti-inflammatory, and wound-healing effects	12-O-Tetradecanoylphorbol-13-acetate-induced skin inflammation and ulceration	Highest antioxidant and anti-inflammatory effects were obtained from ethylene glycol containing vesicles rather than ethosomes and transcutol containing vesicles	Susp	^Citation131
Griseofulvin	Guinea pigs	Evaluation of antifungal activity	Guinea pig model for dermatophytosis	Complete cure of the fungal infection in 8 days for ethosomes and 14 days for liposomes	Gel	^Citation110
Hyaluronic acid	SKH1^HR strain hairless mice	Skin penetration	Fluorescence spectroscopy	A fivefold enhancement in penetration was found compared to PBS control	Susp	^Citation21
Ibuprofen	Mice, Wistar rats	Pharmacokinetics, analgesic and antipyretic effects	Tail-flick nociception mice, brewer’s yeast-induced fever rat	The analgesic effect of ethosomal ibuprofen gel was comparable to oral treatment	Gel	^Citation111
Insulin	SD rats	Blood glucose levels lowering effectiveness	Diabetic rats	Up to 60% decrease in blood glucose levels	Patch	^Citation120
Imiquimod	SD rats	Skin deposition	Fluorescence spectrophotometer	Transethosomes showed significantly higher skin deposition of the drug than the marketed product Aldara^®	Susp	^Citation29
Isoeugenol and MDG	Humans	Evaluation of the allergens induced responses	Patch-test conditions	Significantly enhanced patch-test reactions in comparison with the allergen hydroethanolic solution	Susp	^Citation61
Ketoconazole	Wistar rats	Antifungal activity	Rats with skin, induced fungal infection	Transethosomes enhanced the antifungal activity in a shorter duration of time than other vesicles	Susp	^Citation26
Lidocaine	Guinea pigs	Anesthetic activity	Pinprick tests	Shorter onset and longer duration than the liposomes or hydroethanolic solution	Susp	^Citation59
Ligustrazine	SD rats	Pharmacokinetics	Determination of plasma drug concentration by HPLC	Ethosomal system-enhanced drug absorption and bioavailability	Patch	^Citation34
Ligustrazine	SD rats	Pharmacokinetics, antimyocardial ischemic effects	Rat model of acute myocardial ischemia	Highest AUC was achieved by the ethosomal patch	Patch	^Citation118
Ligustrazine phosphate	SD rats	Anti-Alzheimer’s disease effects	Scopolamine-induced amnesia model in rats	Ethosomal system is a potential alternative therapy for Alzheimer’s disease	Gel	^Citation106
Low-molecular-weight heparin (LMWH)	Hairless mice	Pharmacokinetics	Measurement of anti-factor Xa activity as an indicator of LMWH bioactivity using Coates^® colorimetric plasma assay	Better skin permeation and bioavailability of LMWH achieved with flexible liposomes than ethosomes	Susp	^Citation94
Lycopene extract from tomato	NMRI mice	Antioxidant and anti-inflammatory activities	Anthralin-induced ear edema animal model	Ethosomes were able to decrease the level of anthralin-induced ear swelling in a way that was highly comparable to the positive control	Susp	^Citation54
Matrine	SD rats	Anti-inflammatory activity	Reflection spectrophotometer	Improved anti-inflammatory activity	Susp	^Citation38
Melatonin	Albino rabbits	Skin irritation studies	Scoring degree of erythema	Good skin tolerability of the ethosomal system	Susp	^Citation44
Meloxicam	Albino Wistar rats	Anti-inflammatory activity	Carrageenan-induced rat paw-edema model	Significantly higher percentage inhibition of edema in comparison with the oral route	Gel	^Citation101
Methoxsalen	Wistar rats	Skin-photosensitization studies	UV-light exposure	Ethosomal methoxsalen showed profoundly less phototoxicity on the skin	Gel	^Citation103
Mitoxantrone	BALB/c nude mice, Wistar rats	Antimelanoma	Melanoma-bearing mice	Ethosomal mitoxantrone showed higher antimelanoma effect than the same drug solution	Gel	^Citation114
Mouse epidermal growth factor (mEGF)	C57BL/6 mice	Penetration mechanisms and biological effects	Penetration pathways and depth were observed by CLSM	Penetration was mainly through the pilosebaceous unit and partly through the intercellular domain	Susp	^Citation132
Psoralen	SD rats	Evaluation of drug release in the skin	Using skin microdialysis	Peak concentration and AUC of ethosomal psoralen were 3.37 and 2.34 times higher than psoralen tincture, respectively	Susp	^Citation55
Psoralen	SD rats	Skin deposition studies	Extracted drug determined by HPLC	Ethosomes showed enhanced psoralen permeability and targeting deep skin via intercellular and intracellular transport pathways	Susp	^Citation133
Psoralen	Rats	Investigating biocompatibility of the vesicles with the skin	Testing the skin using inverted fluorescence microscopy	Ethosomes and liposomes were found to be safe following daily application and for 7 days	Susp	^Citation129
Repaglinide	Albino Wistar rats	Antidiabetic activity	Alloxan solution-induced diabetes model	Prolonged antidiabetic effect of the drug over a significantly longer period of time in comparison with the equivalent oral dose	Gel	^Citation53
Silymarin	SD rats	Pharmacokinetics and tissue distribution of orally or IV-administered ethosomes	Using liquid chromatography with tandem mass spectrometry (LC–MS/MS)	Tissue-distribution patterns of silymarin ethosomes and liposomes were similar, except that lung and spleen accumulation of silymarin ethosomes was higher than that of liposomes	Susp	^Citation134
Short interfering RNAs (siRNAs)	BALB/c mice	Drug penetration	Using the Micro BCA protein assay and KDalert GAPDH assay kits	Results confirmed the efficacy of transethosomes in delivering GAPDH siRNA into the skin	Susp	^Citation22
Tacrolimus	BALB/c mice	Pharmacologic effects	Animal model of atopic dermatitis	Ethosomal tacrolimus displayed the lowest ear swelling compared to traditional liposomes and commercial ointment	Susp	^Citation12
Testosterone	Rabbit pinnae	Skin permeation and blood levels	Using radioimmunoassay	Significantly higher testosterone blood levels from ethosomal patch than the marketed patch	Patch	^Citation6
Testosterone propionate	SD rats	Bioavailability	Using a Cobas 411 analyzer	Improved absorption and bioavailability of the drug in comparison to liposomes and hydroethanolic solution	Susp	^Citation21
Tetrandrine	Wistar rats	Antiarthritic activity	Freund’s complete adjuvant-induced arthritis	Ethosomes significantly enhanced the therapeutic efficacy of tetrandrine in comparison to liposomes	Susp	^Citation91
Tretinoin	LACA mice	Antipsoriatic activity	Mouse-tail model	Ethosomes were not of much utility for treatment of superficial skin disorders such as psoriasis	Gel	^Citation78
Triptolide	SD rats	Anti-inflammatory activity	Methyl nicotinate-induced skin erythema model	Ethosomes reduced erythema rapidly and completely	Susp	^Citation80
Valsartan	Albino Wistar rats	Pharmacokinetics	Drug plasma concentration determined by HPLC	A significant increase in the bioavailability of the transdermal ethosomal valsartan (3.03 times) in comparison to the oral suspension	Patch	^Citation37
Valsartan	Albino Wistar rats	Antihypertensive activity	Methyl prednisolone acetate-induced hypertension	Better and prolonged antihypertensive activity compared to the orally administered suspension	Gel	^Citation51
Valsartan	Albino Wistar rats	Antihypertensive activity	Methylprednisolone acetate-induced hypertension	Ethosomal gel was found to be effective, with a 34.11% reduction in blood pressure	Gel	^Citation107
Vancomycin hydrochloride	SD rats	Antibacterial activity	Methicillin-resistant S. aureus-induced mediastinitis	No statistically significant difference between intramuscular vancomycin treatment and treatment conducted by combined ethosomes and iontophoretic method	Susp	^Citation67
Vinpocetine	SD rats	Pharmacokinetics	Drug plasma concentration determined by HPLC	AUC and elimination half-life of transdermal administration were significantly higher than that by intragastric administration (P<0.01)	Gel	^Citation104
Voriconazole	Hairless mice	Skin deposition studies	Extracted drug from the skin determined by HPLC	Enhanced skin deposition of the drug in the dermis/epidermis region compared to other formulations	Susp	^Citation17
Zidovudine	SD rats	Vesicle–skin interaction study	Histological studies using optical microscope	Ethosomes affected the ultrastructure of the stratum corneum	Susp	^Citation45

Abbreviations: AUC, area under the (plasma drug concentration–time) curve; CLSM, confocal laser-scanning microscopy; C_max, maximum concentration; DCB, dinitrochlorobenzene; DF, dosage form; HPLC, high-performance liquid chromatography; IV, intravenous; MDG, methyldibromoglutaronitrile; PBS, phosphate-buffered saline; PD, potassium dichromate; SD, Sprague Dawley; Susp, suspension; UV, ultraviolet.

Table 6 Summary of the clinical trials

Drug/agent	Dosage forms/types	Volunteers, n	Clinical trial type	Reference(s)
Acyclovir	NM	40	Pilot clinical trial	^Citation135
Clindamycin phosphate and salicylic acid (CLSA) combination	Ethosomal gel	40	Pilot clinical trial	^Citation136
Prostaglandin E1 (PGE1)	NM	15	Pilot clinical trial	^Citation125

Abbreviation: NM, not mentioned.

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