Ultradeformable phospholipid vesicles as a drug delivery system: a review

Figures & data

Figure 1 A representative scheme of the lipids and EA comprising UDVs and the carried molecules.

Note: Copyright © 2013. Dove Medical Press. Adapted from Romero EL, Morilla MJ. Highly deformable and highly fluid vesicles as potential drug delivery systems: theoretical and practical considerations. Int J Nanomedicine. 2013;8:3171–3186.¹⁰
Abbreviations: EA, edge activator; UDV, ultradeformable vesicle.

Figure 2 Different cell strata of the epidermis and dermal structures.

Notes: From bottom to top, the strata are as follows. SB (stratum basale): A basal layer containing stem cells (undifferentiated cells that give rise to keratinocytes), keratinocytes (cells that synthesize keratin), and melanocytes (cells that synthesize the pigment melanin that shields DNA from ultraviolet radiation). (A) The different types of intercellular junctions connecting the cells of epidermis. At this level, the cells are bridged by desmosomes (mechanical junctions, involved primarily in cell cohesion; the intracellular ends of desmosomal cadherins form desmosomal plaques, to which keratin filaments bind). The SB is attached to the basal membrane by hemidesmosomes. In the SB, the desmosomes are infrequent and small. SS (stratum spinosum): Several cell layers deep, made of keratinocytes (which become somewhat flattened and “spiny-shaped”) and Langerhans (dendritic) cells. The size and number of desmosomes rise significantly. Adherens junctions (intercellular network that coordinates the behavior of a population of cells, coupling intercellular adhesion to the actin cytoskeleton) are present. SG (stratum granulosum): Three to five cell layers deep, made of keratinocytes that accumulate vesicles (granules) filled with the protein keratin and glycolipids, which are exocytosed. The exocytosed keratin wraps around the cell membrane of the keratinocyte, creating a thick coat that provides protection from abrasion and puncture; the exocytosed glycolipids fill the extracellular spaces between the keratinocytes and provides a waterproofing property to skin. The SG forms a barrier between the surface cells and the deeper layers of the epidermis and cuts off nutrient supply to the cells of upper layers. Only at this level, the tight junctions (occluding junctions occurring in simple epithelial and endothelial cells, separating the apical membrane domain from the basolateral part) are found. A reduced number of desmosomes (which are dynamically subjected to degradation by hydrolases), as compared with SS, and adherens junctions are also found. SC (stratum corneum): The SC is a transparent 10–15 μm thick outermost protective dead layer of the skin. It consists of multiple cornified cell layers, the corneocytes (flat dead cells filled with keratin filaments, water, and the natural moisturizing factors), embedded in SC lipids (ceramides, cholesterol, and saturated long-chain free fatty acids, approximately at equimolar ratios. Low levels of other lipid classes are also present, such as cholesterol sulfate, glucosylceramides, and cholesterol esters). The lower SC (SC compactum) contains corneodesmosomes, drastically differing from desmosomes in morphology. The layered structure of the intercellular portion of the junction is lost, whereas the intracellular plaque becomes embedded within the cross-linked cornified envelope. The corneodesmosomes remain functional and their ordinate digestion will eventually permit dissociation of the horny layer and desquamation of superficial corneocytes. The loss of cells from the SC is compensated by the cell growth in the innermost layer of the epidermis, the stratum basale. In this way, the thickness of the epidermis remains approximately constant. (B) A schematic representation of the pathway followed by the UDVs across the canyons of the epidermis; (C and D) A confocal fluorescence microscopy image of the epidermis organization in canyons and cell clusters.⁶⁸ (B1) A schematic representation of the fate of hydrophobic/hydrophilic drugs within UDVs during penetration across the canyons. Reprinted from Colloids Surf B Biointerfaces, 121. Carrer DC, Higa LH, Defain Tesoriero MV, Morilla MJ, Roncaglia DI, Romero EL. Structural features of ultradeformable archaeosomes for topicaldelivery of ovalbumin. Pages: 281–289., Copyright 2014, with permission from Elsevier.68
Abbreviations: BM, basal membrane; ECM, extracellular matrix; UDVs, ultradeformable vesicles.

Table 1 Anti-inflammatory, antihypertensive, and anti-infective drugs incorporated in UDVs

Type of drug and properties	Vesicle composition	Vesicle properties	Results
Anti-inflammatory drugs against osteoarthritis
Piroxicam^Citation41: lipophilic, 331.3 Da	SPC:NaDchol, 40 mg: 2% w/v	150 nm; −22.7 mv	Cumulative permeation was 52% for UDVs after 24 hours, with a flux of 14.48 μg/cm^2/h vs 7.43 μg/cm^2/h for the free drug in porcine ear skin ex vivo.~UDVs and the free drug produced 74% and 60% inhibition of edema, respectively, after 24 hours, in carrageenan-induced paw edema model
Lornoxicam^Citation43: lipophilic, 371.8 Da	SPC:chol:T80, 100:7.74:2.5 w/w/w	EE: 35%~280 nm~16 mv	Ex vivo permeation on dorsal skin of rabbit
Diclofenac and curcumin^Citation44: lipophilic, 369.3 Da	SPC: NaChol, 3:1 molar ratio, diclofenac and curcumin were added to organic solvents	EE: 98%–95%~67 nm	Cumulative amount of diclofenac and curcumin in UDVs was 37.94 μg/cm^2 and 737.78 μg/cm^2, respectively, with corresponding fluxes of 1.58 mg/cm^2 · h and 30.74 μg/cm^2 · h, respectively, on rat skin ex vivo
Ketorolac trometha mine^45: hydrophilic, 255.3 Da	SPC:T80, 86:14 w/w, 7% v/v ethanol solution of drug	EE: 73%~128 nm, −12 mV, 18.6 μg drug/mg SPC	UDVs showed long lag time (10 hours), only ~7.7% permeated after 24 hours on pig’s ear skin ex vivo~Total amount of ketorolac permeated was 7–26 μg with a penetration distance of 6–33 μm on healthy human volunteers
Anti-inflammatory drugs against atopic dermatitis
Tacrolimus^Citation50: lipophilic, 822.9 Da	SPC:T80, 60:18 w/w	EE: 70%–83%	Cumulative amount of drug was 6.66 mg/cm^2 and 4.22 mg/cm^2 for UDVs and CLs, respectively, on rat skin layers ex vivo. Drug was not detected in the fluid collected
		123 nm	On rat skin in vivo, UDVs, CLs, and ointment displayed same distributions of drug in the SC. In epidermis and dermis, amounts of drug in UDVs were 3.8 and 4.2 times as ointment, respectively; in CLs, the amount was only 1.7 times and 1.4 times that of ointment; treatment (twice a day for 7 days) with UDVs in gel reduced ear swelling to the minimum, as compared with CLs and ointment
Glycyrrhetic acid^Citation51: lipophilic, 470.6 Da	SPC:NaDchol, 3.5:0.62 w/w, 10% v/v ethanol	EE: 73%~87 nm~−42.5 mv	Cumulative amount of drug was 6.94 μg/cm^2 and 1.30 μg/cm^2 for UDVs and CLs, respectively, on abdominal rat skin ex vivo.~Concentration of drug increased immediately after UDV application and reached Cmax at 3 hours on mice skin in vivo.~Drug was not detected in plasma. Treatment (twice per day every 3 days × 21 days on ear 1 hour before and 12 hours after application of DNFB) produced 25.5% and 34.8% inhibition of ear thickness for UDVs and for positive control, respectively
Cetirizine^Citation52: lipophilic, 388.8 Da	SPC:SA:Span 80, 150:15:16.6 w/w/w	EE: 76%~140 nm~12.73 mv	Skin retention of drug was in the following order: UDV in gel (16.9%) > liposomal gel (7.6%) > cream (3.7%) on skin of mice ex vivo Treatment (once every alternate day for 2 weeks after half an hour of oxazolone administration) with UDVs in gel significantly decreased itching score and erythema, as compared with cream-treated mice
Antihypertensive drug
valsartan^Citation53: lipophilic, 435.5 Da	SPC:NaDchol, 85:15 w/w	EE: 86%	UDVs showed maximum flux over CLs (626.6 μg/cm^2/h vs 18.5 μg/cm^2/h) on abdominal skin of Wistar rats ex vivo
		130 nm	Oral valsartan controlled the hypertension at 3 hours, then blood pressure rose gradually up to 48 hours. UDVs gradually decreased blood pressure, with the maximum effect observed at 6 hours, and controlled the blood pressure for up to 48 hours
Felodipine^Citation54: lipophilic, 384.2 Da	EggPC:Span 80, 95:5 w/w	EE: 85.14%~76 nm	UDVs showed highest cumulative drug permeation (94.9%), skin deposition (8.1%), and transdermal flux (23.7 μg/h/cm^2) on rat skin ex vivo. The maximal permeation from UDVs in gel was 2.6 times higher as compared with free drug gel at 24 hours
		−49.8 mv	Tmax for topical UDV was 6hours and Cmax was 8.05 ng/ml, Tmax for oral drug was 4.85 hours and Cmax was 2.31 ng/ml, in rats.~AUC0−∞ was 162.26 and 45.27 ng · h/mL for UDVs in gel and oral formulation, respectively
Anti-leishmanial drug
Paromomycin^Citation57: hydrophilic, 713.7 Da	SPC:NaChol: ethanol, 20:2:5 w/w	EE: 60% 200 nm −14 mv	UDVs showed higher percentage of drug retention in the skin, as compared with the cream on mice skin ex vivo UDVs (twice a day for 4 weeks started at Week 4 after infection) induced significantly smaller lesion size and lower spleen parasite burden than control groups and free drug cream, in BALB/c mice infected with Leishmania major
Zn phthalocyanine^Citation59: hydrophobic, 1,052 Da	SPC:NaChol, 6:1 w/w	EE: 85% 100 nm, −36.7 mv	UDVs showed 100% antipromastigote and 80% antiamastigote activity against Leishmania braziliensis after 15-minute sunlight irradiation (15 J/cm^2). Free phthalocyanine showed 20% of antipromastigote and antiamastigote activity
Anti-infective drugs
Neomycin sulfate^Citation61: hydrophilic, 908.8 Da	SPC:T80 or Span 80, 90:10 w/w, lipid films were hydrated with phosphate buffer saline pH 7.4 containing 1% w/v neomycin sulfate	EE: 34.6% 145 nm	Enhanced deposition of drug in rat skin ex vivo after 24 hours Complete eradication of staphylococcal infections in rats within 7 days
Clotrimazole^Citation62: lipophilic, 344.8 Da	SPC:Span 80, 7% v/v ethanol solution of drug	EE: 73.5% 1–10 μm	High antifungal activity against Candida albicans UDVs, CLs, and free drug decrease 50% TEER of Caco-2 cell monolayer in the first 150 minutes, and these did not recover at 24 hours
Metronidazole^Citation63: hydrophilic, 171.1 Da	EggPC:NaDchol, 170:30 w/w, EE: 40% 400 nm solution of drug	−11 mV	94%, 47%, and 61% of free drug, in CLs, and in UDV permeates at 3 hours, respectively

Abbreviations: AUC, area under the curve; chol, cholesterol; Cmax, maximum (or peak) serum concentration; CL, conventional liposomes; DNFB, 2,4-dinitrofluorobenzene; EggPC, phosphatidylcholine from egg yolk; EE, encapsulation efficiency; NaChol, sodium cholate; NaDchol, sodium deoxycholate; SC, stratum corneum; SPC, soybean phosphatidylcholine; SA, stearylamine; TEER, transepithelial electrical resistance; Tmax, the time at which C_max is observed; T80, Tween 80; UDV, ultradeformable vesicle.

Table 2 Other drugs incorporated in UDVs

Type of drug and properties	Vesicle composition	Vesicle properties	Results
Anesthetic
Butamben^Citation64: lipophilic, 193.2 Da	EggPC:chol 4:3, PEG-8-L at 2:3 EggPC molar ratio	EE: 82.9% 150 nm, −21 mV	UDVs showed maximum flux over conventional liposomes and free drug (29.93 mg/cm^2/h, 23.17 mg/cm^2/h, and 6.95 mg/cm^2/h, respectively) after 8 hours on full thickness pig ear skin
UV protection
Quercetin^Citation65: poorly water soluble, 302.2 Da	SPC:chol:Tween 80, 4:1:1 w/w/w	EE: 80.41%	Penetration rate was 3.8-fold greater for UDVs than for drug suspension. UDvs increased drug deposition in the SC and epidermis/dermis, as compared with drug suspension
		132 nm, −21 mv	UDvs increased cell viability and suppressed reactive oxygen species in keratinocytes induced by UvB irradiation Inflammation and collagen fiber breakage were slighter for skin treated with drug suspension and UDvs in comparison with control animals, after UvB application. The structure of the SC was protected and skin edema was relieved. Histological collagen fibers exhibited no apparent dilatation and congestion around the capillaries in the UDV-treated group
Acne
Tretinoin^Citation66: lipophilic, 300.4 Da	PC:Tween 80	14.7±3.0 drug loading (^g/mg SPC) 131 nm 5.9 mv	UDvs showed the lowest skin irritation potential after daily topical application for 10 days, as compared with commercial tretinoin formulation (Ketrel). UDV-treated skin showed irregular hyperkeratosis and presence of fibroblast proliferation on superficial dermis. For Ketrel-treated skin, hyperplasia of the epidermis and superficial perivascular dermatis were observed
Osteoporosis
Raloxifene^Citation67: poorly water soluble, 510.5 Da	SPC:NaDchol, 300:35 w/w	EE: 91%, 134 nm −2.6 mv	UDvs showed enhancement ratios of 6.25 for drug permeation and 9.25 for skin deposition, respectively, as compared with conventional liposomes on rat skin

Abbreviations: chol, cholesterol; CL, conventional liposomes; EggPC, phosphatidylcholine from egg yolk; EE, encapsulation efficiency; NaChol, sodium cholate; NaDchol, sodium deoxycholate; SC, stratum corneum; SPC, soybean phosphatidylcholine; T80, Tween 80; UDV, ultradeformable vesicle; UVB, ultraviolet radiation B.

Romero EL, Morilla MJ. Highly deformable and highly fluid vesicles as potential drug delivery systems: theoretical and practical considerations. Int J Nanomedicine. 2013;8:3171–3186.

 PubMed Web of Science ®Google Scholar

Carrer DC, Higa LH, Defain Tesoriero MV, Morilla MJ, Roncaglia DI, Romero EL. Structural features of ultradeformable archaeosomes for topicaldelivery of ovalbumin. Colloids Surf B Biointerfaces. 2014;121:281–289.

 PubMed Web of Science ®Google Scholar

Shaji J, Lal M. Preparation, optimization and evaluation of transferosomal formulation for enhanced transdermal delivery of a COX-2 inhibitor. Int J Pharm Pharm Sci. 2014;6:467–477.

 Google Scholar

Taha EI. Lipid vesicular systems: formulation optimization and ex vivo comparative study. J Mol Liquids. 2014;196:211–216.

 Web of Science ®Google Scholar

Chaudhary H, Kohli K, Kumar V. Nano-transfersomes as a novel carrier for transdermal delivery. Int J Pharm. 2013;454:367–380.

 PubMed Web of Science ®Google Scholar

Lei W, Yu C, Lin H, Zhou X. Development of tacrolimus-loaded transfersomes for deeper skin penetration enhancement and therapeutic effect improvement in vivo. Asian J Pharm Sci. 2013;8:336–345.

 Google Scholar

Li S, Qiu Y, Zhang S, Gao Y. Enhanced transdermal delivery of 18β-glycyrrhetic acid via elastic vesicles: in vitro and in vivo evaluation. Drug Dev Ind Pharm. 2012;38(7):855–865.

 PubMed Web of Science ®Google Scholar

Goindi S, Kumar G, Kumar N, Kaur A. Development of novel elastic vesicle-based topical formulation of cetirizine dihydrochloride for treatment of atopic dermatitis. AAPS PharmSciTech. 2013;14:1284–1293.

 PubMed Web of Science ®Google Scholar

Ahad A, Aqil M, Kohli K, Sultana Y, Mujeeb M, Ali A. Formulation and optimization of nanotransfersomes using experimental design technique for accentuated transdermal delivery of valsartan. Nanomedicine. 2012;8:237–249.

 PubMed Web of Science ®Google Scholar

Yusuf M, Sharma V, Pathak K. Nanovesicles for transdermal delivery of felodipine: development, characterization, and pharmacokinetics. Int J Pharm Investig. 2014;4:119–130.

 PubMedGoogle Scholar

Bavarsad N, Bazzaz BSF, Khamesipour A, Jaafari MR. Colloidal, in vitro and in vivo anti-leishmanial properties of transfersomes containing paromomycin sulfate in susceptible BALB/c mice. Acta Trop. 2012;124:33–41.

 PubMed Web of Science ®Google Scholar

Montanari J, Maidana C, Esteva MI, Salomon C, Morilla MJ, Romero EL. Sunlight triggered photodynamic ultradeformable liposomes against Leishmania braziliensis are also leishmanicidal in the dark. J Control Release. 2010;147:368–376.

 PubMed Web of Science ®Google Scholar

Darwhekar G, Jain DK, Choudhary A. Elastic liposomes for delivery of neomycin sulphate in deep skin infection. Asian J Pharm Sci. 2012;7:236–241.

 Google Scholar

Kumar R, Rana AC, Bala R, Seth N. Formulation and evaluation of elastic liposomes of clotrimazole. Int J Drug Dev Res. 2012;4(3):348–355.

 Google Scholar

Vanic Ž, Hafner A, Bego M, Škalko-Basnet N. Characterization of various deformable liposomes with metronidazole. Drug Dev Ind Pharm. 2013;39(3):481–488.

 PubMed Web of Science ®Google Scholar

Cereda CM, Franz-Montan M, da Silva CM, et al. Transdermal delivery of butamben using elastic and conventional liposomes. J Liposome Res. 2013;23(3):228–234.

 PubMed Web of Science ®Google Scholar

Liu D, Hub H, Lin Z, et al. Quercetin deformable liposome: preparation and efficacy against ultraviolet B induced skin damages in vitro and in vivo. J Photochem Photobiol B Biology. 2013;127:8–17.

 Google Scholar

Ascenso A, Salgado A, Euletério C, et al. In vitro and in vivo topical delivery studies of tretinoin-loaded ultradeformable vesicles. Eur J Pharm Biopharm. 2014;88(1):48–55.

 PubMed Web of Science ®Google Scholar

Mahmood S, Taher M, Mandal UK. Experimental design and optimization of raloxifene hydrochloride loaded nanotransfersomes for transdermal application. Int J Nanomedicine. 2014;9:4331–4346.

 PubMed Web of Science ®Google Scholar