Ethosomes- A Novelize Vesicular Drug Delivery System

 

Shraddha Pandey¹*, Shashi Kiran Misra², Nisha Sharma³

¹University Institute of Pharmacy, C.S.M.U, Kanpur

²Assistant Professor, University Institute of Pharmacy, C.S.J.M.U, Kanpur

³HOD and Assistant Professor, University Institute of Pharmacy, C.S.J.M.U, Kanpur

 

 

ABSTRACT:

Ethosomes, a kind of soft, ductile vesicular drug delivery system are widely used in cosmetic and pharmaceutical formulations to capsulate bioactive agent, its protection from degradation, enhancement of bioavailability and also to boost up the therapeutic efficacy. Ethosomes are popular field for researcher owing to its exceptionally skin permeation property and pronounced entrapment efficiency. The present study, a sincere attempt has been made to foreground the properties ,characterstics, evaluation parameters, methodology and patents till date regarding ethosomes. Ethosomes have also been put- upon in systemic drug delivery for the treatment of HIV infections, shaking palsy, angiocardiopathy and for manifestation of malignant melanoma.

 

 

INTRODUCTION:

Ethosomes, are soft, ductile vesicles trimmed for enhanced delivery of active agents¹, which constitutes of hydro/ alcoholic/ glycolic phospholipids in which the engrossment of alcohols or their coalition is relatively high ‘Fig.3’. Their dimension ranges vary from micrometer to nanometers². The synergistic effects of coalition of phospholipids and high concentration of ethanol in vesicular preparations have been suggested to be accountable for deeper distribution and incursion in the skin lipid bilayers. They can ensnare drug molecule with several physiochemical characteristics i.e of hydrophilic, lipophilic, or amphiphilic ³and also delivers magnanimous molecules such as peptides, and protein molecules.

 

Ethosomes are the slight modifications of well established drug carrier liposomes. Their unique structure are able to encapsulate and deliver therapeutics through the skin (cannabinoids, insulin, salbutamol)⁴ and also have been used in systemic drug delivery for the treatment of HIV infections, shaking palsy, angiocardiopathy and topical delivery of various drugs. Malignant melanoma is the most belligerent form of skin cancer, Paclitaxel® loaded ethosome nanoparticles as chemotherapeutic agent used in the treatment of melanoma.

 

Ethosomes is also being employed for topical delivery of DNA molecules to express genes in skin cells. Touitou et al. in their study capsulize the GFP-CMV driven transfecting construct into ethosomal formulation. They applied this preparation to the abaxial skin of 5- week male CD-1 bare mice for 48 hours, treated skin was abstracted and insight of green fluorescent protein (GFP) formulation was ascertained by (Confocal laser scanning microscopy) CLSM. It was discovered that topically used ethosomes – GFP- CMV- driven transfecting retrace enabled effective delivery and manifestation of genes in skin cells⁵. In ethosomes eminent drug loading is feasible for the reasons like solubility of numerous drugs in ethanol, and eminent degree of lamellarity in vesicles. Richly concentration of ethanol construct them pliable as well increases the piercing power because it increases the thermodynamic action due to evaporation of ethanol and aggravates penetration due to decrease in barrier property of stratum corneum . Contempt to these potentials it is much slanted for its stability. Ethosomal system are advanced conceptually, but characterized by easiness in their preparation, safety and efficiency- a rarefied coalition that can amplify their application.

 

THE ETHOSOME TECHNOLOGY

The novel therapeutic technology has solely in licensed and further developed a passive patented and non invasive transdermal drug delivery technology known as the ETHOSOMES™ delivery system. Ethosomes were configured to enhance the delivery of drugs into the deep layers of skin. Relying on the formulation, delivery can be targeted for local delivery or for the systemic use. The structure of an ethosome allows it to carry spacious variety of molecules with various physical and chemical properties.

 

ADVANTAGES OF ETHOSOMES

Ethosomal drug delivery possess certain advantages as a product, in equivalence to other transdermal and dermal delivery systems which includes the increased pervasion of drug viaskin, and the ethosomal system is inactive, non invasive and is accessible for prompt commercialization⁶, it is the uncomplicated method for the drug delivery in equivalent to other complicated methods like iontophoresis and phonophoresis⁷,it consists of non toxic raw material in formulation⁸,ethosomes are platform for the delivery of large and diverse group of drugs^9, producing high patient compliance. ‘Fig. 1’ compiled numerous advantages of ethosomes drug delivery system.

 

Fig. 1Advantages of ethosomes drug delivery system

 

COMPOSITION  OF  ETHOSOMES

Ethosomes are delicate, ductile cyst  collected  principally of phospholipids, ethanol (comparatively eminent compactness) and water. Eventually ‘delicate cyst’ symbolize refreshing vesicular carrier for aggravate bringing to or through the skin. The size of ethosomes cyst can be inflected from tens of nanometers to microns^10,11,12. Ethosomes are primarily put upon for the deliverance of drugs through transdermal route. ¹³

 

Fig.2  Schematic structure of ethosome

 

Different additives are employed for the formulation of ethosomes which are mentioned in table 1

 

Table1: Additives used in formulation of ethosomes

S.no	Ingredients	Examples	Application
1.	Phospholipid	Soya phosphatidyl choline Egg phosphatidyl choline Dipalmityl phosphatidyl choline Distearyl phosphatidyl choline	Vesicle forming agent
2.	Vehicle (alcohol)	Isopropyl alcohol Ethanol	skin penetration enhancer and provide  softness to vesicle membrane
3.	Poly glycol	Propylene glycol	skin penetration enhancer
4.	Cholestrol	Cholestrol	provide the stability to vesicle membrane,  as a stabilizer
5.	Dye	Rhodamine -123 Rhodamine red Fluorescene Isothiocynate (FITC) 6 carboxy fluorescence	May be used for characterization study
6.	Polymer	Carbopol 934	Used as a gel former

 

 

 

PHYSICOCHEMICAL PARAMETERS AND EVALUATION OF ETHOSOMES

Evaluation and visualization of ethosomes can be done by various techniques and instruments like SEM, TEM and other instruments can be used for the evaluation parameters of ethosomes. Table 2 shows various evaluation parameters of ethosomes which are as follows.

 

 

Table 2 : Evaluation Parameters  of  Ethosomes

S. no	Parameters	Instruments	Significance
1.	Vesicle Shape	Transmission electron microscopy (TEM) , Scanning electron microscopy	Determines skin efficiency for penetration
2.	Vesicle Size and Zeta Potential	Dynamic Light Scattering(DLS), Photon correlation Spectroscopy(PCS) and Zeta Meter	Determines skin penetration and stability of vesicles
3.	Transition Temperature	Differential Scanning Calorimetry(DSC)	Determines transition temperature of lipid vesicles
4.	Drug Entrapment	Ultracentrifugation Technique	Suitability of method
5.	Surface Tension Measurement	Ring method in a Du Nouy ring tensiometer	Determines surface tension activity of drug in aqueous solution
6.	Drug Content	UV Spectrophotometer, High Performance Liquid Chromatographic Method(HPLC)	Important in deciding the amount of vesicle preparation to be used
7.	Stability Studies	Dynamic Light Scattering(DLS), Transmission Electron Microscopy(TEM)	To determine the shelf life of vesicle formulation
8.	Skin Permeation Studies	Confocal Laser Scanning Microscopy(CLSM)	Determines rate of drug transport through skin
9.	In –vitro Dissolution	Franz diffusion cell	Determines the drug release rate from vesicle

 

 

MECHANISM  OF DRUG PENETRATION AND  ACTION THROUGH  ETHOSOMES INTO SKIN

The first part of the mechanism of drug delivery from ethosomes into skin  is due to, ethanol effect whereby embolism of the ethanol into intercellular lipids enhancing lipid fluidity and  lowering the density of the lipid multilayer.¹⁷ This is accompanied by the ethosome effect, which involves inter lipid pervasion and perspicacity by the perforation of recent pathways due to the plasticity and coalition of ethosomes with skin lipids, ensuant in the acquittance of the drug in deep layers of the skin..The  drug  absorption probably occurs in following two phases :

 

ETHANOL EFFECT

Ethanol acts as a penetration enhancer through the skin . It permeates into intercellular lipids, enhances the fluidity of cell membrane lipids through lowering the density of lipid multilayer of cell membrane.

 

ETHOSOMES EFFECT

Through increased cell membrane lipid fluidity, the permeation via skin increases inside the deep dermal layers. Meanwhile drug carraying ethosomes fuses with skin lipids and liberates the drug at target site of the skin.

 

 

DIAGRAMMATIC REPRESENTATION OF ETHANOL EFFECT AND ETHOSOMAL EFFECT

 

Fig. 4

MECHANISM  OF ACTION  OF  ETHOSOMES

The mechanism of action of ethosomes implies synergistic effects of coalition of phospholipids and high concentration of ethanol suggested to be accountable for deeper distribution and incursion in the skin lipid bilayers. Permeation enhancers heightens the permeability of the skin so that drugs can transverse through the skin easily as it is shown in the form of flowchart in ‘Fig. 5’

 

Fig. 5                                                                                         

 

METHODS OF PREPARATION OF ETHOSOMES

Ethosomal preparation can be disposed by three very easy methods which are convenient, as described in ‘Fig. 6’ and do not require any advance equipment and are simple to scale up at industrial level.

The conventional methods used for the preparation of ethosomes:

·        Cold method

·        Hot method

·        Ether injection method

 

Fig. 6

APPLICATIONS OF ETHOSOMAL  FORMULATION

Ethosomes can be used for variety of purposes in drug delivery. They are primarily used as a replenishment of liposomes, principally the transdermal route of drug delivery is favoured. Ethosomes can be put upon for the transdermal delivery of hydrophilic and impermeable drugs via skin . Several drugs have been used with ethosomal carrier as depicted inTable 4, ethosomes are also used in the delivery of anti- viral drugs , in the topical delivery of DNA, for transcellular delivery and used as antineoplastic agents, steriodal agents antiasthmatic agents as well as cerebrovascular agent. Several other applications of ethosomes are described in ‘Fig. 7’.^18-32

 

Fig. 7

 

MARKETED FORMULATIONS OF   ETHOSOMES

Ethosome was fabricated and apparent by Prof. Elka Touitou at Hebrew University. Novel Therapeutic Technologies (NTT) of Hebrew University has been a achiever in fostering a variety of products to the market founded on ethosomes delivery system. Table 3 consists the list of marketed products of ethosomes.

 

 

 

Table 3 :List of marketed products of Ethosomes

S. No	PRODUCTS	APPLICATIONS	MANUFACTURER
1.	Cellutight EF	Topical cellulite cream, contains a powerful combination of ingredients to enhance metabolism and breakdown of the fat	Hampden Health, USA
2.	Decorin Cream	Anti aging cream, treating, repairing, and delaying the visible aging signs of the skin including wrinkle lines, sagging age spots, loss of elasticity, and hyperpigmentation	Genome Cosmetics, Pennsylvania, US
3.	Nanominox	First minoxidil containing product, which uses ethosomes. Contain 4% Minoxidil, well known hair growth promoter that must be metabolized by sulfation to the active compound	Sinere, Germany
4.	Noicellex	Topical anti – cellulite cream	Novel Therapeutic Technologies, Israel
5.	Skin genuity	Powerful cellulite buster, reduces orange peel	Physonics, Nottingham, UK
6.	Supravir Cream	For the treatment of herpes virus, formulation of acyclovir drug has a long shelf life with no stability problems, stable for at least three years, at 25C. Skin permeation experiments showed that the cream maintained its initial permeation enhancing properties even after three years	Trima, Israel

 

 

ETHOSOMES FOR TOPICAL USE

For the topical delivery of ethosomes certain active pharmaceutical ingredients has been which are used for topical delivery. Table 4 summarizes the list of ethosomes used for topical delivery.

 

 

Table4: List of Ethosomes used for topical delivery

S. No	Active Pharmaceutical ingredient	Medical condition	Dosage form	In Vivo/ Ex vivo release medium and time	Results
1.	AZELAIC ACID ETHOSOME	Acne	Ethosomal gel	Isotonic Palitzsch Buffer / Ethanol 70:30 (v/v) for 6 hours	Release rate was more rapid from ethosomal system than from liposomal system
2.	KETOPROFEN	Inflammation	Suspension	Phosphate Buffer Saline, pH 7.4 for 24 hours	Enhanced transdermal delivery
3.	VALSARTAN	Hypertension	Suspension	Ethanol: Phosphate saline , pH 7.4 for 24 hours	Nanoethosomal formulation potentially useful carrier for transdermal delivery. Enhancement of skin permeation and bioavailability of valsartan
4.	ALFUZOSIN HYDROCHLORIDE	Inflammation	Suspension	Phosphate buffer Saline pH 7.4 for 24 hours	Ethosomes are better Carriers for Alfuzosin hydrochloride transdermal delivery
5.	CICLOPIROX OLAMINE	Fungal infection	Suspension	Not reported	Enhanced accumulation of ciclopiroxoxolamine via ethosomal carrier within the skin might help to optimize targeting to the epidermal and dermal sites
6.	KETOCONAZOLE	Fungal infection	Suspension	Phosphate Buffer ,pH 7.4 with 1% sodium lauryl for 72 hours	Enhanced properties with increasing concentrations of ethanol and by subjecting vesicles for sonication
7.	FLUCONAZOLE	Fungal Infections	Ethosomal cream	Phosphate buffer Saline, pH 7.4 and 10% methanol for 72 hours	Better antifungal activity compared to marketed formulation
8.	DICLOFENAC	Inflammation , Benign prostatic hyperplasia	Suspension	Saline (Nacl 0.9%, w/v) for 24 hours	Diclofenac loaded Penetration enhancer containing vesicles, are capable of localizing the drug at site of inflammation as compared to conventional
9.	CURCUMIN	Inflammation	Solution	0.25% sodium dodecyl sulfate and 10% ethanol solution for 24 hours	Curcumin- Propylene glycol liposome had the best encapsulation efficiency and the highest and longest inhibition on paw edema , followed by ethosomes and Traditional liposomes
10.	AMMONIUM GLYCYRRHIZINATE	Inflammation	Suspension	pH7.4 isotonic phosphate- buffered solution for 24 hours	Prolongation of its therapeutic activity,Promising carrier for topical administration due to the enhanced delivery of drugs
11.	5-AMINOLEVULINIC ACID (ALA)	Inflammation	Suspension	pH 5 citrate-phosphate buffer for 12 hours	ALA containing ethosomes improved penetration of ALA and the formation of protoporphyrin IX and reduced tumor necrosis factor –a compared to ALA aqueous solution
12.	TRAMADOL HYDROCHLORIDE		Ethosomal Gel	Phosphate buffered saline, pH 7.4 for 12 hours	Optimum drug release and efficiency and non irritant on skin
13.	TRETINOIN	Acne	Suspension	Mixture of 0.01% M saline phosphate buffer, pH 7.4 and 0.1% PEG- 40  for 6 hours	Tretinoin-ultradeformable vesicles formulation proved to be suitable for dermal delivery
14.	KETOTIFEN	As mast cell stabilizer	Suspension	pH 7.4 isotonic phosphate buffer with 0.11% (w/v) formaldehyde for 24 hours	Ethosomes containing Ketotifen both inside and outside the vesicles exhibit superior skin deposition
15.	PACLITAXEL	Actinic keratoses		Water/Ethanol solution for 24 hours	Paclitaxel loaded ethosomes represent a promising topical drug delivery system for the clinical treatment of Actinic keratoses and squamous cell carcinoma.
16.	ERYTHROMYCIN ETHOSOME	Meliorate cellular uptake	_	_	Antimicrobial
17.	BACITRACIN ETHOSOME	Meliorate cellular uptake , increase bioavailability, and enhances dermal deposition and reduction in drug toxicity	_	_	Antibacterial
18.	TRIHEXYPHENIDYL HYDROCHLORIDE	Enhances bioavailability	_	_	Treatment of Parkinson’s disease
19.	CANNABIDOL	Enhance skin permeation	_	_	Treatment of Rheumatoid arthritis
20.	MINOXIDIL	Pilocebaceoustargeting , Accumulation in skin increased significantly	_	_	Treatment of baldness
21.	SALBUTAMOL	Enhanced drug delivery through skin with ethosome	_	_	Anti asthmatic
22.	CYCLOSPORIN- A	Improved bioavailability , betterment of skin deposition	_	_	Treatment of inflammatory skin
23.	TESTOSTERONE	Betterment of oral bioavailability , Reduced side effects	_	_	Steriodal hormone
24.	ANTI –HIV  AGENTS ( Lamivudine, Zidovudine)	Better cellular uptake, reduced drug toxicity. Improves transdermal flux, prolongs drug action,	_	_	Anti HIV

 

 

PATENTS ON ETHOSOMES

Ethosome was invented and patented by Prof.  Touitou Elka with her students of department of Pharmaceutics at the Hebrew University School of Pharmacy. Novel Therapeutic Technologies Inc (NTT) of Hebrew University has been succeeded in  delivering a number of products to the market based on ethosome delivery system. Noicellex™ an anti-cellulite containing pure grape seed extracts(antioxidant) is marketed in USA.

 

Similarly Physonics is marketing anti –cellulite gel skin Genuity in London. Nanominox© containing monoxidil is used as hair tonic to promote hair growth is marketed by Sinere.^51,52

 

In 1995 and 1996  Prof. Touitou Elka field first patent on  ethosomes titled composition for applying active substances to or through the skin US 5716638 and compositions for applying active substances to or through the skin US5540934 A, respectively. It included the transdermal passage of an active ingredient, or introduction of such agent into the skin.^53,54. Table 5 summarizes patents on ethosomes for drug delivery.

 

 

Table 5 : Patents on ethosome

 

 

ETHOSOMES  IN  LAST  15  YEARS

Ethosomes in last 15 years have been used assteroidal  agents,  used  in  herbal drugs , used  as anti diabetics , antiviral and antineoplastic agents . The topical delivery of antibiotics is a best choice for enhancing the therapeutic efficacy of these agents. Conventional oral therapy induces many allergic reactions along with various side effects . Conventional external preparations own less permeability to deep skin layers and subdermal tissues. Ethosomes can outwit this problem by delivering adequate quantity of antibiotic into deeper layers of skin. Ethosomes perforate rapidly through the epidermis and take appreciable quantity of drugs into the deeper layers of skin and restrain infection at their root. With this aim in mind Godin and Touitou developed bacitracin and erythromycin loaded ethosomal formulation for dermal and intercellular delivery. The results revealed that ethosomal formulation of antibiotic could be extremely effective and would get over the problems connected with conventional therapy. Several other uses of ethosomes are described  below in ‘Fig’. 8.^66-8

 

Fig. 8

 

FUTURE  PROSPECTS

Innovation  of  Ethosomes has  initiated a recent area in vesicular research for transdermal drug delivery. Ethosomes have also been shown up to display mellow encapsulation efficiency for a vast array of molecules embracing lipophilic drugs.⁸⁷There is a promising future of ethosomes in devising transdermal delivery of various agents more effectual. Further, research in this area will permit meliorate control over drug release in vivo, permitting physician to attain the therapy more effective. Ethosomes presents a beneficial chance for the non invasive delivery of small, medium and large sized drug molecules. The first clinical study of acyclovir ethosomal preparation accounts this conclusion. Multiliter quantities of ethosomal preparation can be formulated very easily. Therefore, it can be a coherent conclusion that ethosomal preparations own promising future in effective dermal transdermal delivery of bioactive agents.

 

CONCLUSION:

Ethosomes have been found as much more efficient at delivering drug to the skin, they have been tried to capsulize hydrophilic drugs, cationic drugs, proteins and peptides. Ethosomal carrier affords new challenges and opportunities for the evolution of novel improved therapies. Ethosomes acts as penetrating enhancer and more pervasion occurs in ethosomes than other transdermal vesicular drug delivery. An extended variety of active agents of different therapeutic functions were formulated into ethosomes in transdermal and dermal drug delivery system. Therefore, on the criteria of all these studies we concluded that ethosomes are the present and future of vesicle system in dermal and transdermal delivery of various drugs.

 

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Accepted on 30.06.2017        © RJPT All right reserved