TITLE OF THE TOPIC: “FORMULATION DEVELOPMENT & PERFORMANCE EVALUATION OF SKIN CARE
PRODUCT”
6.0
7.0
BRIEF REVIEW OF THE INTENDED WORK 6.1. Need for the study
In recent years, skin whitening (Also called “Skin Lightening”, used here interchangeably) products have become and continue to be the best selling skin care products in Asia. Asia is the largest market for skin whitening products, with other parts of the world also growing at a rapid rate. Not only do they want a general improvement of the evenness of the complexion but also the reduction of hyper pigmentations such as age spots on sun exposed areas. This market is hence no longer limited to Asian countries. With the world population aging, it is expected that more and more people will develop age-related pigmentation disorders regardless of race. This will be the main driving force outside of Asia for worldwide consumer demand for skin whitening products, mainly to treat pigmentation disorders such as age spots.
Skin color is mainly determined by the amount of melanin present in the skin. Melanin protects the body from the damaging effects of ultraviolet radiation, and it is synthesized in melanocytes that are normally found in the epidermal basal layer. The darkness of the color observed in the skin is proportionate to the amount of melanin synthesized by melanocytes and transferred to the keratinocytes. In some cases, it is desirable to reduce or inhibit melanogenesis, for example, to cause skin lightening, to eliminate "age spots", or to reduce hyperactive melanocytes. “Skin lightening" means decreasing melanin in skin, including one or more of overall lightening of basal skin tone, lightening of hyperpigmented lesions including age spots, melasma, chloasma, freckles, post inflammatory hyperpigmentation or sun-induced pigmented blemishes, etc.
From the biosynthesis pathways of melanin formation, skin lightening can be achieved by inactivating the tyrosinase activity, or blocking the chain reaction at the various points of the pathways. Skin lighteners can inhibit or even reverse melanin biosynthesis, and are thus useful in whitening or lightening the human skin. Furthermore, skin lightening effects can also be achieved by reducing the amount of tyrosinase or blocking the synthesis of tyrosinase. At the cellular level, the skin lightening effects can be achieved by blocking the melanin transfer from the melanocytes to keratinocytes, and/or by accelerating the desquamation of the keratinocytes. In addition, inhibition of TRP-1 and/or TRP-2 also leads to reduction in melanin formation and therefore skin lightening.
The intrinsic activity of skin whiteners, however, is only half the story. The deliverability is also important and is up to the pharmacist that the formulation results in true clinical efficacy. It is obvious from the above discussion that pharmacist have a great incentive to combine multiple skin whitening mechanisms in a cosmetic product to overcome the problem of side effects.
6.2. Review of Literature
N. Baurin, E. Arnoult, T. Scior, QT , P. Bernard reported in their efforts to find new active tyrosinase inhibitors for skin-whitening or anti browning preparations, we investigated 67 tropical plants belonging to 38 families, which were evaluated for their anti-tyrosinase activity. The results of our investigation show that extracts of 5 plants, Stryphnodendron barbatimao, Portulaca pilosa, Cariniana brasiliensis, Entada africana and Prosopis Africana present interesting in vitro mushroom tyrosinase inhibition (over 90%), similar to a positive control: Morus alba . These 5 plants will be studied in order to isolate and identify phytochemical compounds, involved in this biological activity1.
Andrea P, Cassandra LQ, Maria LV, Paola M, Giulia S, Luigina S et al, reported an ethno pharmaceutical study focused on domestic cosmetics, cosmeceuticals, and remedies to heal skin diseases traditionally used in the inland part of the Marches region (Central-Eastern Italy) has been conducted. At present, traditional knowledge concerning home-made phytocosmetics is represented by both the remnants of an orally transmitted folk heritage and also by new forms of knowledge, sometimes coming from popular phytotherapeutical books and the mass media (out of the scope of this survey), but also as a result of recent migration trends from Eastern Europe. We recorded approximately 135 cosmetic or cosmeceutical preparations prepared from more than 70 botanical species and a very few animal or mineral ingredients. Among the recorded preparations, developing a clear distinction amongst cosmetics, cosmeceuticals and pharmaceuticals for skin diseases is very problematic, confirming that in folk knowledge systems medicinal products for healing skin diseases and cosmetics have often been perceived as two poles of a continuum. Many of the quoted species represented well-known medicinal plants of the European phytotherapy, although we also recorded a few unusual plant taxa, which are briefly discussed under the perspective of their eventual phytochemical and/or phytopharmacological potentialities. Exotic drugs or precious essences, even native of the Mediterranean, were not quoted as ingredients for preparing perfumes and fragrances by the interviewees of the present study, thus indicating that popular cosmetic practices in rural Central Italy have taken a much separated path away from the cosmetic “know-how” of the aristocracy and high bourgeois classes of the last centuries2.
Yi-Pei L, Feng-Lin H, Chien-Shu C, Ji-Wang C, Mei-Hsien L. reported tyrosinase is a copper-containing monooxygenase that catalyzes melanin synthesis in skin melanocytes. Herein, 13 compounds from the Formosan apple (Malus doumeri var. formosana), an indigenous Taiwanese plant, were isolated and identified. The active constituents were identified as 3-hydroxyphloretin (7) and catechol (9); they exhibited potent hydroxyl radical-scavenging (IC50 values, 0.6 and 1.1 lM) and cellular tyrosinase-reducing activities (IC50 values, 32 and 22 lM) in human epidermal melanocytes. In addition, we evaluated the level of several tyrosinase-related proteins by Western blot analysis. In contrast to 3-hydroxyphloretin (7), which showed no effect on the level of these proteins, catechol (9) reduced their activity and the expression of the respective genes, as determined by quantitative real-time PCR. In a kinetic analysis of mushroom tyrosinase, 3-hydroxyphloretin (7) was a competitive inhibitor. These two constituents exhibited metal-coordinating interactions with copper ions in a virtual model of molecular docking with human tyrosinase. Thus, 3-hydroxyphloretin (7) and catechol (9) were the most active constituents from the Formosan apple; they exhibited anti-oxidant and tyrosinase reducing activities, suggesting their possible use as cosmetic agents3.
Hui-Min W, Chung-Yi C, Chun-Yen C, Mei-Ling H, Yi-Ting C, Hou-Chien Chang et al, reported in this study, a natural product, (_)-N-formylanonaine isolated from the leaves of Michelia alba D.C. (Magnolianceae), was found to inhibit mushroom tyrosinase with an IC50 of 74.3 lM and to have tyrosinase and melanin reducing activities in human epidermal melanocytes without apparent cytotoxicity to human cells, superior to the known tyrosinase inhibitors, such as kojic acid and 1-phenyl-2-thiourea (PTU). Based on homology modeling, the compound binds the active site by coordinating with two Cu2+ ions. In addition, the compound had antioxidation activities in tests for scavenging 1,1-diphenyl-2-picrylhydrazyl (DPPH), reducing power, and chelating metal ions. To our knowledge, this is the first study to reveal the bioactivities of (_)-N-formylanonaine from this plant species4.
Y.B. Ryu, I.M. Westwood, N.S. Kang, H.Y. Kim, J.H. Kim, Y.H. Moon et al. reported that it is well known that flavanones, sophoraflavanone G 1, kurarinone 2, and kurarinol 3, from the root of Sophora flavescens, have extremely strong tyrosinase inhibitory activity. This study delineates the principal pharmacological features of kurarinol 3 that lead to inhibition of the oxidation of L-tyrosine to melanin by mushroom tyrosinase (IC50 of 100 nM). The inhibition kinetics analyses unveil that compounds 1 and 2 are noncompetitive inhibitors. However similar analysis shows kurarinol 3 to be a competitive inhibitor. Compounds 1 and 2 exhibited potent antibacterial activity with 10 mg/disk against Gram-positive bacteria, whereas kurarinol 3 did not ostend any antibacterial activity. Interestingly, kurarinol 3 inhibits production of melanin in S. bikiniensis without affecting the growth of microorganism. It is thus distinctly different from the other tyrosinase inhibitors 1 and 2. In addition, kurarinol 3 manifests relatively low cytotoxic activity (EC50430 mM) compared to 1 and 2. To account for these observations, we conducted molecular modeling studies. These suggested that the lavandulyl group within 3 is instrumental in the interaction with the enzyme. More specifically, the terminal hydroxyl function within the lavandulyl group is most important for optimal binding6.
Antonella F, Marcella C, Benedetta E, M. Benedetta, Elias Q, Lourdes S et al. reported in their work the contribution of the coumarin moiety to tyrosinase inhibition. Coumarin-resveratrol hybrids 1-8 were resynthesized to investigate the structure-activity relationships and the IC50 values of these compounds were measured. They showed that these compounds exhibited tyrosinase inhibitory activity. Compound 3-(3’, 4’, 5’-trihydroxyphenyl)-6, 8-dihydroxycoumarin (8) is the most potent compound (0.27 mM), more so than umbelliferone (0.42 mM), used as reference compound. The kinetic studies revealed that compound 8 caused non-competitive tyrosinase inhibition8.
Nan Kyoung L, Kun Ho S, Hyeun Wook C, Sam Sik K, Haeil P, Moon Young et al. carried out tyrosinase assay in order to find new tyrosinase inhibitors and the effects of prenyl residue on flavonoid molecules, eight prenylated and three synthetic vinylated flavonoids were examined on their inhibitory effect against tyrosinase activity. From the results, kuwanon C, papyriflavonol A, sanggenon D and sophoflavescenol were found to possess the considerable inhibitory activity. Especially, sanggenon D is revealed as a potent inhibitor (IC50 = 7.3 μM), compared to the reference compound, kojic acid (IC50 = 24.8 μM). However, the prenylation with isoprenyl group or the vinylation to flavonoid molecules did not enhance tyrosinase inhibitory activity9.
Nico S, Jana V, Stan P. reported various naturally occurring skin whitening agents most of them which were competitive inhibitors of tyrosinase the key enzyme in melanogenesis and also others which inhibit the maturation of this enzyme or the transport of pigment granules (melanosomes) from melanocytes to surrounding keratinocytes. In this review they presented an overview of (natural) whitening products that may decrease skin pigmentation by their interference with the pigmentary processes10.
Santos P, Watkinson AC, Hadgraft J, Lane ME. reported the uses of the microemulsions in dermal & transdermal drug delivery. Microemulsions are thermodynamically stable colloidal dispersions of water and oil stabilized by a surfactant and, in many cases, also a co surfactant. In the pharmaceutical field, microemulsions have been used as drug carriers for percutaneous, ocular, oral and parenteral administration. This review discusses some of the applications of microemulsions specifically for topical and transdermal applications. Microemulsion nomenclature and composition, with particular emphasis on choice of surfactant and co surfactant, is discussed. Methods used to characterize microemulsions are reviewed. Microemulsion formulations for dermal and transdermal delivery of pharmaceutical agents with particular emphasis on anti-inflammatory and anaesthetic agents are critically evaluated. Finally, the issues which warrant further investigation by researchers in order to realize the full potential of the technology are discussed.11
Bidyut KP, Satya PM. reported that since the discovery of microemulsions, they have attained increasing significance both in basic research and in industry. Due to their unique properties, namely, ultralow interfacial tension, large interfacial area, thermodynamic stability and the ability to solubilize otherwise immiscible liquids, uses and applications of microemulsions have been numerous. The objective of this review is to present briefly the possible applications of the novel compartmentalized systems of microemulsions.14
Gallarate M, Carlotti ME, Trotta M, Grande AE, Talarico C. reported an o/w microemulsion formulated using lecithin and an alkyl glucoside as mild, non-irritant surfactant was proposed as a cosmetic vehicle for arbutin and kojic acid, naturally occurring whitening agents . After assessing the physicochemical stability of the microemulsion in the presence and absence of whitening agents, several perfumed compositions developed using fragrant molecules of natural or synthetic origin, were introduced and the olfactory impact of the perfumed microemulsion was evaluated. The photo stability to UVB irradiation of both whitening agents was determined in aqueous solutions and in microemulsion as and also in the presence of the perfumed compositions. The stability of arbutin and kojic acid was higher in microemulsions than in aqueous solutions, and only in some cases did the presence of odorous molecules appear to influence it: linalool exerted some protective effect towards kojic acid photodegradation.15
Navved A, Yasemin Y. reported the study to see the effect of two anti aging agents in one stable multiple emulsion prepared using natural oil. Vitamin C, which is a very unstable ingredient and is decomposed in the presence of oxygen, active as an antioxidant, was entrapped in the inner aqueous phase of w/o/w multiple emulsion. In this way, slow release can be expected and the effect of vitamin C can be increased since it is protected from the external environment by entrapping it in the internal phase. The other ingredient which is a product of wheat proteins was also used as an anti aging agent in the oily phase. Both of the ingredients increase the synthesis of collagen fibers in the dermis. Therefore, a synergistic effect can be produced by using the two ingredients in one formulation. In this study, multiple emulsions were prepared by the two-step method. Basic formulation containing no active material and a stable formulation containing vitamin C in the internal aqueous phase and wheat protein in the oily phase were prepared. The oil used was macadamia nut oil since it contains a high quantity of palmitoleic acid which is the natural ingredient of the young skin. Basic formulations as well as the active formulation after confirming their stabilities were applied to the cheeks of 11 human volunteers for four weeks. Different parameters of the skin were monitored every week to see any effect produced by these emulsions. The data obtained was evaluated statistically. It was found that the active formulation as well as base increased the moisture of the skin as verified by statistical tests. However, there were no significant variations in other parameters like skin sebum, pH, elasticity, melanin and erythema, concerning the two formulations.16
Sarmad AE, Saringat B. reported the formulation of nanoemulsion using virgin coconut oil (VCO)-in-water, nano-emulsion in the form of cream stabilized by Emulium Kappa® as an emulsifier, was prepared by using the Emulsion Inversion Point method. A nano-emulsion with droplet size <300 nm was then obtained. VCO has recently become a more popular new material in the cosmetic industries. Emulium Kappa® is an ionic emulsifier that contains sodium stearoyl lactylate, the active whitening ingredient was Kojic Dipalmitate. Ostwald ripening is the main destabilizing factor for the nano-emulsion. This decline can be reduced by adding non-soluble oil, namely squalene, to the virgin coconut oil. We tested VCO: squalene in the ratios of 10:0, 9.8:0.2, 9.6:0.4, 9.4:0.6, 9.2:0.8, 9:1 and 8:2 and discovered that squalene’s higher molecular weight (above critical molecular weight) resulted in low polarity and insolubility in the continuous phase. The continuous partitioning between the droplets results in the decline of Ostwald ripening. Furthermore, flocculation may occur due to the instability of nano-emulsion, especially for the preparations with little or no squalene at all. The stability of the nanoemulsion was evaluated by the electrophoretic properties of the emulsion droplets. The zeta potential values for the emulsion increased as the percentage of squalene oil increased.17
Pakpayat N, Nielloud F, Fortuné R, Tourne-Peteilh C, Villarreal A, Grillo I et al. reported ascorbic acid microemulsions for topical application were developed. In this study, microemulsions were prepared using HLD (hydrophilic lipophilic deviation) concept to optimise the formulation. From this optimal formulation, the realization of dilution ternary diagrams leads to obtain microemulsion zones. In addition, the effects of composition variable on the physicochemical characteristics of each system were investigated. After optimization of the microemulsion systems, ascorbic acid was loaded in the formulations. Surface tension and small angle neutron scattering were used to characterize the surface properties and the structure of the microemulsions. Bicontinuous structure microemulsions were identified, and the influence of ascorbic acid localization at the interface leading to modifications of the microemulsion structure was pointed out. The solubilization of ascorbic acid, the stabilization and in vitro transdermal penetration ‘‘Frantz cells” of ascorbic acid microemulsions were studied. Three different microemulsions were envisaged. The results confirmed that these microemulsion systems present a real interest for formulation and protection of ascorbic acid. Regarding their transcutaneous penetration behaviour, the different microemulsions studied could be useful for different topical applications. A major location of ascorbic acid found in the epidermis where the decomposition of melanin occurred indicates that microemulsion could be considered as a suitable carrier system for application of ascorbic acid as a whitening agent. In addition, a good passage of the drug in the dermis could be interesting for the relative oxygen matrix damage.18
Yi-Hung T, Ko-Feng L, Yaw-Bin H, Chi-Te H, Pao-Chu W. reported that hesperetin is one of the flavonoids and possess anti-inflammatory, UV-protecting and antioxidant effects. Permeation issues for topical delivery systems of such effects are occasionally problematic, and in view of the fact that microemulsions are potential carriers for transdermal delivery system, the objective of this study was to design an optimal microemulsion formulation by in vitro permeation study for hesperetin topical dosage form and determine its topical photo protective effect and skin irritation by in vivo study. The hesperetin-loaded microemulsion showed an enhanced in vitro permeation compared to the aqueous and isopropyl myristate (IPM) suspension dosage form of hesperetin. In comparison, the effect of co surfactant on the drug permeation capacity, propylene glycol showed highest permeation rate, followed by ethanol, glycerol and polyethylene glycol (PEG 400). Sunscreen agent padimate O, as a transdermal enhancer could increase the permeation rate of hesperetin. In case of in vivo study, the hesperetin loaded microemulsion showed significant topical whitening effect and diminished skin irritation when compared with the non-treatment group, indicating that the hesperetin microemulsion could be used as an effective whitening agent.19
Polona Š, Miha H, Andreja Z, Mirjana G. reported that sodium ascorbyl phosphate is a hydrophilic derivative of ascorbic acid, which has improved stability arising from its chemical structure. It is used in cosmetic and pharmaceutical preparations since it has many favorable effects in the skin, the most important being antioxidant action. In order to achieve this, it has to be converted into free ascorbic acid by enzymatic degradation in the skin. In the present work, o/w and w/o microemulsions composed of the same ingredients, were selected as carrier systems for topical delivery of sodium ascorbyl phosphate. We showed that sodium ascorbyl phosphate was stable in both types of microemulsion with no significant influence of its location in the carrier system. To obtain liquid microemulsions appropriate for topical application, their viscosity was increased by adding thickening agents. On the basis of rheological characterization, 4.00% (m/m) colloidal silica was chosen as a suitable thickening agent for w/o microemulsions and 0.50% (m/m) xanthan gum for the o/w type. The presence of thickening agent and the location of sodium ascorbyl phosphate in the microemulsion influenced the in vitro drug release profiles. When incorporated in the internal aqueous phase, sustained release profiles were observed. This study confirmed microemulsions as suitable carrier systems for topical application of sodium ascorbyl phosphate.20
6.3. Objective of the Study
Following are the objectives of the present study
To screen various herbal & non herbal ingredients for melanin inhibition activity.
To select suitable ingredient i.e. either herbal or non herbal.
To check the synergistic effect of the ingredients.
Formulation development of skin care product.
Accelerated stability studies.
Final Product evaluation.
Plan of work
The work will be executed as follows.
Screening of various herbal & non herbal components for skin whitening
Evaluation of efficacy of screened compounds.
Formulation and development of skin whitening product.
Final evaluation of formulated product.
Characterization of the formulated product.
Evaluation using a mexameter.
Skin sensitivity testing.
MATERIALS AND METHODS
Materials
Ingredients : Either herbal or non herbal eg. arbutin, azelaic acid, aloesin, glabrene etc
Additives : surfactants like lecithin, tweens spans, and other co surfactants of natural and synthetic origin.
Formulation and Development of skin care product by suitable technique. Like microemulsions or multiple emulsions, creams, lotions etc.
7.1 Source of Data
Review of Literature from
The details of the drug and dosage form has been collected from various standard books, journals and other sources like research literature databases such as Medline, Science direct, etc.
a) Journals such as,
International Journal of pharmaceutics.
Journal of Ethnopharmacology.
European Journal of Pharmaceutics and Biopharmaceutics.
International Journal of Molecular Sciences.
Journal of Food and Drug Analysis.
JOURNAL OF COSMETIC SCIENCE.
International Journal of Drug Delivery Technology.
Cellular and Molecular Life Sciences.
b) World Wide Web
c) J-gate@Helinet
Library: Siddaganga College of Pharmacy
e) E-library: Siddaganga College of Pharmacy
7.2 - Does the study require any investigations or interventions to be conducted on patients or other humans or animals? If so, please describe briefly.
“NOT APPLICABLE”
7.3 - Has ethical clearance been obtained from your institution in case of 7.3?
“NOT APPLICABLE”
8.0
REFERENCES
Baurin N, Arnoult E, Scior T, Do QT, Bernard P. Preliminary screening of some tropical plants for anti tyrosinase activity. Journal of Ethnopharmacology 2002;82:155-158.
Andrea P, Cassandra L, Maria LV, Paola M, Giulia S, Luigina S et al. Ethnopharmacognostic survey on the natural ingredients used in folk cosmetics, cosmeceuticals and remedies for healing skin diseases in the inland Marches, Central-Eastern Italy. Journal Ethnopharm 2004;91:331–344.
Yi-Pei L, Feng-Lin H, Chien-Shu C, Ji-Wang C, Mei-Hsien L. Constituents from the Formosan apple reduce tyrosinase activity in human epidermal melanocytes. Phytochemistry 2007;68:1189–1199.
Hui-Min W, Chung-Yi C, Chun-Yen C, Mei-Ling H, Yi-Ting C, Hou-Chien C et al. (-)-N-Formylanonaine from Michelia alba as a human tyrosinase inhibitor and antioxidant. Bioorg. Med Chem 2010;18:5241–5247.
Chan EWC, Lim YY, Wong LF, Lianto FS, Wong SK, Lim KK et al. Antioxidant and tyrosinase inhibition properties of leaves and rhizomes of ginger species. Food Chem 2008;109:477-483.
Ryua YB, Westwoodb IM, Kanga NS, Kima HY, Kima JH, Moonc YH et al. Kurarinol, tyrosinase inhibitor isolated from the root of Sophora flavescens. Phytomedicine 2008;15:612–618.
Mahmud Tareq HK, Iqbal MC, Atta-ur-R, Reyhan PM, Manzura AA, Mukhlis NS et al. Tyrosinase inhibition studies of cycloartane and cucurbitane glycosides and their structure–activity relationships. Bioorg. Med Chem. 2006;14:6085–6088.
Antonella F, Marcella C, Benedetta E, Benedetta MF, Maria JM, Elias Q et al. Tyrosinase Inhibitor Activity of Coumarin-Resveratrol Hybrids. Molecules 2009;14:2514-2520.
Lee NK, Kun HS, Chang HW, Kang SS, Park H, Heo MY et al. Prenylated Flavonoids as Tyrosinase Inhibitors.Arch Pharm Res 2004;27:1132-1135.
Smit N, Vicanova J, Pavel S. The Hunt for Natural Skin Whitening Agents. Int. J. Mol. Sci. 2009;10:5326-5349.
Santos AC, Watkinson J, Hadgraft ME, Lane. Application of Microemulsions in Dermal and Transdermal Drug Delivery. Skin Pharmacol Physiol 2008; 21:246–259.
Rao YS, Deepthi K, Chowdary KPR. Microemulsions: a novel drug carrier system. IJDDT 2009;1(2):39-41.
Azeem A, Rizwan M, Ahmad FJ, Khan ZI, Khar RK, Aqil M et al. Emerging Role of Microemulsions in Cosmetics. Recent Pat Drug Deliv Formul 2008;2:275-289.
Paul KP, Moulik SP. Uses and applications of microemulsions. Current science. 2001;8:990-1001.
Gallarate M, Carlotti ME, Trotta M, Grande AE, Talarico C. Photostability of naturally occurring whitening agents in cosmetic microemulsions. J. Cosmet. Sci. 2004;55:139-148.
Akhtar N, Yazan Y. Formulation and in vivoevaluation of a cosmetic multiple emulsion containing vitamin c and wheat protein. Pak. J. Pharm. Sci. 2008;21:45-50.
Sarmad A, Saringat B. Formulation and stability of whitening VCO-in-water nano-cream. Int J pharm. 2009;373:174–178.
Pakpayat N, Nielloud F, Fortuné R, Tourne-Peteilh C, Villarreal A, Grillo I et al. Formulation of ascorbic acid microemulsions with alkyl polyglycosides. Eur J Pharm Biopharm 2009;72:444–452.
Yi-Hung T, Ko-Feng L, Yaw-Bin H, Chi-Te H, Pao-Chu W. In vitro permeation and in vivo whitening effect of topical hesperetin microemulsion delivery system. Int J pharm. 2010;388:257–262.
Polona Š, Miha H, Andreja ZV, Mirjana G. Sodium ascorbyl phosphate in topical microemulsions. Int J pharm. 2003;256:65–73.
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