PA nd | -toas wise L EPT: 2 PRINCI Or. KAMLA PATHAKAText Book Of COSMETIC SCIENCE Concepts & Principles As Per PCI Regulations B. PHARM. Semester VIII Dr. Kamla Pathak M. Pharm. (Pharmaceutics); Ph D (Pharmacy) Professor Pharmacy College Saitai Uttar Pradesh University of Medical Sciences Saifai, Etawah 206130, Uttar Pradesh Dr. Ankur Vaidya M. Pharm, (Pharmaceutical Chemistry); Ph D (Pharmacy) Assistant Professor Pharmacy College Saifa Uttar Pradesh University of Medical Sciences Saifai, Etawah 208130, Uttar Pradesh Instagram - @Study_Pharmacy_29 NIRALI PRAKASHAN COV TSPreface Inclusion of “Cosmetic Science” as an individual elective subject in B. Pharmacy Curriculum by the Pharmacy Council of India is laudable. It prepares students for careers in the consumer products industry, researching, developing, and testing new cosmetics, perfumes, toiletries, household products, and more. The contents of the book are in accordance to syllabus prescribed for the elective subject Cosmetic Science, by Pharmacy Council of India. Care has been taken to incorporate all the elements described in the syllabus. Additional topics that might be useful for a student gearing up for cosmetic industry have also been included. The language is kept as simple as possible and illustrations have been used for easy grasping. In order to directly correlate the product description examples of marketed products have been included. This however does not imply that the authors are in any way promoting the exemplified product. We hope this book will be a valuable guide for not only getting success in the examinations but also for those pursuing career in cosmetic industry. Particular effort has been made to avoid mistakes, but if found and brought to our notice, will be corrected in the next edition. Kamla Pathak Ankur Vaidya Instagram - @Study_Pharmacy_29Acknowledgement W. render our regards to: * Dr. (Brig, T. Prabhakar, Vice Chancellor, Uttar Pradesh University of Medical Sciences, Saifai, Etawah, Uttar Pradesh 206130. © Prof. Devender Pathak Dean (Pharmacy), Pharmacy College Saifai, UPUMS, Etawah 206130. Kamla Pathak Ankur Vaidya Instagram - @Study_Pharmacy_29Pee (rnNcere ar First Edition : February 2018 lo 2 Authors The test of this publication, or any part thereof, should not be reproduced of transmitted in any form or stored in any compute storage system or device for distribution including photocopy, recording, taping or information retrieval system or reproduced on any disc, Rape, perforated rredio or other nlormation storage devce ete, wihout the written permission of Authors with whom the ngMs ar reserved. Breach of this condition is lable for legal acto. Every effort has been made to avoid ero" or omissions in ths publication In spite of this, ertors may have crept. 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Tol : (080) 64513344, 64513355, Mob : 9880582331, 9845021552 Emaikbharatsavla@yahoo.com CHENNAI Pragati Books : 9/1,Montieth Road, Behind Taas Mahal, Egmore, ‘Chennai 600008 Tamil Nadu, Tel : (044) 6518 3535, Mob : 94440 01782 / 98450 21582 / 98805 82331, Email: bharatsavla@yahoo.com Note = Every possible effort has been made 0 avoid errors or amissons inthis book. In spe 1s, errors may have crepin. Any fpe of ero jor mistake so noted, and shall be brought to our notice, shal be teen care of inthe next edtion. tis notified that neither the publisher, nor Ihe author or book seller shall be responsible for any damage or loss of action to any one of any kind, in any manner, thereftom. The reader} Imust cross check all the facts and contents wth original Government notification or publicationContents 1. Cosmetics and Cosmeceuticals: Definition and Evolution 1.1 -1.32 1.1 Definition of Cosmetics as per Indian Regulations 14 1.1.1 Cana Product be both a Cosmetic and a Drug? 11 1.1.2 Establishing Product's Intended Use 13 1.2 Cosmetic Regulation in US 13 1.3 Cosmetic Regulation in the European Union 14 1.3.1. The United States and European Union: Regulating Cosmetic Safety 14 1.4 Cosmetic Regulation in Japan 15 1.5 Cosmetic Regulation in Canada 15 1.6 Cosmeceuticals 1.6 1.6.1 Skin Cosmeceuticals 1.6 1.6.2, Hair Cosmeceuticals 1,13 1.6.3 Other Cosmeceuticals 114 1.6.4 Rationale to Create a Cosmeceutical Category 1.15 1.7 Cosmetics as Quasi Drugs 1.16 1.7.1. Whitening Quasi Drugs 117 1.7.2. Mechanism of QDs 1.20 1.7.3 Perspectives 1.21 1.8 Cosmetics as OTC Drugs 1.22 1.8.1 Cosmetic OTC drugs 1.23 1.8.2 Cosmetic Monographs 1.25 1.9 Key components of a regulatory model for Cosmeceuticals in Indian Context 1.26 Classification of Cosmetics and Cosmeceutical Products 2.1-2.18 Introduction 21 2.1. Classification of Cosmetics 24 2.1.1 Regulatory Aspects 27 2.2 Cosmeceuticals 27 2.2.1 Mechanism of Action of Cosmeceuticals 2.8 2.2.2 Classification of Cosmeceutical Products. 29 2.2.3 Formulation Considerations 2.14 2.2.4 Regulating Cosmeceuticals 214 2.2.5 Categorization of Cosmeceuticals in Few International Markets 2.15 Cosmetic Excipients 3.1-3.22 Introduction 3.1 3.1 Surfactants 3.2 3.1.1 Types of Surfactants 3.3 3.1.2 Surfactant in Shampoos and Conditioners 3.4 3.2 Rheology Modifiers 3.6 3.2.1 Mechanism of Action 3.83.3 3.4 3.5 Preservatives 3.3.1 Types of Cosmetic Preservatives Humectants 3.4.1 Classification of Humectants 3.4.2. Humectants for Hairs 3.4.3 Hair Penetrating Oils 3.4.4 Anti Humectants Emollients 3.5.1 Classification of Emollients Skin and Skin Care Products 41 Introduction 41 42 43 44 45 46 Hair and Hair Preparations 5.1 5.2 5.3 5.4 5.5 5.6 57 5.8 Structure of Skin 4.1.1 Functions of Skin Cleansers and Face Wash Cleansers Moisturizing Cream 4.4.1 Classification 4.4.2 Disadvantages of Moisturizer Cold Cream 4.5.1 Beeswax-Borax Emulsion Type Cold Cream 4.5.2. Sensory Advantages of Cold Cream 4.5.3. Limitation 4.5.4 Cold Cream as Cosmeceutical Vanishing Creams 4.6.1. Sensory Advantages of Vanishing Cream 4.6.2. Limitations 4.6.3. Vanishing Creams as Cosmeceuticals Hair Structure Hair Growth Cycle Hair Care Products Conditioning Shampoo 5.4.1 CO-WASHES/CO-POOS Hair Conditioners 5.5.1 Types of Conditioners Antidandruff Shampoo Hair Oils 5.7.1. Classification of Hair Oils 5.7.2. Indian Standards for Oil Hair Dye 5.8.1 Classification of Hair Dyes 5.8.2. Chemistry of Permanent Hair Colouring 5.8.3 Plant based dyes9. Oral Cavity: Problems and Products for Care 6.1 - 6.20 Introduction 61 6.1 Gum Disease 63 6.1.1 Treatment 65 6.2 Bleeding Gums 66 6.2.1 Bleeding Gums Treatment 67 6.2.2 Therapy and Care 67 6.3 Tooth Sensitivity 6.10 6.4 Care for dental senstivity and toothpaste 611 6.4.1 Fluoride Toothpastes 6.11 65 Tooth Discolouration 6.12 6.6 Teeth Whitening 6.14 6.7 Halitosis — Bad Breath 6.16 68 Cold Sores 6.17 6.9 Mouth Ulcers 6.17 6.10 Mouth Washes 6.18 Sun Protection 71-712 Introduction 7 7.1 Sunscreens 72 7.1.1 Physical Sunscreens 72 7.1.2. Chemical Sunscreens 73 7.2. Sunscreening Agents 76 7.2.1 Baby Sunscreens 77 7.3. Sun Protection Factor 78 7.4 Water Resistant Sunscreens 7.10 Herbs in Cosmetics 8.1-8.24 Introduction 81 8.1 Herbal Cosmetics for Skin Care 8.4 8.1.1 Aloe vera 8.10 8.1.2 Turmeric 8.11 8.2 Herbal Cosmetics for Hair Care 8.12 8.2.1 Henna 8.15 8.2.2. Amla (Embilica officinalis) 8.16 8.3 Herbal Cosmetics for Oral Care 8.17 83.1 Clove 8.18 8.3.2 Neem (Azadirachata indica) 8.19 8.4 Quality Control of Herbal Cosmetics 8.20 Analytical Cosmetics 9.1 - 9.36 9.1 Bureau of Indian Standards 91 9.2. Shampoo 9.2 9.3. Toothpaste 9.13 9.4. Skin Creams 9.2910. 411. 12. 13. 14, Principles of Evaluation of Cosmetics Introduction 10.1 Sebumeter 10.2 Corneometer 10.3 Moisture Meter 10.4 Tewameter 10.5 Skin Colour Measurement 10.6 Hair Tensile Strength 10.7 Hair Combing Properties Soaps and Syndet Bars Introduction 11.1 Soaps 11.1.1 Vegetable Soap 11.2 Bathing Bars 11.3 Syndet Bar 11.4 Soap Versus Syndet 11.5 Cleanser Variants Cosmetic Skin Problems 12.1 Blemishes 12.1.1 Preventing Blemishes 12.2 Wrinkles 12.3 Acne Vulgaris 12.4 Prickly Heat 12.5 Body Odour Cosmetic Hair Problems 13.1 Dandruff 13.2 Hair Loss Antiperspirants and Deodorants 14.1 Hyperhidrosis 14,2 Mechanism of action 10.1 - 10.22 10.1 10.2 10.5 10.6 10.7 10.11 10.16 10.20 11.1- 11.8 114 11.2 113 11.4 11.5 11.6 17 12.1 -12.16 12.1 12.2 12.6 12.9 12.11 12.13 13.1 - 13.6 13.1 13.4 14.1-14.8 14.1 14.3 YouTube - Study PharmacySyllabus BP809ET : COSMETIC SCIENCE (THEORY) [45 Hours] Unit 1 [10 Hours] Classification of Cosmetic and Cosmeceutical Products. Definition of Cosmetics as per Indian and EU regulations, Evolution of Cosmeceuticals from Cosmetics, Cosmetics as Quasi and OTC drugs. Cosmetic excipients: Surfactants, Rheology modifiers, Humectants, Emollients, preservatives. Classification and Application. : Basic Structure and Function of skin. : Basic Structure of Hair. Hair growth cycle. Oral Cavity: Common problem associated with Teeth and Gums. Unit 1 [10 Hours] Principles of Formulation and Building Blocks of Skin Care Products: Face Wash, Moisturizing cream, Cold Cream, Vanishing Cream and their Advantages and Disadvantages. Application of these products in Formulation of Cosmecuticals. Antiperspants and deodorants: Actives and Mechanism of Action. ples of formulation and Building Blocks of Hair Care Products: Conditioning Shampoo, Hair Conditioner, Anti-Dandruff Shampoo. Hair Oils. Chemistry and Formulation of Para-phylene Diamine based hair dye. Principles of Formulation and Building Blocks of Oral Care Products: Toothpaste for Bleeding Gums, Sensitive Teeth. Teeth Whitening, Mouthwash. Unit OT [10 Hours] Sun Protection, Classification of Sunscreens and SPF. Role of herbs in cosmetics: Skin Care: Aloe and Turmeric. Hair Care: Henna and Amla. Oral Care: Neem and Clove. Analytical Cosmetics: BIS Specification and Analytical Methods for Shampoo, Skincream and Toothpaste. Unit IV [08 Hours] Principles of Cosmetic Evaluation: Principles of Sebumeter, Corneometer. Measurement of TEWL, Skin Color, Hair tensile strength, Hair combing Properties. Soaps and Syndet Bars. Evolution and Skin Benefits. Unit V [07 Hours] Oily and Dry Skin, Causes leading to Dry Skin, Skin Moisturisation. Basic Understanding of the terms Comedogenic, Dermatitis. Cosmetic problems associated with Hair and scalp: Dandruff, Hair fall causes. Cosmetic problems associated with skin: blemishes, wrinkles, acne, prickly heat and body odor. Antiperspirants and Deodorants: Actives and mechanism of action.Unit I Chapter ... 1 COSMETICS AND COSMECEUTICALS: DEFINITION AND EVOLUTION + LEARNING OBJECTIVES ¢ This chapter would enable the students to learn about: * Definition of Cosmetics as per Indian Regulations * Regulations of Cosmetics in various countries across globe * Introduction to Cosmeceuticals and their future prospects * Understanding Cosmetics os Quasi Drugs and their Mechanism * Understanding Cosmetics os OTC Drugs © FDA Monograph of Cosmetic/OTC Products Instagram - @Study_Pharmacy_29 1.1 DEFINITION OF COSMETICS AS PER INDIAN REGULATIONS As per Section 3(aaa) of the Drugs and Cosmetics Act 1940 and Rules 1945, Cosmetic means any article intended to be rubbed, poured, sprinkled or sprayed on, or introduced into, or otherwise applied to, the human body or any part of body for cleansing, beautifying, promoting attractiveness, or altering the appearance, and includes any article intended for use as a component of cosmetic. Whether a product is a cosmetic or a drug under the law, is determined by a product's intended use. Different laws and regulations apply to each type of product. Firms sometimes violate the law by marketing a cosmetic with a drug claim or by marketing a drug as if it were a cosmetic, without adhering to requirements for drugs. Cosmetics are regulated in India under the provisions of the Drugs and Cosmetic Act 1940 and Rules 1945 vide Gazette notification G.S.R 426(E). The copy of the Gazette notification GSS.R 426 (E) is available in Linkchttp://cdsco.nic.in/cosmetics/ G.S.R 426 (E).pdf. 1.1.1 Can a Product be both a Cosmetic and a Drug? Some products meet the definitions of both cosmetics and drugs. This may happen when a product has two intended uses. For example, a shampoo is a cosmetic because its intended use is to cleanse the hair. An antidandruff treatment is a drug because its intended use is to treat dandruff. Consequently, an antidandruff shampoo is both a cosmetic and a drug. (ayCosmetic Sclence (Sem. Vill) 1-2 Cosmetics and Cosmeceuticals Among other cosmetic/drug combinations are toothpastes that contain fluoride, deodorants that are also antiperspirants, and moisturizers and makeup marketed with sun-protection claims, Such products must comply with the requirements for both cosmetics and drugs. The scope of effects/efficacies of general cosmetic products is listed in Table 1.1. Table 1.1: The scope of effects/efficacies of general cosmetic products 1 g 2: Pd 2 a 15. 16. 19. 20. 21. 22. To clean hair and scalp. To reduce bad odor from hair and scalp by using aroma. To maintain health of hair and scalp. To increase bounce and resilience of hair. To increase moisture of hair and scalp. To maintain moisture of hair and scalp. To increase suppleness of hair. To make hair combing easier. To maintain gloss of hair. . To increase gloss of hair. . To remove dandruff and itching. . To reduce dandruff and itching. . To replenish and maintain moisture and oil of hair. To prevent split ends, breakage, or damaged hair. To dress hair and maintain a hair style. To prevent electrostatic charges in hair. . To clean skin (by removing dirt). 18. (Facial cleaners) To prevent pimples and prickly heat (by washing). To condition skin. To improve skin texture. To maintain health of skin, To prevent skin roughness. . To tighten skin. 24, . To replenish and maintain moisture and To increase moisture of skin. oil of skin. 26. 27. 2 29. 30. 3. 32. 33. 34, 35. 36. 37. 3% 3s 40. 4 4 43. 44, 4 & 4 4 49, 50. 2 Pp 2 SP . To maintain health of lips. 46. = N To maintain suppleness of skin. To protect skin. To prevent dry skin. To soften skin. To increase bounce of skin. To increase gloss of skin. To smoothen skin. To make shaving easier. To condition skin after shaving. To prevent prickly heat powder). To prevent sunburn. To prevent spots or freckles due to sunburn. To impart aroma. To protect nails. To maintain health of nails. (applying To increase moisture of nails. To prevent chapped lips. To improve texture of lips. To increase moisture of lips. To protect lips and prevent dry lips. To prevent stiff lips due to dryness. To smoothen lips. To prevent cavities (toothpaste, etc, for brushing teeth). To whiten teeth (toothpaste, etc, for brushing teeth).Cosmetic Sclence (Sem. Vill) 1-3 Cosmetics and Cosmeceuticals 4.4.2 Establishing Product's Intended Use The intended use of a product may be established in a number of ways. The following are some examples: * Claims stated on the product labeling, in advertising, on the Internet, or in other promotional materials. Certain claims may cause a product to be considered as a drug, even if the product is marketed as if it were a cosmetic. Such claims establish the product as a drug because the intended use is to treat or prevent disease or otherwise affect the structure or functions of the human body. Some examples are claims that products will restore hair growth, reduce cellulite, treat varicose veins, increase or decrease the production of melanin (pigment) in the skin, or regenerate cells. * Consumer's perception may be established through the product's reputation. This means asking why the consumers buying it and what the consumer expects it to do. * Ingredients that cause a product to be considered a drug because they have a well- known (to the public and industry) therapeutic use. An example is fluoride in toothpaste. This principle also holds true for "essential oils.” For example, a fragrance marketed for promoting attractiveness is a cosmetic. But a fragrance marketed with certain “aromatherapy” claims, such as assertions that the scent will help the consumer sleep or quit smoking, meets the definition of a drug because of its intended use. Similarly, a massage oil, that is simply intended to lubricate the skin and impart fragrance is a cosmetic, but if the product is intended for a therapeutic use, such as relieving muscle pain, it's a drug. 41.2 COSMETIC REGULATION IN US The FD&C Act defines cosmetics by their intended use, as “articles intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to the human body for cleansing, beautifying, promoting attractiveness, or altering the appearance” (FD&C Act, sec. 201(i)). Among the products included in this definition are skin moisturizers, perfumes, lipsticks, fingernail polishes, eye and facial makeup, cleansing shampoos, permanent waves, hair colors, and deodorants, as well as any substance intended for use as a component of a cosmetic product. It does not include soap. But, if the product is intended for a therapeutic use, such as treating or preventing disease, or to affect the structure or function of the body, it's a drug (FD&C Act, 201(g)), or in some cases a medical device (FD&C Act, 201(h)), even if it affects the appearance. Other "personal care products” may be regulated as dietary supplements or as consumer products. The two most important laws pertaining to cosmetics marketed in the United States are the Federal Food, Drug, and Cosmetic Act (FD&C Act) and the Fair Packaging and Labeling Act (FPLA). FDA regulates cosmetics under the authority of these laws. In the United States, federal laws are enacted by Congress. In order to make the laws work on a day-to-day level, Congress authorizes certain government agencies such as FDA, to create regulations. A change in FDA's legal authority over cosmetics would require Congress to change the law.Cosmetic Sclence (Sem. Vill) 1-4 Cosmetics and Cosmeceuticals 1.3 COSMETIC REGULATION IN THE EUROPEAN UNION The European Union Cosmetics Directive defines a cosmetic as “any substance or preparation intended to be placed in contact with the various extemal parts of the human body (epidermis, hair system, nails, lips and extemal genital organs) or with the teeth and the mucous membranes of the oral cavity with a view exclusively or mainly to cleaning them, perfuming them, changing their appearance and/or correcting body odours and/or protecting them or keeping them in good condition. “The European Union requires that cosmetic products placed on the EU market be safe; that is, they "must not cause damage to human health when applied under normal or reasonably foreseeable conditions of use.” Asin the US, manufacturers are responsible for ensuring that cosmetic products comply with the law before they are marketed. The manufacturer or importer of cosmetics is responsible for demonstrating that the product is safe for its intended use. Regulations are enforced at the national level, and each country in the EU has an authoritative body that is responsible for upholding compliance. The 27 European Union Member States have transposed the European Union Cosmetics Directive, enacted in 1976, into national law, Each Member State has health authorities which then regulate cosmetics within their respective national boundaries according to the law. 1.3.1 The United States and European Union: Regulating Cosmetic Safety The United States (US) and European Union (EU) both work to ensure the safety of cosmetics for consumers through rigorous regulation. In the United States, the cosmetics industry is regulated by the U.S. Food and Drug Administration (FDA) which has been granted broad regulatory authority under the federal Food, Drug and Cosmetic Act, enacted in 1938. In both the United States and the European Union, cosmetics manufacturers ensure product safety prior to marketing, list all ingredients on the product label and comply with any restrictions that are established for cosmetic ingredients and products. Any potential risk from a product is assessed as part of its safety evaluation. In the US, the Cosmetic Ingredient Review (CIR) Expert Panel conducts independent safety reviews of ingredients as a part of the cosmetic safety process, with the results published in the International Journal of Toxicology and on the CIR website. The EU Scientific Committee on Consumer Safety is responsible for reviewing all special and active cosmetic ingredients and assessing conditions for safe use. The results are subsequently published on the Committee's website, In the United States, cosmetic and personal care products companies work with leading scientific and medical experts every day and invest millions of dollars in sophisticated laboratory equipment and facilities to ensure cosmetic product safety. In addition to this strong commitment to safety, federal law requires that every cosmetic product be substantiated for safety before it goes to market. The FDA statistics confirm that cosmetics are one of the safest product categories used by Americans today.Cosmetic Sclence (Sem. Vill) 1-5 Cosmetics and Cosmeceuticals The US and EU have slightly different ways of regulating the cosmetic and personal care industry, but both systems provide consumers with a high degree of safety. Some argue that cosmetics are more strictly regulated in the EU, citing recent actions taken in the EU to red flag or ban certain chemicals from use in cosmetics. However, an examination of Annex I of the EU Cosmetics Directive, a list of approximately 1,300 banned ingredients, reveals that a large number of those chemicals are not used and never have been used in cosmetics in the US. or Europe. For example, the EU list includes substances such as jet aircraft fuel, various petroleum refinery byproducts and carbon monoxide. Another difference between the EU and USS. systems of regulating cosmetics is that the EU allows the marketing of cosmetic products with certain medicinal effects, while the United States has required extra regulatory hurdles because they are classified as drugs. Some of the substances include sunscreens, anti-caries toothpaste and lip balms, Even though color additives are not classified as over-the-counter (OTC) drug actives, they are also subject to. more regulatory scrutiny in the US than they are in Europe. 1.4 COSMETIC REGULATION IN JAPAN The Japanese government regulates the cosmetics industry through its Ministry of Health, Labor and Welfare according to the Pharmaceutical Affairs Law (Law No. 145) established on August 10, 1960. Japan has adopted a list of prohibited ingredients, a list of restricted ingredients, a positive list of UV filters and a positive list of preservatives. Other than these restrictions, the burden of ensuring product safety has been shifted to cosmetic manufacturers. As such, any ingredient that can be shown to be safe may be used in a cosmetic product. Until recently, a manufacturer or importer of cosmetics was required to obtain a pre-market approval and license from the Ministry of Health, Labor and Welfare. Since 2001, however, Japanese cosmetics companies are required only to provide notification of the product's brand prior to manufacturing or importing. Japan is an excellent example of a nation where costly pre-market registration procedures were replaced with manufacturer responsibility for product safety and with post-market surveillance (similar to the systems in the U.S, and EU) without compromising consumer safety. 1.5 COSMETIC REGULATION IN CANADA The Canadian government regulates the cosmetics industry through Health Canada's Cosmetics Program. The basis for the regulatory authority for the Cosmetics Program comes from the Food and Drugs Act and Cosmetic Regulations, Cosmetics are defined as "any substance or mixture of substances, manufactured, sold or represented for use in cleansing, improving or altering the complexion, skin, hair or teeth and includes deodorants and perfumes." This definition also includes cosmetics used by professional esthetic services, as well as bulk institutional products (e.g. hand soap in school restrooms). Health Canada's Cosmetics Program has the mandate to protect the health of Canadians by minimizing theCosmetic Sclence (Sem. Vill) 1-6 Cosmetics and Cosmeceuticals risk associated with the use of cosmetics marketed in Canada, The program defines and communicates requirements for the manufacture, labelling, distribution and sale of cosmetics, and evaluates compliance. As in the US, manufacturers are responsible for ensuring that products comply with the law before they are marketed. The manufacturer or porter of cosmetics is responsible for demonstrating that the product is safe for its intended use. Regulations are enforced by Health Canada, and are overseen by Product Safety Officers who manage inspections, investigations, seizures, recalls and prosecutions from regional offices. 4.6 COSMECEUTICALS. Background The Egyptians were the first to recognize the health properties of cosmetics. Up to the 19th century, there was no clear distinction between cosmetics and pharmaceuticals; the separation occurred when the first modern pharmaceutical industry was developed. Cosmeceuticals rapidly expanded in the 1980s due to hydroxy acids (natural fruit acids) used as exfoliants against wrinkles. Raymond Reed, founding member of the United States Society of Cosmetic Chemists, coined the term ‘Cosmeceutical’ in 1961. In 1971, Albert Klingman reactivated interest in cosmeceuticals by developing a formula to improve the appearance of UV damaged and wrinkled skin, using retinoic acid. They are applied topically as cosmetics, but contain ingredients that influence the skin's biological function. Cosmeceuticals improve appearance, but they do so by delivering nutrients necessary for healthy skin, Desirable features of cosmeceutical agents are efficacy, safety, formulation stability, novelty, and patent protection, metabolism within skin and inexpensive manufacture. Even though some products claim to be unique botanical extracts or containing some rare ingredients with magic anti-aging properties, most of the cosmeceutical formulations use fundamental ingredients such as peptides, retinol, coenzyme Q-10, ceramides, alipoic acid, a-hydroxy acids, B-hydroxy acids, Aloe vera, panthenol, kinetin and vitamin A, C, E. 1.6.1 Skin Cosmeceuticals Cosmetics and skin care products are the part of everyday grooming. Protecting and preserving the skin is essential to good health. Skin, the largest organ in the body, separates, and protects the internal environment from the external one. UV radiations from sunlight penetrate the skin and accelerate damage due to free radicals, which includes inflammation, wrinkling and hyper- pigmentation. Due to prolonged exposure to UV radiation, the collagen and elastin fibres of the skin are broken down by enzymes collaginase and elastate and the texture of skin deteriorates. Collagen and elastin are responsible for maintaining the elasticity and integrity of the skin. Cosmeceuticals being cosmetic products having medicinal or drug- like benefits are able to affect the biological functioning of skin owing to the type of functional ingredients they contain. There are skin care products that go beyond coloring and adorning the skin. These products improve the functioning/texture of the skin byCosmetic Science (Sem. Vill) 1-7 Cosmetics and Cosmeceuticals encouraging collagen growth by combating harmful effects of free radicals, thus maintaining keratin structure in good condition and making the skin healthier. Table 1.2 enlists the desirable attributes from each category of cosmeceutical. Table 1.2: Types and Efficacies of Cosmeceutical Products Type of Cosmeceutical Effect / Efficacies Product Shampoo Prevents dandruff and itching. Prevents bad odor of hair and scalp. Cleans hair and scalp. Maintains health of hair and scalp. Improves suppleness of hair and scalp. Rinse Prevents dandruff and itching. Prevents bad odor of hair and scalp. Replenishes and maintains moisture and oil of hair. Prevents split ends, breakage, or damaged hair. Maintains health of hair and scalp. Improves suppleness of hair and scalp. Beauty lotion Treats rough or chapped skin. Prevents prickly heat, chilblains, chapping, cracks, or pimples. Treats oily skin. Prevents razor burn, Prevents spots or freckles due to sunburn. Treats hot flashes due to sunburn or snowburn. Tightens, cleans or conditions skin. Maintains health of skin or increases moisture of skin. Cream, milky lotion, hand | Treats rough or chapped skin. cream, and cosmetic oil Prevents prickly heat, chilblains, chapping, cracks or pimples. Treats oily skin. Prevents razor burn. Prevents spots or freckles due to sunburn. Treats hot flashes due to sunburn or snowburn. Tightens, cleans, or conditions skin. Maintains health of skin or increases moisture of skin. Protects skin or prevents dry skin. contd. ...Cosmetic Science (Sem. Vill) 1-8 Cosmetics and Cosmeceuticals Shaving preparation Prevents razor burn, Protects skin and makes shaving easier. Sunscreen Prevents skin roughness due to sunburn or snowburn. Prevents sunburn or snowburn. Prevents spots or freckles due to sunbum. Protects skin. Face pack Treats skin roughness or chapped skin. Prevents pimples. Treats oily skin, Prevents spots or freckles due to sunburn. Treats hot flashes due to sunburn or snowburn. Smoothens skin. Cleans skin. Medicated soap Soap with a disinfectant as the main agent (including facial cleaners) | Cleans, disinfects, or sanitizes skin. Prevents bad body odor and prevents pimples. Soap with antiphlogistic as the main agent Cleans skin and prevents pimples, razor burn and skin roughness. OLAY vitamin line, which includes vitamins A, C, D, E, selenium, and lycopene, pycnogenol plus zinc and copper, is a well established skin care line. The treatment of aging skin with a cream containing a hormone such as estrogen results in a fresh appearance with a rejuvenating effect. Dry emollient preparation containing monounsaturated Jojoba esters is used for cosmeceutical purpose. Novel cosmetic creams or gels with active ingredients and water-soluble barrier disruption agents such as vitamin A palmitate have been developed to improve the deteriorated or aged skin. Plant extract of genus Chrysanthemum have been utilized in a cosmetic composition for stimulating skin and/or hair pigmentation. In general, vitamins, herbs, various oils, and botanical extracts may be used in cosmeceuticals, but the manufacturer may not claim that these products penetrate beyond the skin's surface layers or that they have drug like or therapeutic effects. For cosmetic labels, no division between active ingredients and other ingredients is required; they are all listed together. The most important botanicals pertaining to dermatologic uses, such as cosmeceuticals, include teas, soy, pomegranate, date, grape seed, pycnogenol, horseCosmetic Science (Sem. Vill) 1-9 Cosmetics and Cosmeceuticals chestnut, German chamomile, curcumin, comfrey, allantoin, and aloe; only green and black tea, soy, pomegranate, and date have been studied to the extent that clinical trials. Few botanical-based cosmeceuticals have uses that are supported by evidence-based science. The anti-aging creams currently in the market include Rosmarinus officinalis, Vitis vinifera (grape seed extract), citronellol, Limonene, Oenothera biennis (evening primrose), Glycyrrhiza glabra (licorice extract), Aframomum angustifolium seed extract, diosgenin (wild yam), N6 furfuryladenine (kinetin), and ergothioneine. Randomized controlled trials are still needed, although some ingredients may have a scientific basis for their use. Chemoprevention by oral or topical use of dietary or pharmacologic agents to inhibit or reverse the development of cancer is a possibility. Potential cosmeceutical agents in this category include green tea, grape seed extract, vitamin £, and beta-carotene. Table 1.3 highlights the cosmeceutical agents obtained from botanical sources. Table 1.3: A Cross-section of Botanical based Cosmeceuticals available Commercially a-hydroxy acid Exfoliates and improves circulation (Fm: Asphodelaceae) Fruit acids (citric acid, tartaric acid, pyruvic aci maleic acid) Cosmeceutical | Purported action Source Commercial agent preparation Allantion Skin soothening Comfrey Soft cleansing (Fm: Boraginaceae) _| emulsion Aloe vera Softens skin Aloe vera Lotus herbal moisturizer Garnier anti-wrinkle preparation formation (Fm: Asteraceae) - bisabolol Anti-inflammatory, | Chamomile flower _| Adrien Arpel C, ry, Ps antibacterial, calms | (Fm: Asteraceae) Vitamin C Facial irritated skin Treatment Capsules Boswellia Anti-inflammatory Boswellia serrata Aroma silk boswelia and antiaging (Fm:Burseraceae) anti-wrinkle cream B-carotene Minimizes lipid Carrots and Environ body cream peroxidation and | tomatoes cellular antioxidant | (Fm: Umbelliferae and Solanacea) Calendula Softens, soothens Calendula Weleda calendula skin, promotes cell | officinalis paste contd. ...Cosmetic Sclence (Sem. Vill) 1-10 Cosmetics and Cosmeceuticals Coleus forskoflii oil Antimicrobial, aromatherapy/ perfumer Coleus spp. Ayush neem plus Coenzyme Q1O (Ubiquinone) Cellular antioxidant Naturally occurring in skin Lavere sensation cream smoothes, rejuvenates and promotes youthful (Fm: Ginkgoaceae) Essential fatty acids | Smoothens, Linolenic and Parachute hair oil moisturizes and arachidonic Acid protects Lupeol Antioxidant and Crataeva nurvula | Seatonic stretch skin conditioning —_| (Fm: Ceapparidaceae) | mark removing agent cream Ginko Antioxidant that Ginkgo biloba Embryo revitalizer cream Neem oil limonoids properties, anti- oxidant, anti- microbial and anti- inflammatory Antimicrobial Azadirachta indica (Fm: Meliaceae) appearance Green tea extract | Antioxidant Green tea Alchemy conditioner (Camellia sinensis) Licorice extract Skin whitening Glycyrrhiza glabra__| Liquorice balm Himalaya neem face wash (lemon, citrus fruits, oils from sunflower and safflower) Retinoic acid Smoothes skin, Vitamin A Renova cream promotes cell renewal and improves circulation to skin Turmeric oil Antibacterial and | Curcuma longa Vicco turmeric anti-inflammatory | (Fm: Zingiberaceae)_| cream Vitamin A Antioxidant Vitamin ACE Everyouth peelCosmetic Sclence (Sem. Vill) 1-11 Cosmetics and Cosmeceuticals Some cosmeceutical agents widely used for topical application are described below. Retinoids A great amount of research has concentrated on its use as an anti-aging compound as well as its use for other cutaneous disorders. Vitamin A and its derivatives have two main functions: they act as antioxidants, and they activate specific genes and proteins. Structural changes underlying the cosmetic benefits include correction of epidermal atrophy, deposition of new collagen, generation of new vessels, and enhancement of mitogenesis. This enhanced mitogenesis promotes the shedding of melanin-laden keratinocytes, resulting in bleaching and subsequent depigmentation. The ability of topical tretinoin to improve the appearance of aged and photo-damaged skin by reducing wrinkles, decreasing laxity, bleaching hyperpigmented spots, and bringing about a smoother surface have been well studied and documented. Hydroxy acids Hydroxy acids are organic carboxylic acids classified into alpha hydroxy acids (AHAs) and beta hydroxy acids (BHAs) according to their molecular structure. Many are derived from natural sources and are often referred to as fruit acids. The different AHAs include: glycolic acid, lactic acid, citric acid, mandelic acid, malic acid, and tartaric acid. AHAs have shown to decrease the signs of aging. The skin appears smoother and more uniform. BHAs are aromatic compounds. Salicylic acid is the reference BHA; it has dermolytic properties and helps in various xerotic and ichthyotic disorders. Other BHAs include 2-hydroxy-5-octanoyl benzoic acid, also known as B-lipohydroxy acid and tropic acid. Studies show that AHAs may increase sensitivity to UV radiation and that sunscreen application may be advisable when these products are used. Antioxidants In addition to the external insults like UV radiation, drugs, air pollutants, and heat and/or cold, the skin also has to cope with endogenous mitogens, most importantly Reactive Oxygen Species (ROS) and other free radicals. These species are continuously produced during physiological cellular metabolism. To counteract the harmful effects of ROS, the skin is, equipped with an antioxidant system to maintain equilibrium between the pro-oxidants, or damaging agents, and the antioxidants, or protective agents; these antioxidants intervene at different levels in the protective process. The examples of antioxidants include vitamin C, vitamin E(a-tocopherol), panthenol, lipoic acid, niacinamide, dimethylaminoethanol, spin traps [species that react with reactive free radicals to produce fairly stable, unreactive free radicals, thus blocking the free radicals from damaging cellular components e.g. DMPO (5, 5-dimethyl-1-pyrroline-N-oxide), DEPMPO (5-diethoxyphosphoryl-5-methyl-1-pyrroline- N-oxide), TEMPONE-H (1-hydroxy-2, 2, 6, 6-tetramethyl-4-oxo-piperidine]. Others include melatonin (a hormone secreted by the pineal gland), catalase, glutathione, superoxide dismutase, glucopyranosides, polyphenols, cysteine, uric acid and carnosine,Cosmetic Sclence (Sem. Vill) 1-12 Cosmetics and Cosmeceuticals Allantoin Allantoin promotes cell proliferation, aiding in the healing process. Allantoin has long been known to enhance the effectiveness and desirability of cosmetic creams and lotions by its action as a skin protectant. Allantoin has been incorporated into shampoos, lipsticks, shaving creams, sun tanning products, bath foams, hair gels, baby powders, and various aerosol preparations. Allantoin has been called a cell proliferant, an epithelization stimulant, and a chemical debrider. It is said to clean away necrotic tissue, hastening the growth of new healthy tissue. Furfuryladenine Furfuryladenine (Kinerase) is a natural plant growth factor that retards the aging process in plants. It is marketed as the natural evolution of anti-aging treatment with similar effects in vitro on human skin cells as that in plants, helping to slow and reverse alterations that naturally occur in the cell-aging process. Depigmenting agents Hyperpigmentation is the result of an increased amount of melanin in the epidermis, the dermis, or both. This pigmentary change can be divided into two pathophysiological processes: melanocytosis (increased number of melanocytes) and melanosis (increased amount of melanin). Hyperpigmentation, the most common and distressing condition afflicting a large subset of the population, requires cosmeceutical skin-lightening agents and corrective camouflage formulations. Combination agents with sunscreen are often the most effective treatment available. Depigmenting agents work best when melanosis or melanocytosis is restricted to the epidermis. Depigmenting agents can be divided into several groups: 1. Phenolic compounds include the following: Hydroquinone, monobenzylether of hydroquinone, 4-methoxyphenol, 4-isopropylcatechol, 4-hydroxyanisol, N-acetyl-4- S-cysteaminylphenol. 2. Non-phenolic compounds include the followin. acid, N -acetylcystein, L-ascorbyl-2-phosphate. 3. Kojic acid combination formulae including: Kligman's formula, Pathak's formula, Westerhof's formula. Sunscreens Regular use of an effective sunscreen is the most important step to maintain healthy, youthful-looking skin. Primarily, the ultraviolet light from the sun causes most of the visible effects of ‘aging’ skin. Traditional chemical sunscreens act primarily by binding to skin protein and absorbing ultraviolet B (UVB) photons (280-320 nm) and most are based on para- aminobenzoic acid (or its derivatives), cinnamates, various salicylates and benzophenones, dibenzoylmethanes, anthraline derivatives, octocrylene and homosalate. Avobenzone (Parsol-1789) is a benzophenone with excellent ultraviolet A (UVA) protection. Physical Corticosteroids, tretinoin, azelaicCosmetic Science (Sem. Vill) 1-13 Cosmetics and Cosmeceuticals agents, or sun blocks, act as barriers, which reflect or scatter radiation. Direct physical blockers include metal containing compounds such as iron, zinc, titanium, and bismuth. Zinc oxide and titanium dioxide are highly reflective white powders, but submicron zinc oxide or titanium dioxide powder particles transmit visible light while retaining their UV blocking properties, thus rendering the sun block invisible on the skin. Some commercially available sunscreens are benzophenone-8, Neo Heliopan MA and BB, Parsol MCX and HS, Escalol 557, 587 and 597. A patent reports a sunscreen composition comprising of activated platelet factor as an ingredient in a cosmeceutically acceptable carrier. Such a composition in the form of a shaving cream or foam, after shave lotion, moisturizing cream, sun tan lotion, lipstick, would assist in restoring the skin to its natural condition when the skin is damaged by cuts, abrasions, sun, wind, and the like. Moisturizers Moisturizers function to smooth out the age lines, help brighten, and tone the delicate skin, Moisturizers usually incorporate emollients to smoothen the skin surface by working their way into the non-living outer layers of the skin, filling spaces between the layers and lubricating, and humectants to help skin cells to absorb and retain moisture in these layers. Healthy Remedies Balancing Lotion® has been created for menopausal women containing ingredients, which diminish the appearance of fine lines, and wrinkles, uplift the neck area and moisturize the dry, sagging skin. Some of those ingredients include black cohosh, soy extract, and vitamins A and E. Augmenting the skin's natural moisture balance is a nourishing complex containing hyaluronic acid and a revival complex containing green tea leaf extract, and glutathione. Bleaching agents Bleaching agents are used for bleaching/fading the various marks and act to block the formation of the skin pigment melanin. Hydroquinone is the most commonly used agent for ‘bleaching’ brown marks, liver spots and melasma. It has been developed as a synthetic detergent bar for skin-bleaching. The bar is composed of a synthetic anionic detergent, hydroquinone, a stabilizer for hydroquinone, water, a buffer which maintains the pH between 4 and 7, and excipients such as waxes, paraffin, dextrin, and starch. Similarly, a skin bleaching preparation comprising hydroquinone, tertiary butyl hydroquinone, and optionally an additional stabilizer and buffer to maintain the pH between about 3.5 and 7.5 has also been developed. Because of the maintenance of low pH and the presence of a stabilizer, hydroquinone is not oxidized and thus the product is characterized by an extended shelf life. 4.6.2 Hair Cosmeceuticals Hair care, color, and style play an important role in individual's physical appearance and self perception. Among the earliest forms of hair cosmetic procedures in ancient Egypt were hair setting by the use of mud and hair coloring with henna. In ancient Greece and Rome, countless ointments and tonics were used for the beautification of the hair, as well asCosmetic Sclence (Sem. Vill) 1-14 Cosmetics and Cosmeceuticals remedies for the treatment of scalp diseases. While shampoos have primarily been products aimed at cleaning the hair and scalp, current formulations are adapted to the variations associated with hair quality, hair care habit, and specific problems such as treatment of oily hairs, dandruff and for androgenic alopecia related to the superficial condition of the scalp. Cosmetics for the treatment of hair are applied topically to the scalp and hair. While they can never be used for therapeutic purposes, they must be harmless to the skin and scalp, to the hair, and to the mucous membranes and should not have any toxic effect, general or local, in normal conditions of their use. A hair care cosmetic composition comprising iodopropynyl butylcarbamate and/or a solution of zinc pyrithione in N-acyl ethylenediamine triacetate has been patented, which includes an appropriate carrier and a non-allergenic dry extract of yarrow (Achillea millefolium L.), obtained by oxidation of a water- alcohol solution extract of flower tops of yarrow. The extract containing less than 0.5% by weight of polyphenolic derivatives, is used for the treatment of hair, in particular oily hair, based on extract of yarrow. A patent describes a method for treatment for androgenic alopecia wherein Liquor Carbonic Detergents are topically applied. It is generally accepted that genetic hair loss arises from the activation of an inherited predisposition to circulating androgenic hormones. Typically, a hair cosmeceutical product includes - conditioning agents, special care ingredients, and hair growth stimulants. Conditioning agents are intended to impart softness and gloss, to reduce flyaway and to enhance disentangling facility. A number of ingredients may be used, mostly fatty ingredients, hydrolyzed proteins, quaternized cationic derivatives, cationic polymers, and silicones. Accordingly, current antidandruff ingredients are virtually all-effective antifungal agents — zinc pyrithione, octopirox, and ketoconazole. Hair growth stimulants cannot be expected to have any impact on hair growth due to short contact time and water dilution. A minoxidil-related compound (2, 4-diamino-pyrimidine-3-oxide) is a cosmetic agent with claim of acting as a topical hair growth stimulant. Its target of action has been proposed to be the prevention of inflammation and perifollicular fibrosis. Some degree of efficacy of 2, 4-diamino-pyrimidine-3-oxide has been claimed in the prevention of seasonal alopecia. In United States recent approval of two new products, Propecia and Rogaine Extra Strength (Minoxidil) 5%, indicated in men to promote scalp hair growth, have added a new dimension to treatment options offered by physicians in treating androgenetic alopecia. 1.6.3 Other Cosmeceuticals The skin beneath the eye lacks subcutaneous fat and has virtually no oil glands. This delicate skin needs protection and plenty of moisture to replenish and repair, which helps to reduce the signs of premature aging. As the skin ages, it becomes thinner, drier, and rougher. Over-exposure to the elements and to environmental pollution aggravates this condition. Many topical skin soothing products intervene in this process, but products for this area need to be particularly gentle and specially formulated with ingredients that work from theCosmetic Science (Sem. Vill) 1-15 Cosmetics and Cosmeceuticals inside out by interacting with the cells under the skin's surface — without irritating the eyes. There are numerous cosmeceutical eye creams that nourish the skin with natural emollients and beneficial nutrients. The other functional ingredients include butcher's broom, chamomile, and vitamin E, antioxidants — vitamins A, C and E, green tea and tiare flower, Ginkgo biloba and also cucumber, calendula and a-bisabolol, an active constituent of chamomile, to calm irritated skin. A key ingredient in the eye lifting moisture cream — that treats puffiness, irritation, and also protects against future skin damage is yeast which helps to plump up the wrinkles. The eye wrinkle cream helps to forestall the signs of aging and generally contains wheat germ and corn oil, squalene and carrot extract. Eye firming fluid has aosain, an algae extract from seaweed that helps the skin to maintain elasticity. Lawlor had developed dental care compositions, which are useful for providing a substantive composition on the surfaces of oral cavity, which can provide prophylactic, therapeutic, and cosmetic benefits. 1.6.4 Rationale to Create a Cosmeceutical Category Absence of proper regulatory framework and dilemma over understanding of the term cosmeceuticals has become undue advantage of cosmetic manufacturer. Manufacturing, labeling, sale and advertisement of such products need proper regulatory framework to safegaurd the interest of consumers and control the regulatory market. The current legal definitions of drugs and cosmetics are arachic and unworkable. At present the dividing line between the two is not sharp and the transition towards acceptability of cosmeceuticals is relatively slow as far as regulatory framework is concerned. The regulatory framework shall help to (support use of pharmaceuticals by health care professionals. (ii) ensure and provide factual information to public regarding pharmaceuticals. (iii) protect the consumers from unproven claims and unsafe products. (iv) drive the growth and export of pharmaceuticals. By the addition of small amount of cosmeceutical agents to the cosmetic formulations which do not require medical regulations would improve the production of cosmeceuticals that could help to improve the skin, nail, and body mass growth. New challenges will also be presented to government regulatory agencies as more chemicals with true biological activity are invented and tested. In conclusion, cosmeceuticals are not only for the external beautification but also for improvement of the internal beauty through the health related function. The convergence of cosmetics and foods, so-called nutricosmetics, refers to oral supplementation of nutrients, marketed mainly for anti-aging effects, ie. reducing wrinkles by fighting free radicals generated by solar radiation. Nutricosmetics include antioxidants such as carotenoids (beta-carotene, lycopene, lutein, zeaxanthin, and astaxanthin) and polyphenols (anthocyanidins, catechins, flavonoids, tannins, and procyanidins).Cosmetic Science (Sem. Vill) 1-16 Cosmetics and Cosmeceuticals Quasi-drugs are a unique product classification in Japan. A quasi-drug is defined in Japan as product that has minimal to moderate pharmacologic activity, but is restricted in use to specific indications. Quasi-drugs in Japan include categories of products that are often defined as drugs, cosmetics or Over-the-Counter (OTC) products in other regions. Products in this class include some energy drinks containing taurine, some vitamin preparations, hair tonics, bath preparations, skin whitening products, acne products, anti-dandruff shampoos, fluorinated toothpaste, hair dyes and many others. These products are considered as borderline medicinal products, which are categorized differently in various markets. Manufacturers of quasi drugs need to be accredited by the Minister of Health, Labor and Welfare (MHLW) according to Article 13-3 of the Japanese Pharmaceutical Affairs Law (JPAL). This applies to domestic manufacturers as well as to foreign manufacturers when importing products into Japan. Essentially this means that in Japan such products must be manufactured under CGMP conditions and the supply chain managed in a similar way as a drug product. Additionally, a pre-marketing approval of all quasi-drugs is required by the Pharmaceutical and Food Safety Bureau of the MHLW applies according to Article 14 of the PAL. For the application of the marketing approval a foreign manufacturer must appoint a drug marketing authorization holder (MAH) in Japan who performs all procedures with the MHLW on behalf of the applicant. The MAH can as well apply for the manufacturing license of the manufacturer and is also authorized to market the products. All summary documentation and forms filed for the market authorization applications is required to be submitted in Japanese. The MAH must also comply with all regulations for the holder of a market authorization for a drug in Japan. This means that the MAH must have a quality representative, medical safety officer and General Manager who are qualified to take responsibility for release of the medicinal product in Japan. The regulatory agency conducting the scientific reviews for the marketing approval is the Pharmaceuticals and Medical Devices Agency (PMDA), which also monitors the post marketing safety. Recently the PMDA has translated many of their key regulations and guidelines into English to facilitate interactions with foreign companies. The information required for the marketing approval for a quasi-drug is similar to that of a new drug product. This information includes detailed information on the quality and controls of the ingredients, manufacturing information, stability, storage conditions, expiration date, and quality controls. Additionally, a detailed description of the manufacturing sites of the ingredients and of the drug should be provided. All ingredients of a quasi-drug must have a monograph in the Japanese Pharmacopoeia and comply with the given criteria, They must have an active ingredient declared and when the active ingredient is used within the dosage that was previously approved for other products, the marketing authorization typically takes approximately 8 months. However, when the dose of the active ingredient is higher than previously approved, additional non-clinical data to evaluate theCosmetic Sclence (Sem. Vill) 1-17 Cosmetics and Cosmeceuticals safety, efficacy and stability of the product may need to be provided which requires a lead- time of approximately two years. Changes to the product after approval are completed as an amendment to the market authorization and can take from two weeks for very simple modifications to more than eight months for major changes. Although, when compared to cosmetics, the pre-marketing steps for quasi-drugs are more extensive, marketing of the product is similar and quasi drugs are sold without prescription or restrictions in distribution. Quasi-drugs also have restrictions with regards to the volume of the product sold to limit the exposure to consumers. As such, quasi-drug products cannot be sold in volumes of greater than 100 ml in volume. The labeling must also carefully comply with requirements for quasi-drugs and must provide the consumer with an understanding of what the product contains, the purpose and appropriate dosing instructions. The information must be factual without exaggeration and must be clearly stated on the container or box the container is held in when sold. The requirements for the labeling under the Pharmaceutical Affairs Law are: Name and address of manufacturer Product Trade Name Manufacturers serial number or manufacturing code Listing of all ingredients Weight or volume of the unit of use Expiration date Category name Warnings regarding use and handling Description of the container 474 Whitening Quasi Drugs Skin lightening or whitening quasi-drugs (QDs), a category created in Japan for functional cosmetics, contain active ingredients that prevent or improve hyperpigmentation in disorders, such as melasma and solar lentigo. Although much still remains unknown about the causes of hyperpigmentation, it is thought that the localized and irregular over- production of melanin by melanocytes in the basal layer of the epidermis or the retention of melanin in the epidermis due to aberrant epidermal turnover, or both, play a role in hyperpigmentary disorders. Development of topical materials to treat these cosmetic hyperpigmentary disorders, with the goal of reducing excess melanin production and promoting clearing of accumulated melanin from the epidermis, has contributed significantly to the understanding of melanogenesis and pigmentation as physiological processes. Skin Lightening QDs Developed in Japan Until the late 1980s, ascorbic acid (also termed Vitamin C) and placental extracts were used as skin lightening QDs in Japan. Since 1988, starting with the approval of kojic acid by the MHLW, many companies have begun to develop proprietary QDs. POnanawneCosmetic Science (Sem. Vill) 1-18 Cosmetics and Cosmeceuticals 1. Ascorbic acid and its derivatives Melanin synthesis is regulated by the rate-limiting enzyme, tyrosinase, a membrane- bound copper-containing glycoprotein, which initiates the biosynthetic pathway of melanin by catalyzing the hydroxylation of tyrosine to DOPA. Since subsequent reactions in the melanin synthetic pathway, e.g, the conversion of DOPA to DOPAquinone, as well as other non-enzymatic reactions, are oxidative reactions, antioxidants such as ascorbic acid, are effective inhibitors of melanin synthesis. Ascorbic acid and its derivatives are the most popular skin lightening QDs that have ever been used in Japan (Table 1.4). In clinical trials, a 10% magnesium L-ascorbic acid 2-phosphate-containing formulation was shown to be effective for reducing melasma and age spots. A 2% L-ascorbic acid 2-glucoside-containing cream was shown to accelerate the disappearance of ultraviolet light B (UVB) (280-320 nm)- induced hyperpigmentation of the skin. Table 1.4: Ascorbic acid and its derivatives used as popular skin lightening QDs in Japan Ascorbic acid derivative Mechanism QD approval obtained by | Year Magnesium L-ascorbic | Prevents Takeda Pharmaceutical 1988 acid 2-phosphate polymerization of Company Limited melanin monomers involved in the immediate pigment darkening of the skin Sodium L-ascorbic acid _| Antioxidation Shiseido Co, Ltd. and 1994 2-phosphate, L-ascorbic Kaminomoto Co. acid 2-glucoside L-ascorbic acid ethyl ester_| Antioxidation Shiseido Co, Ltd. 2005 2. Placental Extracts Placental extracts have long been used as an active ingredient for skin lightening QDs, together with ascorbic acid and its derivatives. Previously, a bovine-derived placental extract was the primary commercial source. However, swine-derived placental extracts are now used because of concern over mad cow disease. Various amino acids and minerals are at high concentrations in placental extracts, and the efficient inhibition of melanin synthesis and the enhancement of melanin removal from the skin, occurs due to increased epidermal turnover. Interestingly, although placental extract has a strong history of use to decrease hyperpigmentation, it has also been shown to increase melanogenesis. The lipid fraction of human placental extract was reported to increase melanin synthesis via the enhancement of tyrosinase gene expression.Cosmetic Science (Sem. Vill) 1-19 Cosmetics and Cosmeceuticals 3. Kojic Acid Kojic acid, a pyrone derivative obtained from the fermentation process of Japanese liquor, is known to have an antibacterial activity. Kojic acid was shown to inhibit the activity of tyrosinase by chelating copper atoms in its active site. In clinical trials, a 1% kojic acid- containing formulation was shown to be effective for treating hyperpigmentary disorders, such as melasma, post-inflammatory hyperpigmentation, age spots, and freckles. It was obtained by Sansho Seiyaku Co,, Ltd, in 1988. The MHLW in March, 2003 notified suppliers of kojic acid to delay manufacture or import because of caution about possible carcinogenic effects. However, after revaluation in November, 2005, kojic acid is now accepted to be safe as a cosmetic ingredient, and continues to be used as a skin lightening QD. 4, Ellagic Acid Ellagic acid is a naturally occurring polyphenol found in a variety of plants, such as strawberries, geraniums, and green tea. The inhibitory effect of ellagic acid on melanin synthesis is similar to kojic acid, ie, ellagic acid inhibits tyrosinase activity by chelating copper atoms in its active site. A 0.5% ellagic acid-containing cream was shown to be effective for treating UVB-induced hyperpigmentation of the skin. It was obtained as QD by Lion Corporation in 1996. 5. Arbutin Arbutin, a naturally occurring B-D-glucopyranoside derivative of hydroquinone, is found in cowberry leaves, and inhibits tyrosinase activity competitively, but at non-cytotoxic concentrations in cultured melanocytes. A 3% arbutin-containing formulation was shown to be effective for treating hyperpigmentary disorders, such as melasma. It was obtained by Shiseido Co, Ltd. in 1989. 6. 4-n-Butylresorcinol (Rucinol®) Rucinol® was selected by screening synthetic resorcinol derivatives that can elicit strong competitive inhibition of tyrosinase activity. Melanin synthesis is catalyzed by tyrosinase, together with tyrosinase-related proteins (TRP) -1 and -2, and Rucinol® has been shown to inhibit melanin synthesis in cultured mouse melanocytes via direct inhibition not only of tyrosinase activity, but also of TRP-1 activity. A 0.3% Rucinol®-containing lotion was shown to be effective for treating hyperpigmentary disorders, such as melasma. As QD it was procured by POLA in 1998, 7. Chamomnilla Extract Chamomilla extract has been used as a traditional anti-inflammatory agent, and is the only one so far, in Japan, that has been approved as a skin lightening QD from botanical extracts. It has been shown that keratinocytes secrete endothelin-1, a type of inflammatory cytokine, which activates melanocytes when UV is irradiated on the epidermis. Chamomilla extracts have been shown to act as an antagonist for endothelin-receptor binding, which mediates cell-to-cell signaling between keratinocytes and melanocytes. This antagonismCosmetic Science (Sem. Vill) 1-20 Cosmetics and Cosmeceuticals leads to the inhibition of melanin synthesis in melanocytes. Until then, all earlier skin lightening QDs had been developed to inhibit tyrosinase activity. In contrast, the chamomilla extract is a unique QD focused on affecting the keratinocytes that surround melanocytes. A 0.5% chamomilla extract-containing cream was shown to be effective for treating UvB-induced hyperpigmentation of the skin. For use as QD it was obtained and commercialized by Kao Corporation. 8. Linoleic Acid Obtained by Sunstar Inc. in 2001, linoleic acid is an unsaturated fatty acid (C 18:2) derived from hydrolyzed botanical oils, such as safflower, and is a major component of biological cell membranes. Tyrosinase is degraded endogenously in melanocytes, and linoleic acid has been shown to accelerate tyrosinase degradation, and to decrease tyrosinase levels. These actions lead to the down-regulation of melanin synthesis. In clinical trials, topical application of a 0.1% linoleic acid-containing liposomal formulation has been shown to be effective for treating melasma and to lighten UVB-induced hyperpigmentation of the skin. 9. Tranexamic acid Tranexamic acid (obtained by Shiseido Co, Ltd in 2002) has been used as a traditional hemostatic medicine, and is known as an oral medicine for treating melasma, Plasmin, a kind of protease in the blood serum, functions to enhance the intracellular release of arachidonic acid, a precursor of prostanoid, and also to elevate alpha-melanocyte stimulating hormone processed from pro-opiomelanocortin. Both arachidonic acid and alpha-melanocyte stimulating hormone can activate melanin synthesis by melanocytes. Therefore, the anti- plasmin activity of tranexamic acid is thought to play a role in its topical effectiveness for treating melasma. 10. Others Other skin whitening QDs include: 4-methoxy potassium salicylate (4MSK) (obtained by Shiseido Co,, Ltd. in 2003); Adenosine monophosphate disodium salt (obtained by Otsuka Pharmaceutical Co., Ltd. in 2004); 5,5'-dipropyl-biphenyl-2,2'-diol (Magnolignan®) (obtained by Kanebo Cosmetics Inc. in 2005); 4-(4-Hydroxyphenyl)-2-butanol (obtained by Kanebo Cosmetics Inc. in 2007); and tranexamic acid cetyl ester hydrochloride (obtained by CHANELKK in 2009). 4.7.2 Mechanism of QDs Till date, many private company-originated QDs have been developed that are based on various mechanisms of skin lightening or whitening efficacy (Table 1.5). The major target of those QDs is tyrosinase in melanocytes, while some QDs work on keratinocytes or on epidermal metabolism. An efficient way to decrease tyrosinase protein levels is to reduce tyrosinase mRNA levels, as already reported for lipoic acid and sphingosine-1-phosphate. However, compounds that regulate transcription have not yet been approved by the MHLW of Japan for skin lightening QDs.Cosmetic Sclence (Sem. Vill) 1-21 Cosmetics and Cosmeceuticals Table 1.5: Mechanism of skin whitening QDs approved in Japan Target Mechanism Details Skin lightening QD Melanocyte | Inhibition of Anti-oxidation Ascorbic acid and its tyrosinase activity derivatives Competitive inhibition | Arbutin, Rucinol,AMSK, 4-HPB Chelating copper atoms | Kojic Acid, ellagic acid Decrease of Acceleration of Linoleic acid tyrosinase protein | tyrosinase_ degradation level Inhibition of tyrosinase | Magnolignan® maturation Keratinocyte | Inhibition of KC-MC_| Inhibition of UV Chamomilla extract signaling inflammation Tranexamic acid/derivative Epidermis | Acceleration of Desquamation of Placental extract epidermis turnover _| melanin Adenosine mono- phosphate 1.7.3 Perspectives Now-a-days, many of the hyperpigmentary disorders of the skin can be remedied by various laser therapies. Moreover, the chemical peeling of the stratum corneum using c-hydroxy acids, such as glycolic acid and lactic acid, has also been shown to be modestly effective for treating hyperpigmentary disorders, such as melasma, due to the desquamation of melanin from the epidermis. In addition, this accelerated desquamation is often used to enhance the efficacy of other treatments. Hydroquinone is currently the gold standard topical drug for dyschromia. It remains somewhat controversial however, and at one time, was available only by prescription, because it has been associated with several adverse events. For example, vitiligo-like effects and exogenous ochronosis have been reported after hydroquinone use. In addition, the US FDA has stated that hydroquinone cannot be ruled out as a potential carcinogen and therefore is prohibited for use in cosmetics. However, a change of Japanese Pharmaceutical Law in 2001 now allows the use of hydroquinone as an ingredient of cosmetic formulations at lower and presumably safer concentrations. Hyperpigmentary conditions indicated for skin lightening QDs developed in Japan are limited, that is, clinical trials have demonstrated their efficacy mostly against melasma and solar lentigo. Nevertheless, those QDs remain popular, especially in Asian cosmetic markets, as a convenient means to treat non-pathological hyperpigmentary disorders of the skin.Cosmetic Science (Sem. Vill) 1-22 Cosmetics and Cosmeceuticals In conclusion, the system for distribution of some products, now called quasi-drugs, in Japan was relaxed in 2004. However, those products that are defined as quasi-drug products are still subject to significant regulatory control. While these products are sold directly to the consumer, they must be approved by the MHLW and must meet requirements similar for medicinal products. However, the system in Japan also allows for wide distribution of some products with few limitations on the ability to sell the products to consumers. Thus, the market for quasi-drugs is attractive for many companies, both domestic and foreign, and represents a large market opportunity for these products in Japan. 1.8 COSMETICS AS OTC DRUGS The FDA has the authority to regulate personal care products that contain active ingredients that are Over-The-Counter (OTC) drugs. OTC drugs used in personal care products including cosmetics are subject to FDA approval. Generally, drugs must either receive pre-market approval by FDA or conform to final Federal regulations specifying conditions whereby they are generally recognized as safe and effective, and not misbranded. Currently, certain but not all OTC drugs (that is, non-prescription drugs) that were marketed before the beginning of the OTC Drug Review (May 11, 1972) may be marketed without specific approval pending publication of final rules and regulations under the ongoing OTC Drug Review. Once a regulation covering a specific class of OTC drugs is final, those drugs must either be the subject of an approved New Drug Application (NDA), or comply with the appropriate Federal rules for an OTC drug. The FD&C Act defines drugs, in part, by their intended use, as “articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease” and “articles (other than food) intended to affect the structure or any function of the body of man or other animals". The FD&C Act does not recognize any such category as “cosmeceuticals." The main difference between cosmeceuticals and over-the-counter cosmetics is the concentration of active ingredients. Cosmeceuticals contain many more active ingredients and in much higher concentrations. These active ingredients can therefore penetrate deeper into the dermis layer of the skin, which results in more visible, longer-term benefits. A product can be a drug, a cosmetic, or a combination of both, but the term cosmeceutical has no meaning under the law. OTC drugs are often marketed side by side with cosmetics, and some products qualify both as cosmetics and as OTC drugs. This may happen when a product has two intended uses, with ingredients intended to do two different things. For instance, a shampoo is a cosmetic, since its intended use is to cleanse the hair. An anti-dandruff treatment is a drug, because its intended use is to treat dandruff, Consequently, an antidandruff shampoo is both a cosmetic and a drug. Among other cosmetic/drug combinations are toothpastes that contain fluoride, deodorants that are also antiperspirants, and moisturizers and makeup marketed with sun-protection claims.Cosmetic Science (Sem. Vill) 1-23 Cosmetics and Cosmeceuticals 1.8.1 Cosmetic OTC drugs Antidandruff agents (e.g. in Shampoos) Dandruff occurs when skin cells on the scalp form too fast, meaning more skin cells are shed and become clumps that can be seen by the naked eye. This may be for a variety of reasons- product built up in the hair like shampoo, conditioner, hair spray, gel, wax etc. that's not washed and rinsed properly. A major reason is abnormally high levels of a fungus called Malassezia globosa, which is a type of yeast and is always found on the scalp, even in those without dandruff. Inherent factors like diet, stress levels, weather conditions, hair type (oily hair type is more susceptible to dandruff) and even genetics play a role to some extent. An antidandruff shampoo can be used to break and wash away any product build up in your hair to leave it clean. The antidandruff agents include zinc pyrithione, ketoconazole, selenium sulphide, coal tar, salicylic acid, tea tree oil etc. Although in non-medicated brands these are added in marginal amounts, it's not advisable to use them every day (try alternate days) or leave on the scalp for too long a period. Usually 2-5 minutes should suffice. In medicated brands the concentration of these active ingredients is usually high. Selection of antidandruff shampoo should be made wisely according to hair type. Where the one meant for dry hair will leave the hair moisturised, one meant for oily hair will to strip most oils out of the hair. Additionally, these special formulations in anti-dandruff shampoos tend to temporarily re-balance the scalp's pH balance. Most shampoos vary on the types as well as the strength of these ingredients; hence the pH balance effect does not usually last for long. Most shampoos take about 6-8 weeks of regular use to show results. Fluorides (e.g. in Toothpastes) Fluoride toothpastes make up more than 95% of all toothpaste sales. It is well recognized that the decline in the prevalence of dental caries recorded in most industrialized countries over the past 30 years can be attributed mainly to the widespread use of toothpaste that contain fluoride. Investigations into the effectiveness of adding fluoride to toothpaste have been carried out since 1945 and cover a wide range of active ingredients in various abrasive formulations. Fluoride compounds and their combinations which have been tested for the control of dental decay include sodium fluoride, stannous fluoride, sodium monofluoro- phosphate and amine fluoride. The amount of fluoride contained in fluoride toothpaste should be indicated on the toothpaste tube, although this information may sometimes be hard to locate. It may appear after the label "Active ingredient" or as a component under “Ingredients” on the toothpaste tube. Whereas previously fluoride content was given as a percent of volume (% w/v) or weight (% w/w), it is now accepted that the most efficient method of informing people of the amount of fluoride in a toothpaste is to give the “parts per million” fluoride (ppm F). Most manufacturers now give fluoride content in ppm F. Under EU Directive 76/768/EEC, toothpastes are classified as cosmetic products. EU Directives governing cosmetic products prohibit the marketing of cosmetic products (including toothpastes) with over-the-counter levels of fluoride greater than 1,500 ppm F. FluorideCosmetic Sclence (Sem. Vill) 1-24 Cosmetics and Cosmeceuticals toothpastes are more effective at preventing tooth decay at higher fluoride concentrations. If needed for therapeutic reasons, toothpastes containing more than 1,500 ppm F (e.g, 2,800 ppm F) are available, but may be obtained only with a prescription. Sun protecting agents (e.g. in Sunscreens) Sunscreen, also known as suncream or sunblock, is a lotion, spray, gel or other topical product that absorbs or reflects some of the ultraviolet (UV) radiation and thus helps to protect against sunburn. Skin-lightening products have sunscreen to protect lightened skin because light skin is more susceptible to sun damage than darker skin. Depending on the mode of action, sunscreens can be classified into physical sunscreens (those that reflect the sunlight) or chemical sunscreens (those that absorb the UV light). In addition to moisturizers and other inactive ingredients, sunscreen formulations contain one or more of the following active ingredients, which are either chemical or mineral in nature: * Organic compounds that absorb UV rays e.g. phenylbenzimidazole sulfonic acid, Ensulizole, Eusolex 232, PBSA, Parsol HS, Eusolex OCR, 2-Cyano-3,3-diphenyl acrylic acid, 2-ethylhexylester, 2-Hydroxy-4-Methoxybenzophenone-5-sulphonic acid, 3-Benzoyl-4-hydroxy-6-methoxybenzenesulphonic acid, Benzophenone-4, Escalol 577. * Inorganic particulates that reflect, scatter, and absorb UV light (such as titanium dioxide, zinc oxide, or a combination of both). * Organic particulates that mostly absorb UV light like organic chemical compounds, but contain multiple chromophores that reflect and scatter a fraction of light like inorganic particulates. An example is Tinosorb M. The mode of action is about 90% by absorption and 10% by scattering. Sunscreening agents are used in some hair care products such as shampoos, conditioners and styling agents to protect against protein degradation and color loss. Currently, benzophenone-4 and ethylhexyl methoxycinnamate are the two sunscreens most commonly used in hair products. The common sunscreens used on skin are rarely used for hair products due to their texture and weight effects. Antiperspirant Agents (e.g. in Deodorants) Antiperspirants are personal hygiene products designed to control sweating and body odour. Antiperspirants contain ingredients that control sweat and body odour safely and effectively. They are readily available on the market as sprays (aerosol), sticks, creams or roll- ons. When an antiperspirant is applied to the skin surface, its antiperspirant ingredients - usually aluminium salts — dissolve in the sweat or moisture on the skin surface of the armpit. The dissolved substance forms a gel, which creates a small temporary ‘plug’ near the top of the sweat gland, significantly reducing the amount of sweat that is secreted to the skin surface. Bathing and washing will remove the antiperspirant gel. Re-application of antiperspirants can be beneficial to help to reduce sweating and keep fresh throughout the day. Antiperspirants reduce underarm sweating, but they do not impact on the natural abilityCosmetic Science (Sem. Vill) 1-25 Cosmetics and Cosmeceuticals of the body to control its temperature (thermoregulation). Aluminium salts present in antiperspirants are natural antimicrobial agents, so they also kill bacteria on your skin. High efficacy deodorants (without aluminium salts) are available and rely on the use of specifically developed antimicrobial agents, such as triclosan or polyhexamethylene biguanide. Alcohol is also effective at killing bacteria, so deodorant and antiperspirant products that contain alcohol (or ethanol) are able to reduce body odour by combating the odour-forming bacteria. 1.8.2 Cosmetic Monographs There are a number of cosmetic like products that are classified as over-the-counter (OTC) drugs in the United States. The list of cosmetic/OTC products that are governed by an FDA monograph is detailed below: 1. Anti-acne products: This monograph describes 40 different ingredients that can be used for anti-acne. Rule was finalized in 1990 although there was some action in 2010 on Benzoyl Peroxide. 2. Toothpaste and anti-cavity products: This monograph gives a list of over 20 ingredients that can be used to fight cavities. The final rule was issued in 1995. 3. Topical anti-fungal: Products that are topically applied to places that need anti- fungal effects (diaper rash, feet, etc). Final rule was originally passed in 1993. 4, Anti-microbial products: There is a long list of ingredients that can be used for topical anti-microbial products. For most of the antimicrobial ingredients, the final rule has not yet been issued. It is suggested you to follow the proposed rules when formulating. 5. Antiperspirant: This monograph is for products, that are designed to stop sweating. The final monograph was originally issued in 2003. It lists 26 active ingredients that you can use. 6. Astringents: These are classified as skin protectants. The final rule was originally issued in 2003, Corn and Callus removers: Definitely a niche product, but some cosmetic companies might want to create these formulations. 8. Dandruff products: If you are planning to create an anti-dandruff shampoo, then you have to follow the rules of this monograph. The final monograph was issued in 1991 and revised in 1992. Hair growth / hair loss: The final monograph for these types of products was issued in 1989 and includes nothing that works. However, in 1994, minoxidil was switched from a prescription drug to an OTC. It remains the only non-prescription option. . Nail biting products: There is a monograph for products that are designed to stop people from biting their nails. The final monograph was issued in 1993. 11. Psoriasis: These products are designed to treat the condition of psoriasis. The tentative monograph was issued in 1986 and has yet to be finalized. Only few active ingredients are allowed including coal tar and salicylic acid. x 9. i SCosmetic Sclence (Sem. Vill) 1-26 Cosmetics and Cosmeceuticals 12. Skin bleaching: Skin lightening products are OTCs in US. The tentative final monograph was issued in 1982, but it has yet to be finalized. There are only two active ingredients acceptable for skin lightening. 13. Sunscreen: It's been a long time coming, but a final monograph on this topic was issued in 2011. 14. Topical analgesic: These products find a wide variety of application and cover products such as those designed for diaper rash, cold sore treatments, poison ivy treatments, and others. 15. Wart remover: Products that are used to remove warts. The final monograph was issued in 1990, but updated in 1994. Thirteen active ingredients are listed. While formulating one of these products, the rules described in the OTC monograph should be followed. The monographs list the raw materials, their amounts, and even dictate the claims that can be made, The link that describes the monographs can be accessed at: https://mmw fda. gov/ Drugs/DevelopmentApprovalProcess/DevelopmentResources/Over-the- CounterOTCDrugs/StatusofOTCRulemakings/default htm. 1.9 KEY COMPONENTS OF A REGULATORY MODEL FOR COSMECEUTICALS IN INDIAN CONTEXT. I. Definition of Cosmeceuticals: There is a need to revise the definition of cosmetic in line with our present knowledge of the skin. The definition of cosmetic according to Drug and cosmetic Act, 1940 is narrow and restricted compared to EU, ASEAN and Japan. The definitions should recognize that virtually all topical agents have some effect on the structure or function of skin and that the distinction between drugs and cosmetics is better based on risk-benefit analysis, indication for product use, and character of the skin changes resulting from product use. The cosmeceuticals can be defined as topically applied product with both cosmetic and pharmaceutical functionality. I. Categorization of Cosmeceuticals Categorization of cosmeceuticals will enable cosmetic companies to market their product. Cosmeceuticals could be characterized on the basis of: the product that has the pharmaceutical activity and can be used on normal or near normal skin. The product should have a defined benefit for minor skin disorders (Cosmetic indication). As the skin disorder is mild, the product should have a very low-risk profile. Cosmeceuticals should be categorized as subclass of cosmetic or drug. Il, Dossier Requirements The regulatory requirements for approval and marketing of cosmeceutical products should contain information based on the qualitative and quantitative composition of the products.Cosmetic Science (Sem. Vill) 1-27 Cosmetics and Cosmeceuticals The dossier should be under four major headings: (@ An Administrative dossier (ii) An Ingredient dossier (iii) A Finished product dossier (iv) A Post market dossier The requirements for above four dossiers are discussed below: An administrative Dossier In this dossier an applicant should submit trade name of the cosmeceutical product and responsible person in the company, manufacturer name or distributor name. The dossier should mention the product categories like skin care, hair care etc. The integral composition of the product should be disclosed in administrative dossier. To ensure safety assessments, responsible person should be appointed by the company to maintain product files related to registration of the product. The responsible person shall ensure compliance with guideline like safety assessment, product information file, good manufacturing practices, sampling and analysis, product notification, restrictions for substances, animal testing, product labeling, product claims, information to the public and information provided on substances. For each cosmeceutical product placed on the market the responsible person shall ensure compliance with the relevant obligations set out in the regulations. For an imported cosmeceutical product, each importer shall responsible for the specific cosmeceutical product which he places on the Indian market. In case of distribution of products (distributor) shall be the responsible person, when he places a product on the market under his name or trademark or modifies a product already placed on the market in such a way that compliance with applicable requirements may be affected. Furthermore, responsible person shall take necessary corrective measures if cosmeceutical product fails to deliver and does not conform to the regulations. Further as a corrective action the failed product should be withdrawn from the market or recalled, as the case may be. (ii) An Ingredient Dossier Cosmeceuticals by definition contain ingredients that have an intended pharmaceutical effect, so it should be possible for the manufacturer and ingredient suppliers to prove this. An ingredient dossier should contain detailed information about identity of ingredient suppliers and composition of the ingredients supplied. However, procedure for registration of new ingredients should be relatively simple. Registrations of combination of ingredients as well as individual ingredients are recommended. The dossier should have physiochemistry and microbiology of the ingredients including the physiochemical and microbiological inspections. Further, toxicity data including oral, dermal and inhalation toxicity, local toxicity, like skin irritation, sensitization, photo allergy and photoirritation should be included in dossier when relevant. The dossier should contain repeated dose toxicity data, additional relevant toxicological data. Additionally, the dossier should mention list of animal tests performed with the ingredients. @Cosmetic Science (Sem. Vill) 1-28 Cosmetics and Cosmeceuticals ii) A Finished Product Dossier The finished product dossier should contain details of manufacturing, safety, efficacy, claims and labeling of cosmeceutical products. (a) Manufacture of Cosmeceuticals: Applicant should get manufacturing license from regulatory authority. The manufacturing premises should be inspected by FDA. Even the approval of manufacturing premises should be necessary when located outside the country concemed. To facilitate safe product, GMP of pharmaceutical products must be followed for the manufacture of cosmeceutical products. The respective state FDA shall be made responsible for inspection of compliance with GMP in plants, The complete details about the names, addresses of the directors of the company and addresses of the manufacturing premises and registered office of the manufacturer should be maintained. A copy of the site master file shall be maintained containing a brief description of the manufacturing process of the cosmeceutical products to be manufactured, details of the standards followed by the company for Good Manufacturing Practices, product evaluation, name, qualification and experience of technical staff under whose supervision the cosmeceutical products will be manufactured, copies of ISO or any other certifications, if any, obtained by the firm for its manufacturing facility. (b) Safety of Cosmeceuticals: An important consideration in cosmeceutical development is safety. It is important to recognize that currently no regulations for cosmeceutical safety are in place. Cosmeceuticals are considered as cosmetics by Indian regulatory authorities and, as such, are regulated like cosmetics. As with existing drug and cosmetic groups, cosmeceuticals should have premarket testing requirements. The safety evaluation of cosmeceuticals may therefore, resemble the safety evaluation of other OTC products. The need of the hour is to define reasonable standards for safety testing to enable regulatory agencies to evaluate cosmeceuticals thoroughly, but in timely manner. Before placing the cosmeceutical product on the market, the responsible person shall submit, through electronic means, the following information to the regulatory authorities. The cosmeceutical product safety report should contain following information: * The trade name of the product, address of manufacturer or distributor. * The product information file should state product category. * The name and address of the responsible person where the product information file is made readily accessible. * The country of origin in case of import. * The member state where the product is placed on the market. * The contact details of a person for communication, if needed. * Quantitative and qualitative composition of the product. * Identity and details of supplier and manufacturer of ingredients.Cosmetic Science (Sem. Vill) 1-29 Cosmetics and Cosmeceuticals * Physical /Chemical characteristics and stability data. * Microbiological tests data. * Toxicity data including acute oral, dermal and inhalation toxicity, local toxicity, including skin irritation, eye irritation, sensitization, photo-allergy and photo- irritation when relevant. * List of animals tests performed with the finished product. * Impurities, trace ingredients and information about packaging material. Product notification can be made to authority through an online application. Applications shall be processed faster and timeline should be set. Additional time shall be given to answer queries/objections, if any, raised by relevant regulatory authority. Submission of Product details (Safety, Quality, and Compliance to Bureau of Indian Standards) at the time of notification should continue as current practice and additional data can be stored as ‘Product information file’ with details maintained at the concerned manufacturing location for the regulators review. Product information file should contain the product safety report of cosmeceutical which must be kept up-to-date and shall clearly mention the responsibilities of manufacturer and the safety assessor. Cosmeceutical Efficacy: At present there are no regulations for cosmeceutical safety, even there are no regulations for cosmeceutical efficacy. Typically, human clinical testing should be carried out under the guidance of a research laboratory or dermatologist with defined parameters to substantiate efficacy. To evaluate a new cosmeceutical product which claims a beneficial physiological effect, it is very important to address three issues: * Can the active ingredient penetrate the stratum comeum and be delivered in sufficient concentrations to its intended target in the skin over a time course consistent with its mechanism of action? * Does active ingredient have specific biochemical mechanism of action in the target cell or tissue in human skin? * Are there published peer-reviewed, double-blinded, placebo-controlled, Statistically significant clinical trials to substantiate the efficacy claims? The laboratory and clinical data should be available for the review by the regulatory agencies. (d) Claim Guidelines for Cosmeceuticals: In Indian context cosmeceutical claim guidelines are not on records compared to European Union and ASEAN countries. This can be facilitated by introduction of permissible and non-permissible claim guidelines for cosmeceuticals. Cosmeceuticals are currently defined by the claims that are made about their intended use. Cosmeceutical claim is any public information primarily provided for marketing purposes on the content, the nature, the effect, the properties, or the efficacy of the product. Before claiming an intended use or indication, manufacturer must hold adequate evidence to support all claims made ©