Acta Pharmaceutica Sinica B 2012;2(1):8–15 Institute of Materia Medica, Chinese Academy of Medical Sciences Chinese Pharmaceutical AssociationActa Pharmaceutica Sinica B www.elsevier.com/locate/apsb www.sciencedirect.com REVIEW Lecithin organogel: A unique micellar system for the delivery of bioactive agents in the treatment of skin aging Sushil Rauta,n, Santosh Singh Bhadoriyaa, Vaibhav Uplanchiwara, Vijay Mishrab, Avinash Gahanea, Sunil Kumar Jaina a b Department of Pharmacy, Adina Institute of Pharmaceutical Sciences, Sagar 470002, India Department of Pharmaceutical Sciences, Dr. H.S. Gour University, Sagar 470003, India Received 9 October 2011; revised 15 November 2011; accepted 7 December 2011 KEY WORDS Skin aging; Topical; Lecithin; Biocompatible; Organogel Abstract Skin aging is an unavoidable aspect of human life. Premature skin aging can result from poor care, environmental pollutants, and ultraviolet radiation exposure. Wrinkles, lines, spots, uneven skin tone, and pigmentation are often indicators of skin aging. One cannot avoid aging but cosmetics and pharmaceutical approaches can minimize and delay the damage. Topical applications of biocompatible and biodegradable vehicles have been explored for delivering anti-aging compounds. Lecithin organogel (LO) is an effective vehicle for topical delivery of many bioactive agents used in aging treatment. Lecithin is cell component isolated from soya beans or eggs and purified to show excellent gelation in non-polar solvents when combined with water. LO can form a heat-stable, resistant to microbial growth, visco-elastic, optically transparent, and non-birefringent micellar system. It serves as an organic medium to enhance dermal permeation of poorly permeable drugs by effectively partitioning into the skin. Its ability to dissolve in hydrophilic as well as in lipophilic drugs makes it a dynamic vehicle, which can be explored as a carrier for anti-aging agents. & 2012 Institute of Materia Medica, Chinese Academy of Medical Sciences and Chinese Pharmaceutical Association. Production and hosting by Elsevier B.V. All rights reserved. n Corresponding author. Tel.: þ91 9303749481, þ91 9623603800. E-mail address:
[email protected] (Sushil Raut). 2211-3835 & 2012 Institute of Materia Medica, Chinese Academy of Medical Sciences and Chinese Pharmaceutical Association. Production and hosting by Elsevier B.V. All rights reserved. Peer review under responsibility of Institute of Materia Medica, Chinese Academy of Medical Sciences and Chinese Pharmaceutical Association. doi:10.1016/j.apsb.2011.12.005 Because of the short half-life. where it undergoes enzymatic processing. repeated dosing is necessary. which prevents their delivery to the desired site of action. copperzinc superoxide dismutase.42 discovered that oral administration of vitamin A will result in hypervitaminosis A. hydroxyl radicals. glutathione transferase. which breaks down the collagen and causes premature wrinkling19–21. loss of firmness on the hands and neck. they are delivered as pharmaceuticals. glutathione. Kockaert et al. actinic keratosis. which may result in dermatitis. the major challenge for topical formulations today is to provide a sufficient increase in drug penetration into skin without causing irreversible alterations to the barrier function3–5. and cosmeceuticals. which damage the molecular structure of DNA. sagging. 4. Treatment of skin aging A variety of agents have been tested and are commonly used in the treatment of aging (Table 1). Skin aging and molecular mechanisms Concept behind the use of organogel for topical delivery There are two different types of aging: intrinsic aging and extrinsic aging. The formation of collagen bundles is responsible for the strength and resiliency of the skin16–18. as well as gels are available and marketed for skin aging treatment. Introduction 9 generation include prostaglandin synthesis. rough and leathery skin. Also. One of the most prominent problems associated with skin is aging. and ionizing radiation. drug effects cannot be stopped once administered. The major sources of free radical In order to confront skin aging. De la Lastra et al. and prostaglandins14. It was found that lipid-based formulations work most efficiently by improving penetration through the skin. They can help relieve the signs and symptoms of aging through various mechanisms. Many drugs undergo degradation by gastric acid as well as gutwall enzymes. Generally two mechanisms are involved in natural skin defense: the first is enzymatic. and extracellular superoxide dismutase. singlet oxygen. is prevented by the barrier function of skin. inability to sweat sufficiently. In contrast. some drugs undergo first-pass metabolism. Skin is one of the most important organs of the human body with important protective functions. lipids. a blotchy complexion. and bilirubin. glutathione reductase. the second is nonenzymatic. Therefore. In this review we focus on the potential of LO to deliver bioactive agents in the treatment of skin aging.11. etc. 2. Collagen type I is the most abundant protein of the skin connective tissue present in the dermal extracellular space. Extrinsic aging is caused by environmental factors such as repetitive facial expressions. especially sun exposure. dry skin that may itch. Various creams. Furthermore. Smoking increases the production of collagenase.15. Patients are not always in favor of oral as well as parenteral dosage forms. Also. Skin aging has been defined as the amassing of skin damage over time1. It has been reported that various systemic anti-aging agents required relatively large doses and caused dose-dependent toxicity in many cases. cosmetics. including low-molecular weight compounds such as ascorbate. Lecithin organogels (LO) are promising vehicles to deliver wide variety of agents through the skin because they possess both the properties of oil and aqueous based formulations9. skin is the external organ where the signs and symptoms of aging are readily evident2. Photoaging is the term principally applied to depict extrinsic aging caused by sun exposure. including glutathione peroxidase. The permeation of exogenous substances. fine wrinkles that disappear when stretched. phagocytosis. Although each part of the body ages with the time. b-carotene. graying hair that eventually turns white. ointments. lotions.24. sleeping positions. The frequently visible features of intrinsic aging are fine wrinkles. Skin aging is generally accelerated by reactive oxygen species that result from the oxidation of cellular components. solar elastosis. and skin cancer10. Patients usually tend to pay more attention to topical dosage forms because of the convenient administration. Broadly. non-enzymatic reactions of oxygen. catalase. all the agents listed above were tested in patients systemically as well as locally. including agents used in treating skin aging.8. gravity.43 showed that resveratrol by oral administration undergoes first-pass metabolism. water-based formulations are able to maintain the bioactive state of skin but exhibit poor penetration7. proteins. manganese superoxide dismutase. skin aging can be delayed by cosmetics as well as by pharmaceutical approaches. all of which act as free radical scavengers25–27. Certain hereditary factors and lack of nutrients can also affect skin aging23. often act simultaneously with the normal aging process and cause earlier skin aging. hollowed cheeks and eye sockets. in the case of both oral and parenteral drug delivery. Intrinsic aging occurs inevitably as a natural consequence of physiological changes over time at variable yet inalterable genetically determined rates. many hydrophilic or lipophilic drugs show either poor dissolution or poor absorption on oral administration45. No skilled person is required for administration and drugs will not be degraded by acid or enzymes. Proteins and peptides used in aging treatment can be degraded by the gastric acid and enzymes44. a-tocopherol. Photoaging is often indicated by age spots. Bioactive agents or drugs cross the skin barrier by two mechanisms: transcellular and paracellular transport. Reactive oxygen species include superoxide. Topical delivery of drugs treating skin aging is most favorably accepted nowadays46. uric acid. Generation of endogenous reactive oxygen species takes place under mental as well as physical stress12. cytochrome P-450 enzymes. but the drawback associated with such formulations is that they alter the hydration state of the skin. Parenteral delivery causes pain because of invasiveness and a skilled person is needed to deliver the injection. 3. and hair loss. thin and transparent skin. UV radiation also affects the synthesis of collagen and elastin and changes gene activity by altering signal transduction cascades22. spider veins on the face. The effective concentration can be applied at the . smoking and exposure to the sunlight.13. All these shortcomings restrict the use of oral and parenteral dosage forms. Lipophilic agents move across the barrier by a transcellular mechanism whereas hydrophilic agents are likely to follow a paracellular pathway to cross the skin6. loose skin. hydrogen peroxide. However. Extrinsic factors.Bioactive agents in the treatment of skin aging 1. Lecithin is a complex mixture of acetone-insoluble phosphatides. Figure 1 Structure of lecithin. selenium) Soyabean derivatives Hydration of the stratum corneum and prevention of skin damage31 UV filters32 Reduces collagen breakdown by inhibiting the metalloproteinases33. long-term stability.29 Inhibit production of melanin30 Bioactive agents Vitamin C. Traditionally. phosphatidyl . LOs are thermodynamically stable. octocrylene. Gels are best fitted in all these essential criteria because of their excellent appearance. copper. organogel systems are applied topically when the active agent is oil-soluble or penetration into the deeper skin layer is required. lotions. Since the discovery of simple gelator molecules. which immobilize the continuous phase and thus convert from liquid to viscous gel50. idebenone. non-immunogenic. an aqueous polar phase. and lessened side effects compared to oral and parenteral dosage forms. 1). biocompatible. citric acid. silymarin Hydroquinone and its derivatives. such as LO. linaments and gels are commonly available in the market because of their features including appearance. In addition. triple fruit acid and sugar cane extract Lactic acid Para-aminobenzoic acid derivatives. non-allergic. vitamin E.2-diacyl-sn-glycero-3phosphatidylcholine. LO have jelly-like structure that consists of three-dimensional networks of entangled reverse cylindrical micelles. The chemical name of lecithin is 1. ensulizole. ferulic acid. resulting in more biocompatible products52.10 Sushil Raut et al. For manufacturers. Lecithin organogels LOs are gels consisting of an organic medium in liquid phase. Self-assembly of lecithin molecules in nonaqueous media into reversed giant cylindrical micelles occurred when small amounts of water. gelling agents merge or entangle to form a three-dimensional colloidal network structure. cosmetic products even after the various safety tests may cause some undesirable effects including dermatoses47. desirable features include ease of manufacture. the termination of the topical therapy is easily accomplished. non-ionic surfactant based organogels and polyethylene organogels53. Hence. They observed that the addition of small amount of water into nonaqueous solutions of naturally occurring lecithin caused a sudden rise in the viscosity55. LO was first introduced by Scartazzini and Luici in 198854. gel formulations have been modified to yield an advanced drug delivery system known as ‘‘organogels’’. Mechanism Free radical scavenging and inhibitors of lipid peroxidation28. desired consistency. biocompatible and isotropic gels which are composed of lecithin (Fig. or formamide are added.36 Build skin structural matrix37–39 Link with proteins superoxide dismutase and metallothionein and act as anti-oxidants40 Inhibit protease activated receptor 2 (PAR-2)41 desired site without painful delivery and also avoids first-pass metabolism. smoothness. salicylates. When dispersed in an appropriate solvent. retinoids. Gels are transparent or translucent semisolid formulations containing a high ratio of solvent/ gelling agent. benzophenones. fast drug release. malic acid. butyl methoxydibenzoyl and meradimate Vitamin A Vitamin B N-acetyl glucosamine (NAG) and glucosamine Metals (zinc. topical dosage forms such as creams. The United States Pharmacopoeia (USP) defined gels as semisolids. Recently. clear. But the use of natural and bio-friendly drug-loaded vehicles can help relieve such problems. and effective for the patients. and a polar liquid. In skin aging treatment. which is composed of organic as well as aqueous phases possessing various beneficial properties. pycnogenol. and ready quality control. which limits fluid flow by entrapment and immobilization of the solvent molecules49. which mainly consist of phosphatidyl choline. ointments. researchers seek to develop novel vehicles that are natural. and a surfactant phase. effective at the site of action. and admirable stability. cinnamates. ease of manufacturing and quality assessment.34 Anti-inflammatory effect and anti-acne action35. either suspension of small inorganic particles or large organic molecules interpenetrated with liquid48. gelatin-stabilized organogels. mixed fruit acid. 5. ease of removal. glycerol. LOs are a unique micellar system composed of a non-polar oil phase. green tea. Table 1 Various bio-active agents used in the treatment of skin aging. organogels have attracted increasing attention. A wide variety of organogels have been developed by researchers and classified based on the nature of the organogelators. which is derived from soy or egg lecithin. Among these organogels. Surfactants act as penetration enhancers that alter the membrane bilayer structure and thus reduce the diffusion barrier and enable the drug to penetrate deeply into skin51. viscoelastic. co-enzyme Q10. Many varieties of cosmetic products are available in the market and are commercially advantageous. These novel formulations can be used in small quantities without further additives. limonene GP1/PG organogel. ease of application. glycolic acid. an organic solvent. Nonetheless. the external phase is non-aqueous and the internal aqueous . Many organic solvents are available for LO.62. 5. It may also vary in color from brown to light yellow depending on whether it is bleached or unbleached57. Composition of LO LO is composed of a biosurfactant (lecithin). ethanolamine. n-pentane. Among all these polar solvents. The gel-forming ability of the polar solvent depends on its physicochemical properties such as surface tension. 5. With the addition of small amount of water. which is a dead.3. Lecithin is an important component of all living cells and is recognized by Food and Drug Administration as GRAS (Generally Regarded As Safe. which acts as a penetration enhancer60. 1) performs versatile functions. the lecithin molecules will assemble in spherical reverse micellar form. Oils used in LO may undergo oxidation. rape seed oil and mustard oil possess desired properties as a solvent in LO55. Lecithin is available in various marketed grades like EPIKURON. flexible and worm-like tubular micellar structures (Fig.2. LIPOID S 100. The main sources of lecithin are soya beans and egg yolk. which are derived and purified from either soya beans or eggs. It contributes in the development of reverse micellar structures and furthermore converts these micelles to three-dimensional long tubular networks61. Its unique lipid molecular structure (Fig. the lecithin molecules are randomly dispersed in the organic medium. It The gelation process (Fig. Hydrophilic drugs dissolve in polar phase and lipophilic drugs dissolve in the non-polar phase. water is a very effective and natural polar agent. 1400). which attract the polar drugs and non-polar tails. cosmetics and food industries as an emulsifier.1. n-hexadecane. Lecithin is a biocompatible and biodegradable surfactant as well as a cellular component. trans-decalin. Thus they act as a bridge between two adjacent lecithin molecules to form the linear networks with the hydrogen bonds between polar molecules and phosphate groups of lecithin molecules. cyclopentane. which is attracted to hydrophilic drugs. 5. HydrophilicÀlipophilic balance LOs are well balanced with hydrophilicity and hydrophobicity. Hence. Natural oils including soyabean oil. gel forming and stabilizing agent. and supported its skin penetration enhancing property9. which acts as a gelling agent and a non-polar organic media as external or continuous phase and a polar agent (usually water)59. The organic liquids get entrapped in the spaces between the entangled reverse micelles68–70. It has a wide variety of roles in pharmaceuticals. ethyl myristate. Poorly purified lecithin or synthetic lecithins do not exhibit gelation properties54.55. 5.3. Desired gelation in organic solvent occurs only when the lecithin contains more than 95% phosphatidylcholine and is free from fat as well as moisture. Lecithin molecules are amphiphilic in nature and possess polar headgroups. and CAPCITHIN. With LO. which will affect the stability of LO. cyclooctane. In addition to the abovementioned components. keratinized and compact layer. Lecithin contains phospholipid molecules. which is beneficial for skin hydration and maintains the vitality of the skin. Lecithin varies greatly in its physical form. some other agents like co-surfactants and anti-oxidants are also incorporated in LO to boost its effectiveness. 21 CFR 184. Because of these two aspects. Initially. It can hydrate the upper skin layer (stratum corneum). which are self-assembled to build up the microstructure of organogel. stabilizer. 3) in organogel takes place with the addition of a trace amount of water into the lecithin solution of organic solvent. which is attracted to lipophilic drugs. viscosity modifier. and tripropylamine. 4). A further increase in a small amount of water results in the formation of long. Organic solvent plays a vital role in organogel by providing the desired solvent action for drug as well as lecithin. which possesses viscoelasticity and thermo-reversibility. The lecithin molecule can be divided into two portions. Co-surfactants such as n-butanol and propylene glycol provide thermodynamic stability as well as flexibility to the micellar system in LO. and include ethyl laureate. the fattyacid portion. The unsaturated non-polar part of lecithin molecules can affect the critical packing parameter (CPP).3. and the phosphoric acid portion.Bioactive agents in the treatment of skin aging 11 was observed that they are effective in permeation of drug into skin but they exhibit toxicological manifestations61. This arrangement reduces the interfacial tension between oil and water and makes relatively stable emulsions. The water molecules bind stoichiometrically to the hydrophilic head of the lecithin molecules. lecithin molecules arrange themselves at the boundary between immiscible liquids such as oil and water (Fig. dielectric constant and polarity. Phenomenon of organogelation of lecithin Figure 2 Arrangement of lecithin molecules in micellar systems. ethylene glycol and formamide have strong gelling potential64. 2). Thousands of such tubular micro-structures overlap and entangle with each other to form a three-dimensional gel network. Generally biocompatible and biodegradable organic solvents are preferred because of their safety in use. antioxidants like ascorbic acid are usually incorporated for stability. which solubilize nonpolar drugs44.2. isopropyl myristate. Lecithin is a multi-functional surface-active agent. Co-surfactant lowers the interfacial tension between the nonpolar and polar phase and also enhances skin permeability65–67. It can dissolve a wide variety of guest molecules. Water. sunflower oil. as they are composed of oil and water. solubilizer and penetration enhancer58. trans-pinane.63. n-hexane. glycerol. and phosphatidyl inositol combined with different amounts of other substances such as triglycerides and fatty acids56.1. from viscous semi-liquid to powder depending on the content of free fatty acid. Microbial resistance Micro-organisms grow well in aqueous environments but growth is inhibited in non-aqueous environments. isopropyl palmitate. The polar component acts as structural. Further addition of water makes the short tubular or cylindrical micellar aggregate. Beneficial properties of LO 5. phosphatidyl serine. rape seed oil. Figure 3 Process of organogelation. trans-pinane. With a subsequent increase in shear rate. cyclopentane. minimizing the loss of organogel structure. Optically.3. 5. The use of lecithin in organogel is safe. 5. At lower temperatures lecithin molecules reassemble. When the organogels were sheared at low shear rates.3. When the temperature of organogel system increases. applied to the skin for long-term use. Safety and biocompatibility LO containing non-polar components such as di-butyl ether. sunflower oil. phase and lecithin molecules are well protected from microbial contamination71.12 Sushil Raut et al. 5. cyclo-octane. which can be self-assembled after addition of water. and therefore LOs are inherently thermostable and valuable for the delivery of bioactive agents and for cosmetic applications73. The gelator molecules break the physical interactions from the tubule until the shear stress is high enough to destroy the organogel structure. or mustard oil can minimize such problems. However. Phase behavior of LO Figure 4 Micro-structure of organogel with long tubular network.5. Water as the internal phase can maintain the bioactive state of the skin by hydrating it. n-hexane. This behavior is termed as plastic flow behavior75. Non-birefringence and optical transparency LO is isotropic as it appears as a one-phase system. 5) was constructed for the lecithinÀoilÀwater system.3. trans-decalin. From the results of skin compatibility studies it was revealed that topical use of LO is safe55.72. they behave like a solid and show an elastic property. Lecithin is biocompatible in nature and is a component of cell membranes. it is transparent and provides the benefit of visual inspection so that the presence of any particulate matter can be easily recognized9. the use of biocompatible oils such as soyabean oil. the tubule structures are weakened. lecithin molecules absorb kinetic energy.61.4. and n-hexadecane may cause some allergic and immunological reactions and chronic dermatoses when A pseudo-ternary diagram (Fig. It is constructed by titrating the dispersion of lecithin in oil with water in differing concentration .4. 5. Viscoelasticity The viscous and elastic nature of LO follows the Maxwell model of viscoelasticity74.3. 5.6. Thermostability In the organogel lecithin acts as a gelator molecule.3. n-pentane. NSAIDS. This explains the phase behavior of the organogels. It can dissolve both hydrophilic and lipophilic drugs and hence acts as effective vehicle to deliver wide variety of drugs across the skin. optical transparency. (Edmonton. Phase diagrams for the organogel system also demonstrate the behavior of organogel system such as cloudiness. Category Vitamins NSAIDS Bioactive agents/drugs Vitamin A and C77 Diclofenac. LO provides an effective permeation through the skin by fluidizing the membrane lipids as well as by a hydration mechanism. Ltd. the organogel system is also called a micro-emulsion-based organogel.72 developed lecithin-stabilized microemulsion-based organogels for topical application of ketorolac tromethamine using soya lecithin as surfactant and isopropyl myristate as oil. amino acids. LO in dermal drug delivery LO meets all the essential criteria for effective drug delivery. The phase diagram provides information for the boundaries of the different phases as a function of composition variables and temperatures. After application to the skin. the micro-emulsion turned to a viscous gel.80 performed experiments on rat skin revealing that the permeation of indomethacin was greater with LO.78. It is easy to prepare and handle. It was observed that LO solubilized higher concentrations of ketorolac tromethamine and that its release rate from LO was also enhanced on guinea pig skin. The occlusive nature of LO provides smooth feel on dermal application9.79 reported that LO was found to be more effective and safer for delivery of aceclofenac when compared with hydrogels. phytosphinosine. paroxetine. Clin Dermatol 2008. It has been widely accepted as a superior vehicle for delivering drugs across the skin barrier. it shows additive effects along with incorporated bioactive agents against skin aging. As the lecithin itself provides skin protection against UV-induced skin aging. isotropicity. Histological evidence indicated that no toxicological manifestations were present even upon the prolonged application on the skin. Concentrations of lecithin. Advancement in skin aging: the future cosmeceuticals. and viscosity. Alberta. Shaikh et al. Others 6.R. ibuprofen. Drugs are either hydrophilic or lipophilic in nature. aceclofenac9. As LO contains ingredients that are natural. water in oil micro-emulsion was stabilized by lecithin micelles formed with low concentration of water. Studies of LO have explored its potential as an efficient matrix for dermal administration of many bioactive agents. ketoprofen. indomethacin.26:364–6. It is non-greasy and improves skin penetration of incorporated active ingredients.A. peptides. which is characterized by optical transparency and low viscosity. Giacomoni PU. Zia et al. By applying the LO formulation. hence the concentration of water plays very crucial role in the production of a clear organogel76. amitriptyline. References 1. biocompatible. LO exhibits many desirable physicochemical properties essential for topical vehicles. Initially. Canada) is Phlojels Ultra. Fujii et al.78 Methoxsalen. Thus. One of the marketed products of J. botulinium toxins85 Anti-vitiligo agents Anti-scars Figure 5 LecithinÀoilÀwater phase diagram with lecithinÀoil ratio of 60:40 (w/w). Pharmaceuticals. which is a LO formulated to have cosmetic properties. the amount of drug needed to achieve a relatively high local concentration is greatly decreased81. Thus LO was a desirable drug delivery vehicle for water soluble drugs and is capable of providing an appropriate drug release pattern72. safe and stable. A wide variety of guest molecules such as vitamins A and C. sphinganine. N-hexanoylsphingosine. 7. it is likely to play an increasingly important role in cosmetics as well as pharmaceutical agents in treating skin. glycolic acid84 Scopolamine78 Broxaterol78 Aromatic tetra-amidines85 Nicardipine85 Fluoxetine. but LO can solublize both types of the drugs. trazadone86 Amino acids and peptides78. and water are extremely critical in organogel system. ertraline. corticosteroids. Conclusions LO provides a new perspective for the topical delivery of antiaging agents.77. hormones. azelaic acid. apigenin83 Kojic acid. Skin lightners Anticholinergic b-Adrenergic agonist Anti cancer Anti-hypertensive Psychopharmaceuticals ratios. calcineurin inhibitors82 Sphingosine. As the amount of water increases. It was found that an excess amount of water makes the system turbid. curcumin.77. piroxicam.Bioactive agents in the treatment of skin aging 13 Table 2 Dermal delivery of various bioactive agent using LO. oil. triosalen. . N-acetylsphingosine. it is rapidly absorbed without any residue. local anesthetics and antifungal agents were reported to be effective topically as well as transdermally when delivered by LO (Table 2). In: Draelos ZD. Pharmaceutical dosage forms and drug delivery systems. et al. Peters T. 39. Contact Dermatitis 2007. Retinoids. 28. Free radical theory of aging: an update: increasing the functional life span. 6.12(2)43–50. Webster GF. Bissett DL. Neumann M. Int J Drug Del 2010. Khan ZI. In: Draelos ZD. Katsambas AD. Stratigos AJ. Knuutinen A. 31.297:242–8. Cutis 1987. Morita A. 20. Smoking affects collagen synthesis and extracellular matrix turnover in human skin. -9 and -8 in the skin. Machino C. 13. Guy RH. ´ -Kudla ´ ckova ´ M.65:1061–72. Fisher GJ.30:313–22. Sorsa T. et al. Allen LV. editors. Gillard MO. 2005. ´ ndez MJ.21:77–9.72:5–13.130:1136–42. Skin ageing and its treatment. Mullins LA. p. Kumar R. Villegas I. Arch Dermatol Res 2005. Int J Pharm 1995. Majmudar G.14 2. Luisi PL. Katare OP.26:367–74. Philadelphia: Elsevier Saunders. 2005. Repeated treatment protocols for melasma and acquired dermal melanocytosis. et al. Valachovicova ´ M. Shah S. 42. UV-light-induced signal cascades and skin 22. Ochiai Y. Leyden JJ. Thaman LA. Wei H. 41. The inhibitory effect of glycolic acid and lactic acid on melanin synthesis in melanoma cells. Pharmazie 2002. Pig Cell Res 2006. Schwartz JR. The role of topical retinoids in the treatment of photoaging. Chen HD. .57:30–3. Podhaisky HP. 2005. Topical delivery of aceclofenac from lecithin organogels: preformulation study. 29. Griffiths CE.19: 373. Osborne R. Krajcovicova ´ M. et al. The aging skin. Misteli T. Ann NY Acad Sci 2006. Tuomas H. editor. Kockaert M. de la Lastra CA. Kinget R. Cosmetic formulation of skin care products. Salo T. 27. Menegatti E. 38. Int J Fertil Womens Med 1997. Eur J Pharm Biopharm 1997. The free radical theory of aging. Topical N-acetyl glucosamine affects pigmentationrelevant genes in in vitro genomics testing. Cosmeceuticals. Baumann L. Pinnell SR. Kullavanijaya P.117: 851–60. Skin aging. Montenegro L. J Controlled Release 1995. ´ L. Am J Med 2004. 9.35:185–91. McPhail SJ. 237–50. 16. Usuki A. Shaikh IM.125:231–42. Nagase T. Briden ME. 36. Photoprotection. 37. Reiner AP. 11. J Pak Assoc Dermatol 2011. Physiol Res 2008. Front Biosci 2002. Paukova ´ V. Willimann HL. Popovich NG. Transdermal drug delivery systems. Lecithin organogel as a potential phospholipid-structured system for topical drug delivery: a review. Funasaka Y. 89–95. Resveratrol as an anti-inflammatory and anti-aging agent: Mechanisms and clinical implications. 47. Frequency of dermatoses associated with cosmetics. Kriwet K. Nicotinamide 4% gel for the treatment of inflammatory acne vulgaris. Farmer TL. Justin-Temu M. Harman D. 34. Blanco-Me Lopez-Quintela MA. 46.26:6242–53. Effects of phospholipid based formulations on in vitro and in vivo percutaneous absorption of methyl nicotinate. 21. Hanemaaijer R. Motulsky A. 4. Cosmeceutical metals.2:58–63. Squier TC. Intravaginal gels as drug delivery systems. 33. Meewes C. Bisset DL. Exp Dermatol 2003. Wehr RF. Ahmad FJ. Lafleur M. Exp Gerontol 2001. Raitio A. Int J Cosmet Sci 2008. Yoshimura K. Curr Drug Deliv 2006. Vahakangas K. Systemic and topical drugs for aging skin. Oxidative stress and protein aggregation during biological aging. Sato H. 8. Gide PS. Blaudschun R. Jackson EM. A review of ageing and an examination of clinical methods in the assessment of ageing skin. Oshima J. serum and saliva of smokers and non-smokers. Micron 2004. Delgado-Charro MB. Dixon AE. In: Draelos ZD. Kokkonen N. J Dermatol Treat 1995. Riemschneider S. Boury F.54:106. Ageing Res Rev 2002. Ichihashi M. Kobayasi T. Pisal SS. J Am Acad Dermatol 2003. 43. Recent Pat Drug Deliv Formul 2008. Kallioinen M.6:298–310. Lim HW. 24. 40. Philadelphia: Elsevier Saunders. Characterization and biocompatibility of organogels based on L-alanine for parenteral drug delivery implants.5:557–61.312:1059–63. Kokkonen N. Br J Dermatol 2002. Risteli J. 18th ed. p. Pathan SA. Cutis 2003. 10. 19. Efficacy and safety of innovative cosmeceuticals. J Women Health (Larchmt) 2004. Harman D. Shehzad A. Sandby-Møller J. Topical N-acetyl glucosamine and niacinamide increase hyaluronan. et al. Brenneisen P. 3. editor. Philadelphia: Lippincott Williams and Wilkins. 18.146: 588–94. Biomaterials 2005. Wulf HC. 42:57–66. Wilhelm KP. Nelson BR. UV light and oxidative damage of the skin. Skin aging and natural photoprotection. Topical exfoliation–clinical effects and formulating considerations. Cutaneous photodamage. Azeem A. Levels of matrix metalloproteinase-2. 17. Aiba-Kojima E. van Den Mooter G. 32. J Drugs Dermatol 2003. Cawthon RM.2:435–41. Pro-oxidant and anti-oxidant mechanism(s) of BHT and beta-carotene in photocarcinogenesis. Ziv E. Lamin A-dependent nuclear defects in human aging. 2006. J Am Acad Dermatol 2006. Damian F. Sato K. Black HS. Browner WS. 298–315. 5. Moisturizers: adjunct therapy and advising patients. Kumar L. Muller-Goymann CC. Scrofani N. Am J Contact Dermat 1996. 44. Griffiths CEM. 45. p. 23. 1st ed. Campos Lage AC.177:897–900.3:417–27. Robinson MK. Gniadecki R. Clinical improvement following dermabrasion of photoaged skin correlates with synthesis of collagen I. Effects of diet and age on oxidative damage Dusinska products in healthy subjects. Talegaonkar S. Cortesi R. 14.48:1–19. Jadhav KR. In vitro evaluation of topical gel prepared using natural polymer. Science 2006. 7. 15. 30. and topical antioxidant protection.7:247–50. Rittie aging. Considerations in selection a moisturizer. Dermatol Surg 2006. Wenk J. Ansel HC. Esposito E. Mol Nutr Food Res 2005.56:211–3. Harper JC. Matsumoto D. Iglesias-Vilas VG. Salo T. 12. Wohlrab W. Gao XH.57:647–51. Mian A. Oblong JE. Green BA. 35. et al. 50. J Pathol 2007.39:512–5.49:405–30. Arch Dermatol 1994. Benoit JP. The pathophysiology of photoaging of the skin. Lecithin organogels as matrix for the transdermal transport of drugs. Cutis 2005.1067:10–21.1:705–20. Shalita AR. Clin Dermatol 2008. UV-induced oxidative stress and photoaging. Duarte I. AAPS PharmSciTech 2005. Scaffidi P. Tavakkol A. Exp Dermatol 2003. Tiesman JP.211: 241–51. Khar RK. Yin L.43:37–42. Curr Probl Dermatol 2001. Krochmal L. Hoarau D.34:53–63. Robinson LR. Biochem Biophys Res Commun 1991. Verma R. Fisher GJ. Kahn AJ. Antioxid Redox Signal 2003. Microemulsions: a novel approach to enhanced drug delivery. Bonina FP. Zhang L.2:238–57. p. J Am Acad Dermatol 2005. 26.29:83–94. Cosmeceuticals. Ohashi A. New York: Taylor & Francis. 48. Delivery of a hydrophilic solute through the skin from novel microemulsion systems. oxidative stress. Sushil Raut et al. Kadam VJ. et al. Callaghan TM. 49. 35–45.13:834–44. Berson DS.36:1539–50. Marty JP.75:5–9. Current concepts in the treatment of acne: report from a clinical roundtable. Bergfeld WF. The genetics of human longevity. Chalker DK. Diclofenac release from phos¨ pholipid drug systems and permeation through excised human stratum corneum.32:365–71. Tsuji T. 25.6:8–10. Reichling TD. Tobacco smoke extract induces agerelated changes due to modulation of TGF-beta. Couffin-Hoarau AC.7: 1044–55. Part I: Cellular and molecular perspectives of skin ageing. Wlaschek M. Drugs 2005.12:51–6.52:937–58. et al. Lecithin organogels as matrix for transdermal transport of drugs. ´ nzes T. J Controlled Release 2008. Katare OP. Shaikh IM. Henmi T. Int J Pharm 2001. London: Royal Pharmaceutical Society. 1996. 62.Bioactive agents in the treatment of skin aging 51. Schurtenberger P. Jain K. Pal K. Nazari N. 61. US Patent 20040202640. Gu Z. Sagiri SS. Topical treatment in vitiligo and the potential uses of new drug delivery systems. 84. US Patent 20090285869. Lecithin organogel a micellar system with unique properties. Structural and dynamic properties of polymer like reverse micelles. Int J Pharm 1988.190:83–9. Kumar N. Pan H. US Patent 6290986. Yamanouchi S. Industrial production of phospholipidsÀlecithin processing. Sugibayashi K. 75. 31st ed. Roessler BJ. Langmuir 2000. Zhu D. Weiner ND.43:31–40. Weiss RG. DARU J Pham Sci 2009. Curr Drug Deliv 2009. 77.53:265–88. Zhurnal Fizicheskoi Khimii 2000. Gazzaniga A. Toshiyuki S. Bhatia A. 64.16:7558–61. Drug Dev Ind Pharm 2005. Chang X. et al. Hatzara E. J Phys Chem B 2001. Aigner Z. Shumilina EV. Inventor. Murdock RW. 83. the extra pharmacopoeia. Skin permeation of indomethacin from gel formed by fatty-acid ester and phospholipid. 73. Bakliwal SR. Kadam VJ. et al. 36–9. Liu J. Int J Pharm 1999. Lianos P. Pattarino F. Falkay G. Hoffmann H. October 14. Leser ME. Pandey D. 86. William H. 82.341: 78–84.92:829–33. Inventor. Hydrogelthickened microemulsion for topical administration of drug molecule at extremely low concentration.9:109–16. Int J Compr Pharm 2011. Garg BJ. Kenji H. Bhattacharya S. 53. J Phys Chem 1988. Luisi PL. 60. Method and composition for transdermal administration of pharmacologic agents. Int J Pharm 2007. a microdomain properties investigation. Yama N. Methods for topical tretment of scars with protein kinase skin inhibitors. Reynolds JEE. Daisuke O. p. Trotta M. cetyl palmitate and isopropyl palmitate. Aboofazeli R. Phospholipid-based reverse micelles. Shchipunov YA. 66. 1:13–35. Luisi PL. Cirkel P. Effect and mode of action of aliphatic esters on the in vitro skin permeation of micorandil. Mezzasalma SA. 2009. Int J Pharm 1996. Topical 52. Needhan TE. Hadidi N. Wade A. II. Ramchandran C. 63. Shchipunov YA. Champaign: American Oil Chemist’s Society. Saraswat A. Jadhav SL. Luisi PL. 65. Du D. Bekiari V.183–185:541–54. 76. 71. Aboofazeli R. Leroux JC. . Lipid Tech 1997. Pawar SP. Sahoo S. Washington: Ame Pharm Association. Colloids Surf A 2001. Fujii M. US Patent 20090053290.76:231–8. Crandall WT. Topical transport of hydrophilic compounds using water-in-oil nano emulsions. Xenakis A. Ning M. 23:4438–47. Giuliani AM. Handbook of pharmaceutical excipients. 56. Lecithins sources. Moore J. Lecithin bridging by hydrogen bonds in the organogel. Preparation in vitro and in vivo evaluation of liposomal/niosomal gel delivery systems for clotrimazole. Szuhaj BF.3:43–50.220:63–75. Weller PJ. Mou D. Paszli I. Gallarate M. Chen H. Pisal SS. Int J Pharm Res Dev 2011. et al. Lecithinstabilized microemulsion-based organogels for topical application of ketorolac tromethamine. Hungary. Scartazzini R. Lecithin organogels with new rheological and scaling behavior. Proceedings of conference on colloid 15 chemistry: Memoriam Aladar Buzagh.94:3695–701. Organogels from lecithins. Avramiotis S. Formulation and optimization of microemulsion-based organogels containing propranolol hydrochloride using experimental design methods. Morimoto Y. Pe absorption of piroxicam from organogels—in vitro and in vivo correlation. Eros I. Schneider M. Chen X. 59.125:179–92. 74.2:117–23. Des Monomers Polym 2011. Magid LJ. Khromova Y. 72. 80. Mater Sci Eng C 1995. Riron Oyo Rikigaku Koenkai Koen Ronbunshu 2003.105:10484–8. Organogels and their use in drug delivery—a review. The first determination of the conformation and molecular packing of a low-molecular-mass organogelator in its gelled state. 81. Sand BJ. Patil KD. 52:477–8. In: Horvoelgyi Z. Carlotti ME.17:217–24. 70. 58.298:47–54. Scartazzini R. 1996. Papadimitriou V. 79. 54.31:375–83. 68.74:1210–9. February 26.14:95–108.81:871–4. November 19. 57. 2001. Vintiloiu A. Organogels: properties and applications in drug delivery. Transdermal drug delivery compositions and topical compositions for application on the skin. September 23. 1994. Stroppolo F. Shumilina EV. Gupta S. Luisi PL. Walde P. A study of the structure of lecithin organic gels by Fourier-transform IR spectroscopy. Investigation of the phase behavior of systems containing lecithin and 2-acyl lysolecithin derivatives. Iran J Pharm Res 2003. September 18. 2001.2:1–5. Nemeth Zs. Nasseri AA. 85. Wu H. Eger. In vitro release study. Trimble JO. Shiozawa K. Boicelli CA. The structure of LOs. 1996. Zia H. Sirchio SA. Inventor. Suzuki H. Inventor.137:117–24. Abdallah DJ. Final report on the safety assessment of octyl palmitate. editors. Walde P. Aceclofenac organogels: In vitro and in vivo characterization. Indian J Dermatol Venereol Leprol 2010. Lecithin organogels used as bioactive compounds carriers. Koper G. Shchipunov YA. J Phys Chem 1990. Blazso ´ G. Chem Phys Lipids 1990. manufacture and uses. Singh RP. Sarkar A. Shchipunov YA. Jadhav KR. Koper GJM. Sato K. 2009. Guo Y. Martindale. 67. 2nd ed. Organogel: topical and transdermal drug delivery system. Viscoelastic behavior of organogels. Panchal H. Organogel: a viable alternative for existing carrier system. 78. Hexatriacontane organogels.6:1–7. J Pharm Sci 1992. Langmuir 2007. Int J pharm 2005. 1989. Salt stable lecithin organogel composition.3: 58–66. J Am Coll Toxicol 1982. 69. 55.