Carriers/Vesicle based approaches for penetration enhancement in transdermal drug delivery system
Skin is an important site of drug application for both local and systemic effects. For transdermal delivery of drugs, stratum corneum (SC) is the main barrier for permeation of drug. So to circumvent the SC, different approaches of penetration enhancement are used. Carriers/vesicles such as liposomes, niosomes, ethosomes, microemulsions, complexes, prodrugs provide better alternative method to enhance permeation of drugs through skin. The review presents mainly the routes of penetration through skin and carrier/vehicle based approaches with emphasize on their potential mechanism of action for penetration enhancement in transdermal delivery system.
KeyWords: Transdermal drug delivery, liposomes, ethosomes, niosomes, microemulsions, prodrugs
The skin, our body's largest organ, is generally considered as an impermeable protective barrier against mechanical, chemical, microbial and physical hazards and has four distinct layers of tissue: non viable epidermis i.e. stratum corneum (SC), viable epidermis, viable dermis, subcutaneous connective tissue (hypo-dermis). The success of a dermatological drug to be used for systemic drug delivery depends on the ability of the drug to penetrate through skin in sufficient quantities to achieve the desired effect1. Out of the four layers of the epidermis, it is mainly the uppermost layer (horny layer; SC), which forms the permeability barrier. The efficacy of topically applied actives is often suboptimal because the transport into the skin is slow due to the resistance of the SC2.
Routes of penetration:
There are two diffusion routes for a molecule to penetrate normal intact human skin: the appendageal route and the transepidermal route. The appendageal route seems to be most important for ions and large polar molecules and the transepidermal route is for the unionized molecules which can cross the intact layer3. For a molecule to be delivered into the skin it needs to have adequate lipophilicity and optimum molecular weight. Hydrophilic drugs partition preferentially into the intracellular domains, whereas lipophilic permeants (octanol/water log K > 2) traverse the SC via the intercellular route. Most of the molecules pass the stratum corneum by both routes. But the perfect barrier properties of the epidermis restrict the transport of various drug molecules through the skin4. To avoid these difficulties in permeation through SC, carriers\vesicles can be used as penetration enhancers for circumventing the SC barrier.
Penetration enhancement with special formulation approaches is mainly based on the usage of colloidal carriers. Such carriers include microemulsions, liposomes, ethosomes, complexes, niosomes and prodrugs. These carriers accumulate in stratum corneum or other upper skin layers. Generally, these colloidal carriers are not expected to penetrate into viable skin5-7. Mechanism of action of different carriers is represented in Figure 1.
Microemulsions are isotropic, thermodynamically stable solutions in which substantial amounts of two immiscible liquids (i.e. water and oil) are brought into a single phase by means of an appropriate surfactant or surfactant mixture8. Hydrophilic surfactants produce oil-in-water (O/W) microemulsions, whereas lipophilic surfactants produce water-in-oil (W/O) microemulsions9. Microemulsions offer several advantages for pharmaceutical use, such as ease of preparation, long-term stability, high solubilization capacity for hydrophilic and lipophilic drugs, and improved drug delivery10. The methods for preparation of microemulsions are classified as single surfactant systems and temperature-insensitive microemulsions. Single surfactant systems include single nonionic surfactant systems and single ionic surfactant systems11 and temperature-insensitive microemulsions include three phase behaviour in mixed surfactant system12-14 like mixture of polyoxyethylene-type non-ionic surfactants, mixture of ionic-nonionic or ionic-ionic surfactant and mixture of sucrose monoalkanoate and polyoxyethylene-type non-ionic surfactants15-16.
Mechanism of skin penetration of microemulsions:
Penetration enhancement from microemulsions is mainly due to an increase in drug concentration which provides a large concentration gradient from the vehicle to the skin. Furthermore it has been suggested that the surfactants and the oil from the microemulsion interact with the rigid lipid bilayer structure and acts as a chemical enhancer17. The microemulsions can interact with the SC by changing structural rearrangement of its lipid layers and consequently increasing transdermal drug permeation and so act as penetration enhancer18. This mechanism can be comparable with saturated and unsaturated fatty acids serving as an oil phase. Other permeation enhancers commonly used in transdermal formulations are oleic acid, isopropyl myristate, isopropyl palmitate, triacetin, isostearylic isostearate, and medium chain triglycerides19.
Applications of microemulsions in transdermal drug delivery system (TDDS):
Chandra et al used microemulsion-based hydrogel formulation for transdermal delivery of dexamethasone20. The optimum formulation consists of various vegetable oils as oil phase, egg lecithin as the surfactant, isopropyl alcohol (IPA) as the co-surfactant, and distilled water as the aqueous phase. The microemulsion-based system was chosen due to its good solubilizing capacity and skin permeation capabilities. Reservoir-type transdermal system was prepared using microemulsion based system. The release studies indicated increased permeation rate with microemulsions in transdermal patch as compared without microemulsions. The pharmacodynamic studies indicated that microemulsion based on nutmeg oil demonstrated a significantly higher anti-inflammatory potential. So it has been concluded from this study that microemulsion-based transdermal systems may be used as permeation enhancers for dermal application of dexamethasone.
Liposomes are colloidal particles formed as concentric bimolecular layers that are capable of encapsulating drugs. They are lipid vesicles that fully enclose an aqueous volume. These lipid molecules are usually phospholipids with or without some additives21. Cholesterol may be included to improve bilayer characteristics of liposomes; increasing micro viscosity of the bilayer, reducing permeability of the membrane to water soluble molecules, stabilizing the membrane and increasing rigidity of the vesicle. There are three types of liposomes- MLV (multilamillar vesicles), SUV (small unilamillar vesicles) and LUV (large unilamillar vesicles) 22. Liposomes have already been used to deliver various Anti-cancer drugs such as Doxorubicin, Daunorubicin and Camptothecin.
Method of preparation of liposomes:
The methods of preparation have been classified to 3 basic modes of dispersions - Physical dispersion involving hand shaking and non hand shaking methods23, solvent dispersion involving ethanol injection, ether injection, double vesicle method, reverse phase evaporation vesicle method and stable plurilamellar vesicle method and detergent solublization. Various types of liposomes such as small unilamellar liposomes are prepared by solvent injection, film rehydration extrusion and detergent dialysis method, while multilamellar vesicles are prepared by ether vaporization, thin film hydration and freeze-thaw method. Such methods have also been used for encapsulating drugs, proteins, nucleic acids and other biochemical reagents.
Mechanism of skin permeation of liposomes:
Liposomes can be used as carriers for hydrophilic as well as lipophilic therapeutic agents because of their amphipathic character. They may improve stabilization of unstable drugs by encapsulating them and serve as penetration enhancers facilitating the transport of compounds that otherwise cannot penetrate the skin24. Liposome have higher diffusivity in skin, high biocompatibility, longer release time, greater stability, improved penetration and diffusion properties and controlled degradation. Liposomes may also act as permeation enhancers by penetration of individual lipid components as phospholipids are able to diffuse into the SC. The interactions and enhancer effects of liposomes on the SC are based on the lipid mixing of liposomal phospholipids with lipid bilayers of the skin25. Phospholipids in liposomal systems can disrupt the bilayer fluidity in the SC, decreasing the barrier properties of the skin. Moreover, some investigators report that phospholipids in liposomes may mix with the SC lipids creating a lipid-enriched environment26. This lipid depot in the skin is preferred by lipophilic drugs, resulting in enhanced skin uptake. Liposome penetration into skin depends greatly on lipid composition, the thermodynamic state of the bilayers and presence of ethanol in the formulation. The key for liposome penetration into skin is the liquid or gel state of the vesicles.
Applications of liposomes in TDDS:
Liposomes in transdermal drug delivery enhance skin permeation of drugs with high molecular weight and poor water solubility27. Liposome has already been used as a carrier for delivery of drugs, such as gentamicin in order to reduce toxicity28. This carrier system has also been used for possible drug delivery to the lungs by nebulisation, for ocular drug delivery and in the treatment of parasitic infections29-30.
These are liposomes with high alcohol content capable of enhancing penetration to deep tissues and the systemic circulation31-33. It is proposed that alcohol fluidizes the ethosomal lipids and SC bilayer lipids thus allowing the soft, malleable ethosomes to penetrate.
Method of preparation of ethosomes:
Ethosomal formulation may be prepared by hot or cold method as described below. Both the methods are convenient, do not require any sophisticated equipment and are easy to scale up at industrial level.
In this method, phospholipids, drug and other lipid materials dissolved in ethanol in a covered vessel (room temperature), vigorous stirring is done with the use of mixer. Propylene glycol or other polyol is added during stirring. The mixture is heated to 30degC in a water bath; water is heated to 30 degC in a separate vessel and added to the mixture then stirred for 5 min in a covered vessel. Vesicle size of ethosomal formulation is decreased to desire extent using sonication or extrusion method34-35. The formulation is stored under refrigeration36.
In this method, phospholipid is dispersed in water, heated in a water bath at 40degC until a colloidal solution is obtained and then ethanol and propylene glycol are mixed and heated to 40 degC in a separate vessel. Once both mixtures reach 40 degC, the organic phase is added to the aqueous one. The drug is dissolved in water or ethanol depending on its hydrophilic/hydrophobic properties37. The vesicle size of ethosomal formulation decreased to the desire extent using probe sonication or extrusion method.
Mechanism of skin permeation of ethosomes:
Ethosomal formulations contain ethanol in their composition that interacts with lipid molecules in the polar head group regions resulting in an increased fluidity of the SC lipids. The high alcohol content is also expected to partial extract the SC lipids.This increases inter and intracellular permeability of ethosomes. The ethanol imparts flexibility to the ethosomal membrane that, facilitate their skin permeation. The interdigitated, malleable ethosome vesicles can forge paths in the disordered SC, release drug in the deep layers of skin. The transdermal absorption of drugs results from fusion of ethosomes with skin lipids38-39.
Applications of ethosomes in TDDS:
Oral administration of hormones is associated with problems like high first pass metabolism, low oral bioavailability and several dose dependent side effects. Touitou et al. compared the skin permeation potential of testosterone ethosomes (Testosome) across rabbit pinna skin with marketed transdermal patch of testosterone (Testoderm patch, Alza) 40. They observed nearly 30-times higher skin permeation of testosterone from ethosomal formulation as compared to that marketed formulation. The amount of drug deposited was significantly (p <0.05) higher in case of ethosomal formulation The AUC and Cmax of testosterone significantly improved after application of Testosome as compared to Testoderm. Hence, both in vitro and in vivo studies demonstrated improved skin permeation and bioavailability of testosterone from ethosomal formulation. This group in their further study designs the testosterone non-patch formulation to reduce the area of application41. They have found that with ethosomal testosterone formulation area of application required to produce the effective plasma concentration was 10 times less than required by commercially gel (AndroGel) formulation.
Complexation of drugs with cyclodextrins has been used to enhance aqueous solubility and drug stability. Cyclodextrins are natural cyclic oligosaccharides that were discovered > 100 years ago, but only some years ago did highly purified cyclodextrins become available as pharmaceutical excipients. They are cyclic oligosaccharides containing at least 6 D-(+) glucopyranose units attached by a-(1, 4) glucosidic bonds42. Due to the chair formation of the glucopyranose units, cyclodextrin molecules are shaped like cones with secondary hydroxy groups extending from the wider edge and the primary groups from the narrow edge. This gives cyclodextrin molecules a hydrophilic outer surface, whereas the lipophilicity of their central cavity is comparable to an aqueous ethanolic solution43. The most common natural cyclodextrins consist of six (a-cyclodextrin), seven (v-cyclodextrin) and eight (g-cyclodextrin) glucopyranose units. Because of their structure and physico-chemical properties, cyclodextrins as drug carriers have number of advantages like they provide a number of potential sites for chemical modification44-45, they are available with different cavity sizes which makes it possible to entrap drugs of different molecular dimensions, the microenvironment in their cavity is relatively non-polar and lipophilic, they possess low toxicity and low pharmacological activity, they have a good aqueous solubility, they are rather resistant to hydrolysis by organic acids and many common alpha amylases, and completely resistant to yeast fermentation and beta amylases, they are not decomposed by hot alkali, exhibit a high thermal stability, with a decomposition temperature approaching 300 degC, they protect the included /conjugated drugs from biodegradation, they can be used as process aids to remove specific components from a mixture or minerals.
Mechanism of skin permeation of cyclodextrins:
Cyclodextrins enhance drug delivery through aqueous diffusion layers, but not through lipophilic barriers such as the SC. If the drug release is from an aqueous-based vehicle or if an aqueous diffusion layer at the outer surface of the skin is a rate-determining factor in dermal drug delivery, then cyclodextrins can act as penetration enhancers. However, if drug penetration through the lipophilic SC is the main rate-determining factor then cyclodextrins are unable to enhance the delivery46. Cyclodextrins, by enhancing apparent drug solubility, enhance the drug thermodynamic activity in vehicles and thus cause enhancement of drug release from vehicles. The enhancement of drug release from vehicles by cyclodextrins in turn enhances the dermal drug absorption by improving the drug availability at the lipophilic absorptive barrier surface (i.e. skin) 47-48. Although the drug partition coefficient of lipophilic drug may be decreased on complexation with hydrophilic cyclodextrins, the increased drug solubility and thermodynamic activity in vehicles can lead to increased drug permeability through skin. This is exemplified by increased skin permeability of dexamethasone by HP-v-CD49-50. The vehicle type used, because of its main influence on the drug's membrane/vehicle partition coefficient, can markedly affect cyclodextrin-induced enhancement of drug release. Cyclodextrins to be used as excipients in transdermal drug delivery system should possess the following characteristics: they should be therapeutically inert, should not interfere with the normal functions of the skin such as protection from heat, humidity, radiation and other potential insults, should not alter the pH of the skin, should not interact with any component of the skin and should not cause skin irritation.
Applications of cyclodextrins in TDDS:
In transdermal drug delivery system, hydrophilic, hydrophobic as well as ionizable cyclodextrins have already been used as carriers for drugs. Hydrophilic cyclodextrins like 2,6 dimethyl-v-CD and hydroxypropyl-v-CD have been used to improve the solubility and dissolution characteristics of insoluble drugs. Hydrophobic cyclodextrins such as 2,6 diethyl- v-CD have been used to retard the dissolution rate of water soluble drugs and ionizable CDs like carboxymethyl-v-CD, sulfated and sulfobutylether-v-CD have been used to improve inclusion capacity and reduce side effects associated with drugs. The drugs which have been complexed with cyclodextrins successfully in dermal preparation help to minimize systemic side effects, improve patient compliance for long term therapy and increase solubility51.
Niosomes are nonionic surfactant self-assembled vesicles that presents a structure similar to liposome and hence they can represent alternative vesicular systems with respect to liposomes, due to the niosome ability to encapsulate different type of drugs within their multi environmental structure52. The first application of niosomes was the cosmetic field followed by their use as drug delivery systems53. The main components used in preparation of niosomes are nonionic surfactants. Different types of self-assembling nonionic surfactant were proposed as starting material to prepare niosomes (i.e., the SPAN and the Brij series). The type of surfactant can influence the stability of the vesicular system being able to influence the fluidity of bilayer structures. In particular, the nonionic surfactant can influence the leakiness of the entrapped drug from niosomes with the following increasing order, SPAN80<SPAN20<SPAN40< SPAN60. High niosomal concentration of soluble surfactant agents can influence the solubility of this vesicular colloidal carrier and determine the formation of micelles or complex aggregates. This phenomenon is observed with the presence of actylglucoside in the niosome formulation. This compound can destabilize the niosome bilayer and start a micellization phenomenon. Another fundamental component for the preparation of niosomes is cholesterol. This molecule is used as an additive compound both to reduce the temperature of the vesicular gel to the liquid-crystal phase transition and to decrease the overall HLB value of the surfactant mixture used for the preparation54-55. Thus, cholesterol allows a more efficient aggregation of the nonionic surfactant component into a closed bilayer structure, and then a higher stability of the niosomal vesicles. The inclusion of cholesterol into niosomal formulation can reduce the leakiness of the membrane. A 1:1 molar ratio of cholesterol and nonionic surfactant is generally used for niosome preparation. A parameter that should be taken into account in the choice of the niosome component is the physicochemical property of the encapsulated drug, due to a series of possible interactions occurring with the nonionic surfactant component leading to the formation of homogeneous dispersion or aggregate structure.
Methods of niosome preparation:
Niosomes are prepared through the hydration of a mixture of nonionic surfactant-helper lipid (cholesterol) (1:1 molar ratio) at a temperature ranging from 40 to 70degC followed by a suitable sizing process to obtain the required colloidal dispersion characteristics. The methods used to reduce the niosome mean size and to achieve a homogenous size distribution are similar to those used for liposomes, that is, extrusion through decreasing pore size polycarbonate filters, cycles of sonication, and high pressure homogenization56. Similarly to liposomes, the mean size of niosome formulations is very important to reduce the reticular endothelial system uptake. In addition, other specific preparation methods have been developed for niosomes. Organic solution (ether) of surfactant and cholesterol is injected in a drug aqueous solution and this mixture is heated above the boiling point of the organic solvent leading to formation of an o/w emulsion between a drug aqueous solution and an organic solution of surfactant-cholesterol. Then, the organic phase is evaporated off and an aqueous niosomal colloidal dispersion is obtained.
Mechanism of skin penetration of niosomes:
Niosomal formulations can increase the amount of drug permeated through the SC57, even if the exact mechanism involved in the drug and/or carrier passage has to be investigated and elucidated in a more detailed way. A hypothetical mechanism of skin penetration is related to a possible reorganization of the niosomal membrane at the level of the SC58. In vitro data showed an efficacious transdermal delivery of oestradiol when it was entrapped in C18EO7 and C12EO7 niosomes. The improved drug passage through the outer skin layer seems to be mediated by the high flexibility of the bilayer structure of some niosomal formulations. Similarly, a niosomal formulation made-up of glyceryl dilaurates (C16EO7) and cholesterol also increased the passage through the SC and the penetration of cyclosporine A into the inner layer of the skin. Then, niosome can be used as a TDDS for both hydrophobic and hydrophilic drugs.
Applications of niosomes in TDDS:
Niosomes seems an interesting drug delivery system in the treatment of dermatological disorders. Niosomes have aiso been used in cosmetics and for delivery of peptide drugs. In fact, topically applied niosomes can increase the residence time of drugs in the SC and epidermis, while reducing the systemic absorption of the drug. They are thought to improve the horny layer properties; both by reducing transepidermal water loss and by increasing smoothness via replenishing lost skin lipids59. Thus niosomes are able to act as penetration enhancers.
The term prodrug refers to a pharmacologically inactive compound that is converted to an active drug by a metabolic biotransformation which may occur prior, during and after absorption or at specific target sites within the body60. According to IUPAC (International Union of pure and applied chemistry), prodrug is defined as any compound that undergoes biotransformation before exhibiting its pharmacological effects. In recent years numerous prodrugs have been designed and developed to overcome barriers to drug utilization such as low oral absorption properties, lack of site specificity, chemical instability, toxicity, bad taste, bad odor, pain at application site61. Prodrug has been classified into two types: carrier linked prodrug and bioprecursor. In carrier linked prodrug, the active drug is covalently linked to an inert carrier or transport moiety such as ester and amides. The active drug is released by hydrolytic cleavage either chemically or enzymatically. In bioprecursor, chemical modification of active drug is done but they do not contain a carrier. Such type of prodrug is bioactivated generally by redox biotransformation62-63. These prodrugs have been found to improve patient acceptability, alter or improve absorption, alter biodistribution, metabolism and elimination.
Mechanism of skin permeation of prodrugs:
The prodrug approach has been investigated to enhance dermal and transdermal delivery of drugs with unfavorable partition coefficients64. The factors to be considered which control the penetration kinetics across the skin are the oil-water partition coefficient, lipid solubility, aqueous solubility, molecular size and shape. The prodrug design strategy generally involves addition of a pro-moiety to increase partition coefficient and solubility to increase the transport of the drug in the SC. Upon reaching the viable epidermis, esterases release the active drug by hydrolysis, thereby optimizing concentration in the epidermis. The intrinsic poor permeability of the very polar 6-mercaptopurine was increased up to 240 times using S-6- acyloxymethyl and 9- dialkylaminomethyl promoieties65 and that of 5-fluorouracil, a polar drug with reasonable skin permeability was increased up to 25 times by forming N-acyl derivatives66-70.
Applications of prodrugs in TDDS:
Prodrugs can enhance dermal/transdermal drug delivery via different ways, including increased skin partitioning, increased aqueous solubility, and reduced crystallization. It is also necessary to take care that the delivery system must contain maximum quantity of drug for optimum therapeutic efficacy. Thus the modification of basic drug molecules by chemical methods may improves the physicochemical and biological properties such as patition-coefficient, solubility, pH, absorption, distribution, and ultimately metabolism. The prodrug approach has also been investigated for increasing skin permeability of nonsteroidal anti-inflammatory drugs nalbuphine71-74. Well established commercial preparations using this approach include steroid esters (e.g. betamethasone-17-valerate), which provide greater topical anti-inflammatory activity than the parent steroids.
The skin has an extremely good barrier functions. The understanding of the barrier architecture and the mechanisms of penetration has now improved. At present the research in this area is actively concentrated. However, a detailed knowledge of the mode of action is necessary in order to assess the full potential of vesicle. Carrier/vesicle based approaches of penetration enhancement technique do compromise skin barrier function by circumventing the SC; hence it can serve as the better alternative. These approaches help in the development of novel TDDS. The safe and effective drug delivery is the ultimate target for every new approaches ever explored.
- Kanikkannan N, Kandimalla K, Lamba SS, Singh M. Structure activity relationship of chemical penetration enhancers in transdermal drug delivery, Current Med. l Chem 1999, 6, 593-608.
- Elias PM. Epidermal lipids, barrier function, and desquamation, J Invest Dermatol 1983, 80, 44-49.
- Williams AC, Barry BW. Skin absorption enhancers. Critical Reviews in Therapeutic Drug Carrier Systems 1992, 9, 305-353.
- Fartasch M, Bassukas ID, Dipegen TL. Structural relationship between epidermal lipid lamellae, lamellar bodies and desmosomes in human epidermis: An ultra structural study, Br J Dermatol 1993, 128, 1-9.
- Chein YW, Lee CS. Transdermal Drug Delivery System with Enhanced skin permeability. In Ping IL, William RG, editors. Controlled Released Technology Pharmaceutical Application. Washington DC, American Chemical Society; 1987, 81-299.
- Brain KR, Walters KA, Watkinson AC. Methods for studying percutaneous absorption. In: Walters KA, editor. Dermatological and transdermal formulations, New York, Marcel Dekker Inc, 2002, 241-247.
- Ranade V. Drug delivery systems: Transdermal drug delivery, Clinical Pharmacol 1991, 31(6), 401-408.
- Safran SA, Tlusty T. Curvature elasticity models of microemulsions, Ber Bunsenges Phys Chem 1996, 100, 252-263.
- Solans C, Garcia CMJ. Surfactants for microemulsions, Curr Opin Colloid Interface Sci, 1997, 2, 464-471.
- Heuschkel S, Goebel A, Neubert RHH. Microemulsions - modern colloidal carrier for dermal and transdermal drug delivery, J Pharm Sci 2008, 97(2), 603-631.
- Winsor PA. Solvent properties of amphiphilic compounds, Butterworths Scientific Publications, London. 1954, 68-71.
- Kunieda H, Sato Y. In: Organised Solutions, Friberg SE, Lindman B. (Eds.), Marcel Dekker, New York, 1992, 67.
- Kunieda H, Yamagata M. Three phase behaviour in a mixed nonionic surfactant system, Colloid and polymer Science 1993, 271(10), 997-1004.
- Kunieda H, Nakano A, Akimaru M. The effect of mixing of surfactants on solubilization in a microemulsion system, J Colloid Interface Sci 1995, 170, 78-84.
- Kunieda H, Ushio A, Nakano A, Miura M. Three phase behaviour in a mixed sucrose alkanoate and polyethylene glycol alkyl ether system, J Colloid Interface Sci 1993, 159, 37-44.
- Pes MA, Aramaki K, Nakamura N. Temperature insensitive microemulsions in a sucrose monoalkanoate system, J Colloid Interface Sci 1997, 191, 34-39.
- Schmalfuss U, Neubert R, Wohlrab W. Modification of drug penetration into human skin using microemulsions, J Control Release 1997, 46, 279-285.
- Friberg SE. Micelles, microemulsions, liquid crystals, and the structure of stratum corneum lipids, J Soc Cosmet Chem 1990, 41, 155-171.
- Kogan A, Garti N. Advances in colloid and interface science, 2006, 123-126, 369- 385.
- Chandra A, Sharma PK, Irchhiaya R. Microemulsion-based hydrogel formulation for transdermal delivery of dexamethasone, Asian J Pharm 2009, 3, 30-36.
- Vyas SP, Khar RK. Controlled drug delivery system, Vallabh prakashan. 1st ed. 2005, 417-426.
- Barani H, Montazer M. A Review on Applications of Liposomes in Textile Processing, J Liposome Res 2008, 18 (3), 249-262.
- Mayer LD, Hope MJ, Cullis PR, Janoff AS. Solute distributions and trapping efficiencies observed in freeze thawed multilamellar vesicles, BiochimBiophys Acta 1985, 817,193-196.
- De Leeuw J, De Vijlder HC, Bjerring P, Neumann HA. Liposomes in dermatology today, J Eur Acad Dermat Venereol 2009, 23(5), 509-516.
- Kirjavainen M, Monkkonen J, Saukkosaari M, Valjakka- Koskela R, Kiesvaara J, Urtti A. Phospholipids affect stratum corneum lipid bilayer fluidity and drug partitioning into the bilayers, J Control Release 1999, 58, 207-214.
- Valenta C, Wanka M, Heidlas J. Evaluation of novel soya lecithin formulations for dermal use containing Ketoprofen as a model drug, J Control Release 2000, 63, 165-173.
- Qiu Y, Gao Y, Hu K, Li F. Enhancement of skin permeation of docetaxel: a novel approach combining microneedle and elastic liposomes, J Control Release 2008, 129, 144-150.
- Jia Y, Joly H, Omri H. Liposomes as a carrier for gentamicin delivery: development and evaluation of the physicochemical properties, Int J Pharm 2008, 359, 254-263.
- Zaru M, Mourtas S, Klepetsanis P, Fadda AM, Antimisiaris SG. Liposomes for drug delivery to the lungs by nebulisation, Eur J Pharm Biopharm 2007, 67, 655-666.
- Budai L, Hajdu M, Budai M, Grof P, Beni S, Noszal B, Klebovich I, Antal I. Gels and liposomes in optimized ocular drug delivery: studies on ciprofloxacin formulations, Int J Pharm 2007, 343, 34-40.
- Benson AEH. Transdermal drug delivery penetration enhancement techniques, Curr Drug Deliv 2005, 2(1), 23-33.
- Dayan N, Touitou E. Carriers for skin delivery of trihexyphenidyl HCl: ethosomes vs. liposomes, Biomaterials 2000, 21, 1879-1885.
- Touitou E, Dayan N, Bergelson L, Godin B, Eliaz MJ. Ethosomes: novel vesicular carriers for enhanced delivery: characterization and skin penetration properties, J Control Rel 2000, 65, 403-418.
- Jain S, Umamaheshwari RB, Bhadra D, Jain NK. Ethosomes: A novel vesicular carriers for enhanced transdermal delivery of an anti HIV agent, Ind J Pharm Sci 2004, 66(1), 72-81.
- 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.
- Touitou E. Composition of applying active substance to or through the skin, US patent US5540934 (1998).
- Touitou E. Composition of applying active substance to or through the skin, US patent US5716638 (1996).
- Touitou E, Alkabes M, Dayan N, Eliaz M. Ethosomes- Novel vesicular carriers for enhanced skin delivery, Pharm Res 1997, 14, S305-S306.
- Godin B, Touitou E. New pros-pects in transdermal delivery, Crit Rev Therp Drug Carrier Sys 2003, 20(1), 63-102.
- Touitou E, Dayan N, Bergelson L, Godin B, Eliaz M. Ethosomes: Novel vesicular carriers for delivery, J Control Rel 2000, 65, 403-418.
- Touitou E. Drug delivery across skin, Expert Opin Biol Ther 2002, 2, 723-733.
- Szejtli J. Introduction and General Overview of Cyclodextrin Chemistry, Chem Rev 1998, 98, 1743-1754.
- Fromming KH, Szejtli J. Cyclodextrins in pharmacy, Kluwer Academic Publishers, Dordrecht, 1994.
- Kaneto U, Fumitoshi H, Tetsumi I. Cyclodextrin Drug Carrier Systems, Chem Rev 1998, 5, 2045 -2076.
- Loftsson T, Olafsson JH. Cyclodextrins: new drug delivery systems in dermatology, Int J Dermatol 1998, 37, 241-246.
- Loftsson T, Sigfusson SD, Sigurasson SD, Sigurasson HH, Masson M. The effects of cyclodextrins on topical delivery of hydrocortisone: the aqueous diffusion layer, STP Pharma Sci 2003, 13, 125-131.
- Matsuda H, Arima H. Cyclodextrins in transdermal and rectal delivery, Adv Drug Deliv Rev 1999, 36, 81-99.
- Uekama K, Hirayama F, Irie T. Cyclodextrin drug carrier systems, Chem Rev 1998, 98, 2045-2076.
- Lopez RF, Collett JH, Bently MV. Influence of cyclodextrin complexation on the in vitro permeation and skin metabolism of dexamethasone, Int J Pharm 2000, 200, 127-132.
- Williams AC, Shatri SR, Barry BW. Transdermal permeation modulation by cyclodextrins: a mechanistic study, Pharm Dev Technol 1998, 3, 283-296.
- Loftsson T, Masson M, Sigurdsson HH, Magnusson P, Goffic FL. Cyclodextrins as co-enhancers in dermal and transdermal drug delivery, Pharmazie 1998, 53, 137-139.
- Bouwstra JA, Van Hal DA, Hofland HEJ, Junginger HE. Preparation and characterization of nonionic surfactant vesicles, Colloids Surface A 1997, 123, 71-80.
- Uchegbu IF, Vyas PS. Non-ionic surfactant based vesicles (niosomes) in drug delivery, Int J Pharm 1998 172, 33-70.
- Carafa M, Santucci E, Alhaique F, Coviello T, Murtas E, Riccier FM, Lucania G, Torrisi MR. Preparation and properties of new unilamellar non-ionic: ionic surfactant vesicles, Int J Pharm 1998, 160, 51-59.
- Santucci E, Carafa M., Coviello T, Murtas E, Riccieri FM, Alhaique F, Modesti A, Modica A. Vesicles from polysorbate 20 and cholesterol: A simple preparation and a characterization, STP Pharm Sci 1996, 6, 29-32.
- Gupta P N, Mishra V, Rawat A, Dubey P, Mahor S, Jain S, Chatterji DP, Vyas SP. Non-invasive vaccine delivery in trasferosomes, niosomes and liposomes: a comparative study, Int J Pharm 2005, 293, 73-82.
- Van Hal D, Vanrensen A, Devringer T, Junginger H, Bouwstra J. Diffusion of estradiol from non-ionic surfactant vesicles through human stratum-corneum in vitro, STP Pharm Sci 1996, 6, 72-78.
- Junginger HE, Hofland HEJ, Bouwstra JA. Liposomes and niosomes: interactions with human skin, Cosmet Toilet 1991, 106, 45-50.
- Manconi M, Sinico C, Valenti D, Lai F, Fadda AM. Niosomes as carriers for tretinoin III- a study into the in vitro cutaneous delivery of vesicle incorporated tretinoin, Int J Pharm 2006, 311, 11-19.
- Tripathi KD. Essentials of medical pharmacology, New Delhi, Jaypee Brothers Medical Publishers, 4th edition, 2001, 52-53.
- Verma A, Verma1 B, Prajapati SK, Tripathi K. Prodrug as a chemical delivery system: A Review, Asian J Res Chem 2009, 2(2), 100-103.
- Jain NK. Advances in Controlled and Novel drug delivery, 2001, 1st ed, 268-283.
- Brahmankar DM, Jaiswal SB. Biopharmaceutics and Pharmacokinetics - A treaties, 1st ed, 159-176.
- Sloan KB. Prodrugs: Tropical and ocular drug delivery. Drug and the Pharmaceutical Sciences, New York, Marcel Dekker Inc, 1992, 53-313.
- Beall H, Prankerd R, Sloan K. Transdermal delivery of 5-fluorouracil (5-FU) through hairless mouse skin by 1-alkyloxycarbonyl-5-FU prodrugs: Physicochemical characterization of prodrugs and correlations with transdermal delivery, Int J Pharm 1994, 111, 223-233.
- Beall H, Sloan K. Transdermal delivery of 5-fluorouracil (5-FU) by 1-alkylcarbonyl-5-FU prodrugs, Int J Pharm 1996, 129, 203-210.
- Patrick AI, Beall H, Gilroy P, Sloan K. Effect of vehicles on tropical delivery of 5-flurouracil (5-FU) by 1-acyl-5-FU prodrugs, Int J Pharm 1997, 154, 39-48.
- Beall H, Sloan K. Transdermal delivery of 5-fluorouracil (5-FU) by 3-alkylcarbonyl-5-FU prodrugs, Int J Pharm 2001, 217, 127-137.
- Beall H, Sloan K. Transdermal delivery of 5-fluorouracil (5-FU) by 1,3-bisalkylcarbonyl-5-FU prodrugs, Int J Pharm 2002, 231, 43-49.
- Bonina FP, Puglia C, Barbuzzi T, Caprariis PD, Palagiano F, Rimoli MG. In vitro and in vivo evaluation of polyoxyethylene esters as dermalprodrugs of ketoprofen, naproxenand diclofenac, Eur J Pharm Sci 2001, 14, 123-134.
- Rautio J, Nevalainen T, Taipale H,Vepsalainen J, Gynther J, Laine K. Piperazinylalkyl prodrugs ofnaproxen improve in vitro skin permeation, Eur J Pharm Sci 2000, 11, 157-163.
- Sung KC, Fang JY, Wang JJ, Hu OYP. Transdermal delivery of nalbuphine and its prodrugs by electroporation, Eur J Pharm Sci 2003, 18, 63-70.
- Sung KC, Fang JY, Wang JJ, Hu OYP. Delivery of nalbuphine and its prodrugs across skin by passive diffusion and iontophoresis, J Control Rel 2000, 67, 1-8.
- Sung KC, Fang JY, Wang JJ, Hu OYP. Transdermal delivery of nalbuphine and its prodrugs by electroporation. J Control Rel 2003, 18, 63-70.
Figure 1: Representation of mechanism of various formulation approaches for penetration enhancement
Author profile for Geeta Aggarwal and Sanju Dhawan are already existing.
Aggarwal G, Goel A, Sharma A and Dhawan S
Geeta Aggarwal, Sr. Lecturer, Rayat Institute of Pharmacy, Railmajra, Distt. Nawanshahr, Punjab, India 144533
Arvind Goel, Student, M. Pharm., Rayat Institute of Pharmacy, Railmajra Distt. Nawanshahr, Punjab, India 144533.
Arvind Sharma, Lecturer, Rayat Institute of Pharmacy, Railmajra Distt. Nawanshahr, Punjab, India 144533.
Dr.Sanju Dhawan, Lecturer, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India 160014
Phone No.: +91-9463015019