Phytopharmaceutical delivery through skin: Recent updates on delivery by Vesicular carriers

 

Meena Kharwade¹, Sanjeevani Deshkar²*, Arati Halyali²_, Arun Satpute²

¹Anjuman-I-Islam Kalsekar Technical Campus, School of Pharmacy, New Panvel,

Navi Mumbai-410206, Maharashtra.

²Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune-411018, Maharashtra.

 

ABSTRACT:

Increasing the popularity of herbal medicines in the recent times has attracted the global market and expected to rise by more than 90% in next five years. Many herbal extracts and phytoconstituents having excellent proven in-vitro bioactivity, fail to demonstrate therapeutic action in vivo because of their poor lipid solubility, high molecular size or first pass metabolism. Traditional formulations of phytoconstitutents are primarily administered by oral route but unable to trounce the above confines resulting in low bioavailability and less patient adequacy due to frequent administration. Drug administration via topical route has gained the attention of the researcher because of ease of administration, local drug targeting, patient compliance, controlled drug delivery and bypassing first pass. Literature review indicated the use of nano vesicular systems based on phospholipids for the topical application of phytoconstituents. Mainly vesicular systems like, transferosomes, phytosomes, niosomes, ethosomes and cubosomes are reported for thriving delivery of drug phytoconstituents. These systems can augment the skin drug transport in a secure and proficient ways by drug partitioning into the skin, fusing the lipids in formulation with lipid in the stratum corneum and fluidizing skin lipids. Current review focuses on the major vesicular systems used for the formulations and their application in delivery of phytopharmaceuticals through skin.

 

 

 

INTRODUCTION:

Ayurveda is a 5000 years old medicinal system practiced in India and uses the plants for therapy. Herbalism utilize the parts of the plants either aerial or underground or permutation of both having phytoconstituents as the herbal medicine. The global market for herbal medicine size was estimated at 72 US billion dollars in 2016 indicating the massive use of herbal products and is expected to raise more than 90% till 2024. The innovations in technology are leading to upgradation of analysis, quality control and clinical research and the value of herbal medicine is on ascend in diagnosis and treatment of various diseases.

 

This mainstreaming of herbal medicines has led to less toxicity, low side effects, easy availability, effective though time consuming, and environment friendly with low cost compared to allopath. The single herbal plant, with multiple phytoconstituents like phenols, glycosides, alkaloids, resins etc. with diverse therapeutic activity, may be used to treat the various medical conditions. The herbal industry may show tremendous growth if the existing challenges for phytopharmaceutical like low lipid solubility (affect permeability), high molecular weight (affect passive diffusion and bioavailability), lack of regulation and improper dosing instructions are addressed.

 

Most of the phytopharmaceuticals are available as tablets, capsules, powders, teas, extracts, and fresh or dried plants, to be administered mainly by oral route of administration. The plant extracts, being in liquid form, have high bioavailability but are limited by stability problems. The solid orals like tablets and capsules are preferred over liquids because of patient compliance but fail to improve bioavailability^[1-3]. The novel drug delivery system, mainly nanoparticulate systems are nowadays in demand as they address and overcome the limitations of herbal drugs related to poor solubility and bioavailability^[4].

 

The striking and the most favored routes for the drugs are through skin and drug delivery systems are further classified into topical and transdermal depending on the rationale and target for drug delivery. Topical delivery system intends for the localized action of the drug on the organ applied i.e. skin to wield the actions like skin protectant, lubricant, emollient, drying agent etc, whereas transdermal drug delivery targets the drugs to systemic circulation by overcoming the skin barrier. This route is widely accepted owing to its advantages including controlled and targeted drug delivery, addresses the issues of first pass metabolism and low bioavailability of oral route, ease of application or termination of therapy, avoids peril or hassle related to intravenous therapy and covered almost two third of the body area making it very accessible^[5]. The human skin consists of broadly epidermis, dermis, and subcutaneous fat layer. Stratum corneum, the uppermost layer, serves as the major barrier of skin limiting both topical and transdermal bioavailability. In order to penetrate passively, a compound must cross the stratum corneum before diffusing across the viable epidermis; hence partition coefficient is important^[6]. Conventional topical formulations like creams, gels, ointments, patches etc.do not effectively provide penetration of drugs into the deeper skin for the skin problems like atopic dermititis, burns etc. These formulations also fail to demonstrate sustained or controlled drug release and permeation through skin for systemic effect.

 

In order to cross the natural diffusion barrier of the skin, the ideal drug entrant should be nonionic, molecular weight should be less than or equal to 500 Da, the partition co-efficient should be appropriate (range 1 to 4), have a small dose (less than 50 mg per day), should be non irritant to skin and should possess short half life. This limits the route to only certain drugs with these required characteristics^[7-9].

 

Need of vesicular system for topical or transdermal drug delivery system:

For transdermal and topical delivery of actives, various strategies had been investigated by the scientists, including modification of the stratum corneum, removal of stratum corneum, use of permeation enhancers etc. These methods have certain limitations or side effects e.g. use of permeation enhancers incite the structural changes in the stratum corneum leading to triggering of unwanted immune reactions such as irritation, allergy, or inflammation, metabolism of penetrated drugs etc^[10]. To increase the incursion of the drug molecules via skin, a range of micro and nano vesicular formulations are invented that attain the desired drug concentration into the skin layers for the effective topically or transdermal delivery of actives without any side effects^[11].

 

Nanotechnology has outstanding relevance in the field of dermal formulations. The nanocarrier systems are reported to achieve drug targeting and controlled release with reduced side effects. Vesicular nanocarrier is one of the promising strategies for topical and transdermal applications of drugs. Vesicular carriers like cubosomes, colloidosomes, ethosomes, aquasomes, niosomes, liposomes, transethosomes and phytosomes are preferably prepared from natural phospholipids which can be referred as the building blocks of cell membrane ^[12,13]. The phospholipids can be used as a natural digestive aid and serves as a carrier for lipidic as well as water miscible substances.

 

The phospholipid based nanovesicles are concentric layers made from the natural phospholipids entrapping the aqueous phase. The long-established phospholipid-based bilayer vesicles (liposomes), being natural and biocompatible (as composition similar to biomembrane) are safe and efficient drug carrier in dermal or systemic cure of diseases suitable for any kind of drugs i.e. hydrophilic as well as hydrophobic and due to penetration into the skin but not flexible enough to penetrate deep into the tissues^[14]. The vesicular system were first reported in 1965 by Bingham hence are known as “Bingham bodies” and play a foremost part in modelling biological membranes resulting in transport and targeting of active agents. Transferosmes, niosomes, cubosomes, ethosomes, phytosomes etc. are the modifications of the liposomes which are extensively researched and addresses the problems of low permeable drugs including phytoconstituents for both topical and transdermal administration. These vesicular systems are reported to achieve sustain effect, improve bioavailability by reducing the first pass metabolism, suitable for entrapment of hydrophilic or hydrophobic drugs and prolong the existence of drug by delaying drug metabolism.

 

Mode of action of vesicular systems for drug delivery via skin:

There are different pathways of vesicular systems that are reported for drug release and penetration via skin to achieve better therapeutic actions:

1.     Vesicles act as a carrier to control or sustain the release of drug. Further, the drugs will penetrate based on its physicochemical property. This can be further verified by comparing the study of trans epidermal flux data with the in vitro drug release profile of prepared liposome formulations.

2.     Vesicles penetrate the skin as having similar biocomposition by interrupting the packing characteristics of the stratum corneum (modify the ultrastructure of the intercellular lipid regions) and lowering the permeability barrier with the release of the drug simultaneously.

3.     Vesicle adhere to the skin, fuse with lipid matrix of the stratum corneum increasing the continuity of the lipid matrix hence facilitate the movement of lipophilic molecules. Phospholipids are responsible for increasing partition coefficient of drug towards stratum cornuem lipid bilayer. Based on this suggestion, we should expect improved drug uptake from a saturated aqueous solution after skin pre-treatment with empty vesicles.

4.     Intact vesicle can penetrate the ruptured stratum cornuem in certain diseases like eczema ^{[15, 16]}.

5.     This review article spotlights the literature available on the recent advances on nanovesicular system reported for increasing the penetration through skin, enhancing bioavailability, sustained/controlled effect and increasing the accumulation of phytoconstituents at the target site.

 

Transferosomes:

Transfersomes are ultra-deformable supramolecular concentric lipid vesicles having size ≤300nm loaded with active hydrophilic as well as hydrophobic substances, applied to the skin in form of aqueous formulation and can pass intact through skin. Transferosome consists of inner aqueous compartment surrounded by a phospholipid bilayer with high deformative and flexible property due to the amalgamation of edge activator (surfactant like sodium cholate, span 80, Tween 80, Span 60, Span 65, sodium deoxycholate, Tween 60 etc) into the vesicular membrane. The natural phospholipids like soya phosphatidylcholine, dipalmitoyl phosphatidylcholine are preferably used lipids in transfersomes than synthetic phospholipids due to toxicological aspects and cost. The amplification of deformation of the vesicle by the edge activator is due to weakening of lipid bilayer of the vesicles and decrease in interfacial tension. These deformable elastic vesicles are proficient to squeeze through intercellular province of the stratum corneum under the influence of a transepidermal water activity gradient. Upon application of transfersomes to the skin, the water from the formulation evaporates making vesicles deprived of water which further attracted them to the higher water content layers of the skin, resulting in spontaneous migration of the drug-loaded vesicles through the skin barrier. Others have suggested the various alternative mechanisms which are already mentioned in this review^[17,18]. After passage through stratum corneum, the vesicles regains the size and are distributed among the cells via intercellular route, gathered in the subcutaneous tissue by protecting the drug against the rapid clearance from cutaneous blood vessels augmenting the drug transmission time

 

and bioavailability. Due to the deformability property transfersomes are ideal system for the delivery of small to large sized hydrophilic or hydrophobic drugs so can easily overcome the prominent problems for the passive diffusion of herbal medicines like lipid solubility (affect permeability), low bioavailability, site specificity and high molecular weight^[19-21]. Table 1 summarizes the updated transferosomal work for herbal extract

 

Table 1: Topical or transdermal transferosomal formulation

Phytochemical	Biological activity	Purpose	References
Vincristine	Anticancer agent	Optimize permeation	22
Curcumin	Anti-inflammatory activity, antiwrinkle effect	Improved permeability and bioavailability	23
Capsaicin (Capsium)	Antiarthritic agent	Improved efficiency	24
Colchicine	Antigout	Increase skin penetration	4
Linoleic acid	Treatment of melasma	Optimize skin penetration	25
Ginsenosides (Red Gingsen)	Treat tumor, inflammation	Improve skin penetration	26,27

 

Phytosomes:

Phytoconstituents like phenolics, glycosides, flavonoids etc. are generally water-soluble. Their bioavailability and therapeutic effectiveness is restricted because of poor absorption when applied topically or taken orally. Phytosomes is made up from the term “phyto” means plant and “some” means cell- like and is a patented technology. The acclaim of development of ‘Phytosome®’ technology is fanatical to the Italian pharmaceutical and neutraceutical company ‘Indena’. Phytosomes are the biocompatible complex of phytoconstituents with phospholipids via hydrogen bonding which helps actives to get permeated via skin for superior efficiency or bioavailability when administered by topical or transdermal route in the nano size range [<100 nm]. Because of the amphiphilic heads of the phospholipids, they plays an effective emulsifiers as well as inclusion of the considered extract into an amphiphilic structure results in the self-aggregation of phospholipids, can dramatically enhance the bioavailability of poorly available phytoconstituents. The complex is formed generally in the molar ratio of 1:1 or 2:1 where one or two phosphatidyl choline molecules will be affixed to one drug molecule. This complex looks alike the cells and also known as herbasomes. The advantages of the phytosomes are; better pharmacokinetic and pharmacodynamic profile, better bioavailability, therapeutic efficiency, herbo-protectant, better stability than the conventional herbal products^[28-34]. The articles researched are listed in the Table 2.

 

Table 2: Topical or transdermal phytosomal formulation published and commercially available

Phytochemical	Biological activity	Purpose	References
Green tea (Chammomil)	Anti-inflammatory and phytoprotective	Improve skin penetration	35
Gingko biloba (Bilobalide)	Disorders associated with inflammatory or traumatic neuritic processes	Improvement in skin penetration	36,37
Poly herbal Phytocomplex- Trichosanthes cucumerina and Abrus precatorius aqueous extract	Hair growth promoter	Overcome the side effects of synthetic hair growth promoter	38
Diosmin (Phlebotonic flavonoid)	Treatment of colon and hepatocellular carcinoma.	Improved permeation and dissolution	39
Rutin	Anti-inflammatory	Improve skin penetration	40
Citrus auranticum and Glycyrrhiza glabra	Prevent Skin aging (as rich in polyphenols)	Improve skin penetration	41
18β-glycyrrhetinic acid,	Anti-inflammatory, Prevent Skin aging (as rich in polyphenols)	Increase permeability and efficiency, Skin whitener	42
Silibium marianum	Antiaging and skin protectant	Increase permeability and efficiency	43, 44, 45
Olive oil Phytosome	Antioxidant, anti‐ inflammatory, anti‐hyperlipidemic	Increase in efficiency
Ginkgo PhytosomeTM	Anti‐ skin ageing	Increase permeability and efficiency
OleaselectTM phytosome	Anti-inflammatory	Increase permeability and efficiency
Centella Phytosome	Veins and skin disorder	Collagen restructuring

 

Niosomes:

Niosomes are spherical-shaped bilayer (multilamellar or unilamellar) non-ionic surfactant based vesicles formed by self-assembling of hydrated surfactant monomers enclosing the aqueous phase. The non-ionic surfactants mainly used are sorbitans esters (Spans), ethoxylated esters (Tweens), and cholesterolin place of phospholipids, which are susceptible to heat and oxidative degradation, thus enhancing the stability of the formulations. The negative charge inducers like dicetyl phosphate, dihexadecyl phosphate lipoamine acid or positive charge inducers like sterylamine and cetylpyridinium chloride are used in order to avoid aggregation of the particles by inducing charges on the vesicles. They are responsible for entrapping both the types of drug i.e. hydrophilic and hydrophobic in aqueous phase and vesicular membrane respectively. The better stability, biocompatibility and degradability, lower cost, high purity, low toxicity, sustained or controlled release profile, targeting to the specific site, better skin permeability, by protecting the encapsulated drug and nonimmunogenic, makes it suitable as a substitute to liposomes in topical dosage forms. For phytoconstituents, niosomes may help to increase the lipid solubility, permeation and protective action for the herbal medicines in non-occlusive topical formulations ^[46-48]. The literature published on herbal niosomal formulations are listed in Table 3.

 

Table 3: Topical or transdermal niosomal formulation published and commercially available

Phytochemical	Biological activity	Purpose	References
Curcumin	Anti-inflammatory activity	Stability and prolonged drug release	49
Gallic acid (T Chebula galls)	Anti-aging	Stability and improved effectiveness	50
Neem seed oil	Antibacterial, antiviral, antifungal, antiseptic, and antiparasitic	Improved effectiveness	51
Rice bran bioactive	Anti ageing effect	Skin lightening, superior anti-aging activity	52
Black tea extract	Sunscreen agent	Improved skin penetration	53
Marigold extract	Cytotoxicity, wound healing and antioxidant activity	Improved permeability and bioavailability	54
Myrtus communis (Myrtle)	Antiseptic and disinfectant	Superior antiseptic and antibacterial activity	55

 

Cubosomes:

The term ‘Cubosomes’ is derived from the term ‘phases’ referred as ‘some’ and having cubic crystal lattice. Cubosomes are the nanosized, self assembled, bicontinuous, optically isotropic cubic lattice with three-dimensional honeycomb resembled structures composed of amphiphilic monoglyceride lipids. The term bicontinuous is used because of the presence of two continuous but non-intersecting aqueous region with the surfactant-controlled lipid bilayer in between. Cubosome is the thermodynamically stable, visually clear and viscous system with the square or round shaped particles with internal visible cubic lattices. A optimized ratio of water, amphiphilic lipid, and active moiety instinctively engender the cubosomes which can be the better option for administration via transdermal drug delivery. The key advantages of the cubosomes can be listed as high internal surface area with high entrapment efficiency, simple preparation process, use of biocompatible and biodegradable lipids, the aptitude to incorporate any kind of drug and prolonged or controlled drug delivery. The main components are the amphiphilic lipids which upon hydration results in liquid crystalline phases, stabilizer prevents the reconstitution to bulk cubic phase, and water for hydration. Cubosomes have a considerable viscosity, improved storing stability, less drug leakage possibility and superior fortitude of heat treatment with respect to liposomes^[56-60]. The literature review of cubosomes for herbal drug delivery is listed in Table 4.

 

Table 4: Topical or transdermal cubosomal formulation

Phytochemical	Biological activity	Purpose	References
Curcumin	Anti bacterial activity	Improved stability and antibacterial activity	61
Capsaicin	Treatment of psoriasis, pruritus, apocrine chromhidrosis, and Contact allergy	Improved skin penetration and reduced systemic drug delivery	62,63,64
Hinokitiol	Hair growth promotion agent	Optimize dermal drug delivery	65
Korean barberry	Inflammatory disorders, skin diseases, wound healing	Optimise skin permeation	66
KIOM-MA-128 (ma-128)	Atopic dermitatis	Improved skin permeation	67
Herbal extracts (Poria cocos, Thuja orientalis, espinosilla, lyceum chinense mill, Coix lacryma-jobi and Polygonum multiflorum thumb.)	Hair growth promoter	Enhanced skin permeation	68

 

Ethosomes:

Ethosomes are elastic nano-vesicles made up of biocompatible and biodegradable phospholipids having high content of ethanol [20%-70%] and used to improved skin delivery for both hydrophilic and lipophilic drugs. The ethosomes have attracted the researcher for the drug delivery is because of simple method to prepare, high elasticity to permeate through the skin, soft, high entrapment efficiency, offer effectual delivery in occlusive as well as nonocclusive conditions. Use of high amount of ethanol furnish a negative surface charge resulting the self aggregation of the vesicles due to electrostatic repulsion, increases fluidity, stability, mechanical endurance, high entrapment efficiency and boost skin permeation because of disturbance of skin lipid bilayer of stratum corneum, making it suitable for skin delivery. In recent times, ethosomes are considered as novel promising vesicular systems for the delivery of herbal product and drug.^[69-74]. Table 5 is the compiled literature review of ethosomes for herbal drug delivery for herbal drugs.

 

Table 5: Topical or transdermal ethosomal formulation

Phytochemical	Biological activity	Purpose	References
Ammonium Glycyrrhizinate	Anti inflammatory	Increase of the in vitro percutaneous Permeation	75
Matrine	Anti inflammatory	Improved percutaneous absorption	76
Curcuminoids	Anti wrinkled effect	Enhanced penetration	77
Ligustrazine	Angina pectoris	Improved absorption and increased bioavailability	78
Curcumin,	Anti-inflammatory	Entrapment efficiency, And sustained-release behavior	79
Naringenin	Anti-inflammatory, antioxidant	Optimize skin penetration	80
Seabuck thorn Leaf Extract	Antioxidant	Improvement in skin penetration and bioavailability	81
Cryptotanshinone	Acne treatment	Improve skin penetration	82
Berberis aristata extract	Dermatological disorder	Enhanced skin permeation	83
Sesamum indicum L. seed extract	Anti-pyretic, anti-inflammatory, antioxidant, antimicrobial, anti-hypertensive, anticancer, wound healing activity	Better stability and skin penetration	84
Linoleic acid	Treatment of melasma	Optimize skin penetration	25
Ginsenosides (Red gingsen)	Treat tumor, inflammation	Improve skin penetration	26

 

Pharmacosomes:

Pharmacosome is a nano size vesicular system made up from the words i.e. “Pharmakon” and “soma” means drug and carrier respectively. These lipid conjugated vesicles possessing both positive and negative charge may exist as colloidal, micelles, vesicles or may be in the form of hexagonal assembly enjoying a functional hydrogen atom in the active moiety banking upon the architecture of the phospholipid complex. Hydration of the prodrug results in the formation of pharmacosomes. The main application of the pharmacosomes are optimized entrapment efficiency, can incorporate hydrophilic as well as lipophilic drugs, improved stability, greater shelf life, low side effects, improved bioavailability, aptness for poorly soluble drugs, controlled targeted release, cost effectiveness. The drug molecule with functional hydrogen is renewed to an ester upon reacting with the hydroxyl moiety of the lipid thus act as a prodrug having hydrophilic and lipophilic properties. This moiety may reduce the interfacial tension, high area of contact and improve bioavailability by extradition through the cell barriers. The release of the drug from pharmacosomes is hydrolysis based, which includes enzymatic hydrolysis also. After absorption, their rate of degradation relies on the size, nature of functional group, fatty acid chain length, and presence or absence of spacer chain^[85-86]. This novel drug delivery can be explored in future for the herbal drug delivery system

 

CONCLUSION:

Herbal medicines have globally accepted for its better therapeutic value, fewer adverse effects as compared to modern medicines. Exploring nano vesicular system to conquer the challenges for the delivery of phytoconstituents is having the great future provided the development in the regulatory requirement of herbal products. Alliance of contemporary know-how with herbal drugs will direct to optimize the bioavailability and solubility, abridged toxicity, release the drug in controlled and sustained way, efficiency with dose diminution. The novel vesicular herbal drug delivery system will definitely augment the market of herbal drugs by offering superior and successful therapy to the global population.

 

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Received on 07.09.2019           Modified on 13.10.2019

Accepted on 18.11.2019         © RJPT All right reserved