1. Kuliah Kapita Selekta Estetika PROGRAM S2 HERBAL DEPARTEMEN FARMASI FMIPA UI 2012

2. BAHAN KULIAH DELIVERY SYSTEM 1.Delivery System Design in Topically Applied Formulations: Topical Delivery System 2.Crossing the Lipid Barrier with the Echo- Derm™ Delivery System ( A Skin-Mimicking, Lamellar Matrix System) 3.An All Natural Delivery System Adjuvant

3. BAHAN RUJUKAN Delivery System Handbook For Personal Care and Cosmetic Product. Meyer R. Rosen. William Andrew Publishing. Norwich. New York, USA. 2005

4. 1. Delivery System Design in Topically Applied Formulations: Topical Delivery System A. INTRODUCTION What Is a Delivery System? Factors Affecting the Efficacy of a Delivery System For What Application Areas Are Delivery Systems Useful? B. PENETRATION PATHWAYS INTO THE SKIN The Bulk Stratum Corneum The Appendages and Breaches Created in the Stratum Corneum Skin Penetration Pathways Skin Penetration Enhancers : Chemical and Physical Enhancement of Permeation Effects of Skin Hydration and Supersaturation C. DELIVERY SYSTEM FACTORS Molecular Weight of the Drug Molecule Lipophilicity of the Active Molecule Effect of the Delivery System on Permeation

5. A. INTRODUCTION What Is a Delivery System? An “active” is a substance that can provide beneficial properties to the skin or hair. A delivery system is simply a way of holding, carrying, and transporting an active to a substrate. It typically concentrates the active in a particular location within a formulation and alters the absorption and/or adsorption of actives into and/or onto a substrate. It may provide the benefit of a barrier system by forming a film on the substrate which then becomes the barrier. A delivery system can control the rate of release from a formulation as well as the rate of active absorption. It can minimize the concentration of active in the epidermis and dermis and thereby minimize the potential for irritation. It can also maximize the concentration of active in a part of the substrate— a concept known as the “Reservoir” effect.

6. …lanjutan …..cosmetics do not penetrate the skin …..the active to go into, and perhaps through, the stratum corneum and into the viable layer beneath. ….. certainly valid scientifically if one expects to continue to improve the quality and effectiveness of products used in industry Cosmetics …. Pharmaceuticals - gray area in between a bridge must inevitably be built to connect the two legally defined areas of cosmetics and pharmaceuticals so the enormous potential of each can be used to benefit the other continue the upward climb for the development of safe, effective products that we all want and need:

7. ………lanjutan ….. a delivery system does not have to be a fancy arrangement of molecules in space only. It can include fluids, or emulsions (O/W OR W/O), viscous solutions, surfactant-structured systems and many other forms as well “carriers” on the substrate : being absorbed, adsorbed, volatilized, or remains on the surface. All of these constitute “delivery systems” : putting an active into “something” and then putting that “something” into a finished formulation. This approach allows the active to be protected in the formulation, and enables it to come out when we want it to, where we want it to, and at the rate that we want it to. A delivery system is any type of vehicle that makes an “active” available to a target site. An effective delivery system is one that reaches the target and creates a high concentration reservoir for the active. Delivery systems may provide sustained release, controlled release, or release, without release into the substrate. They concentrate the payload. The bulk concentration is low but the concentrated material is delivered to the intended site.

8. The IDEAL delivery system would be nontoxic to skin or hair, carry the actives into the substrate, provide controlled release (if desired), penetrate deeply or superficially (as needed), improve formulation aesthetics, and allow easy handling of liquid or solid actives. For optimal penetration, the ideal delivery system has to be small enough to penetrate and be similar in polarity to target permeation paths of the skin. ‘Carriers’ themselves can be designed to achieve optimal penetration. Each active has different requirements, and each type of application adds still other requirements to the active/delivery vehicle system. Delivery systems may, or may not slow down. ‘the rate of actives’delivery ‘.They may or may not enhance penetration—and they can be designed to be delivered to different “depths” and to different locations. They generally protect sensitive actives from oxidation and attack by other formulation components or environmental stressors. Delivery systems include to liquid/liquid dispersions such as oil-in-water or water- in-oil emulsions, microemulsions, or multiple emulsions. Some delivery systems allow the incorporation of oil soluble actives in water-based formulations while others enable the incorporation of water soluble actives in oil- based systems. Other forms of delivery systems include liquid/solid systems such as dispersions of inorganic materials like zinc oxide and titanium dioxide for sunscreens. They can also be solid/solid systems such as freeze-dried liposomes, or be actives encapsulated in molecular or macromolecular matrices to provide a dry powder form.

9. Factors Affecting the Efficacy of a Delivery System the ability to penetrate humectancy polarity of the carrier system delivering the active, polarity of the active itself, electrical charge (if any), size of the active molecule, the nature of the delivery system vehicle, aging stability of actives in the system, and the final formulation into which the delivery system is placed.

10. For What Application Areas Are Delivery Systems Useful? In skin care, they are employed in sunscreens, anti-wrinkle products, skin whitening/bleaching, antioxidant delivery, flavor and fragrance delivery, sensory markers (e.g., warming, cooling, tingling), and coloring. In hair care, some applications include nutrient delivery, antistatic agents, relaxing chemicals for ethnic hair, coloring/dyeing, conditioning agents, humectants, and deodorants Controlled and targeted release (site specific); a need to get inside the hair shaft and deliver functional actives; Further enhancement of shelf life via delivery technology, inclusion of sensory markers to convey a sense of immediacy to product performance from the consumer’s viewpoint.

11. One key concept in delivery system technology is the distinction between delivery onto the skin (e.g., acne preparations and sunscreens) and delivery into the skin (e.g., skin lightening). In the latter category, as Johann Wiechers, Principal Scientist, and Skin R&D Manager of Uniqema (author of Ch. 20) likes to say, “we must also inquire as to how deeply into the skin we are talking about.” Johann Wiechers, likes to generate catchy titles and provocative words, recently noted that “we have had the decade of active ingredients. Now we are living in the decade of active’s delivery systems. This decade will last only five years, before we get to the decade of truly functional cosmetics.” With such flexibility becoming available, a whole new range of product distinctions are emerging. These distinctions will give rise to novel ways for formulators to invite marketers and consumers alike into an exciting new world of possibility to enhance beauty in ways not previously available.

12. B. PENETRATION PATHWAYS INTO THE SKIN Routes for Skin Penetration 1. Skin Penetration Pathways 2. Skin Penetration Enhancers 3. Effects of Skin Hydration and Supersaturation

13. Skin Penetration Pathway 1.Transeluler 2.Transapendageal (via sebacea gland) 3.Transappendageal (via sweat gland)

15. Skin Penetration Enhancers Chemical: Alcohols & glycols Accelerants: Amines & amides Fatty acids &their esters Terpenes Metabolic or biochemical Physical: Microneedles Sonophoresis Supersaturation Iontophoresis

16. CHEMICALS Alcohol and Glycols: extracting and/or increasing the fluidity of stratum corneum lipids as well as by interacting with stratum corneum proteins. As a result of rapid permeation behavior, such compounds are used at relatively high concentration. Polyalcohols such as the propylene glycols are most effective when used in combination with other accelerants such as Azone and oleic acid

17. Amines and amides. Compounds such as urea and cyclic urea derivatives, amino acids and their esters, amides, as well as Azone and its derivatives, and pyrrolidones belong to the amine and amide category. Azone was specifically designed as a skin penetration enhancer, and it is one of the most intensely studied absorption promoters since it can enhance the permeation of a wide range of drugs. This material works primarily by fluidizing the intercellular stratum corneum lipids. It is often applied in conjunction with propylene glycol[ where the combination treatment yields synergistic action.

18. Fatty acids and their esters. A large number of fatty acids have been extensively studied for transdermal permeation enhancement. Unsaturated fatty acids have been found to be more active than their saturate counterparts. Potential mechanisms of action for fatty acids include drug solubilization in the vehicle, increased partitioning, increased solvent penetration, and barrier disruption. Terpenes. Terpenes are constituents of volatile oils. They are commonly employed in cosmetics and in some pharmaceutical products. Such materials are usually well tolerated by the body and are considered as Generally Recognized As Safe (GRAS) compounds. They exhibit good toxicological profiles, high enhancement activities, and low cutaneous irritancy at low concentrations (1%–5%). Terpenes are observed to increase the percutaneous permeation of both hydrophilic and hydrophobic drugs. Polar terpenes have been shown to be more effective in enhancing the permeation of polar drugs, while non polar terpenes have been demonstrated to be more effective in enhancing the permeation of lipophilic drugs. DSC studies have indicated that terpenes exert their action mainly by disrupting the intercellular lipid layers.

19. Metabolic or biochemical enhancers. These compounds act by interfering with metabolic events, ultimately inducing elevated skin permeability. This increase in permeability can occur either by inhibition of the synthesis of stratum corneum lipids (especially after acute damage or, alternatively, by promoting the metabolism of existing skin lipids that are responsible for skin barrier function. in vitro topical application of phosphatidylcholine-dependent phospholipase C, triacylglycerol hydrolase, acid phosphatase, and phospholipase A2 enhanced the permeation of benzoic acid, mannitol, and testosterone relative to untreated skin. fatty acid synthesis inhibitor 5-(tetradecyloxy)-2-furancarboxylic acid (TOFA), cholesterol synthesis inhibitor fluvastatin (FLU), or cholesterol sulfate (CS) have all altered the barrier function of acetone-treated skin. In each case, there was an increase in lidocaine absorption, suggesting permeability enhancement.

20. Physical Microneedles. robust enough to create pores that reach throughout the entire depth of the stratum corneum. Such pores have been observed to facilitate the rapid absorption of drugs including even those with large molecular weights These microneedles are coated on the outside by the drug or active agent. Use of this technology has been shown to increase the permeation of calciene (623Da) by 1,000-fold when the microneedles were left embedded in the skin for one second, 10,000-fold when removed from the skin after being embedded for ten seconds, and 25,000-fold when the microneedles were removed from the skin after one hour application. Application of these microneedles permitted an increase in the permeation of both insulin (5,800 Da) and bovine serum albumin (64,000 Da) by more than 10,000-fold above the sensitivity limit

21. Sonophoresis. Sonophoresis is the use of ultrasound to enhance topical or transdermal drug delivery. The technique has been applied for over 40 years by physiotherapists in order to treat various arthritic and inflammatory conditions. Typically, ultrasound in the 0.5 to 3 MHz frequency range has been employed for this purpose and the treatment conducted on a highly subjective and non-quantitative basis. Only modestly effective, if at all, in enhancing the penetration of actives. only very low frequency ultrasound (i.e., in the 0.02 to 0.1 MHz range) can substantially, and reversibly, increase the permeability of the stratum corneum This enhancement process is a result of the development of cavitation, which is the major mechanism of skin permeabilization. The cavitation phenomenon is inversely related to the frequency of the applied ultrasonic beam Cavitation is the ultrasonically induced formation of gaseous cavities or bubbles in a sonicated medium. The volumetric oscillations and collapse of cavitation bubbles generate sufficient disorder in the lipid bilayers of the stratum corneum to temporarily permeabilize the membrane. The extent of cavitation produced is determined by a host of parameters including the frequency, intensity, and time of application of the applied ultrasonic beam Low frequency sonophoresis has been reported to facilitate the transdermal delivery of proteins like insulin, erythropoietin, and gamma interferon in vitro Of vital importance to sonophoresis is that the skin barrier function is returned to normal levels only several hours after sonication is completed. Preliminary experiments have shown that low frequency ultrasound seems relatively safe in terms of its application to human skin However, further work is clearly required to explore the possibilities demonstrated by this method.

22. Iontophoresis. Iontophoresis involves the application of an electrical potential gradient to drive the cutaneous transport of molecules. The technique seems appealing since it offers the possibility of controlling the systemic delivery of drugs, and it is potentially effective for enhancing the penetration rate of any charged molecule. The electrophoretic device basically consists of an anode and a cathode connected to a power supply. Upon application of the electromotive force, charged drug molecules adjacent to the electrode of opposite charge will be repelled into the adjacent tissue The ions permeate via pathways exhibiting the lowest impedance. Examples of such pathways include sweat glands, sebaceous glands, hair follicles, and skin imperfections.

23. Skin Hydration and Supersaturation Skin Hydration: The occlusive or moisture- retaining nature of transdermal patches as well as certain dressings or hydrophobic ointments is shown to often increase hydration of the underlying skin Supersaturation drug solution: Fick’s laws of diffusion state that the flux of a molecule is directly proportional to its thermodynamic activity, drug delivery can be optimized by using saturated solutions or suspensions of drugs.

24. Delivery System Factors Molecular Weight of the Drug Molecule Lipophilicity of the Active Molecule Effect of the Delivery System on Permeation

25. Design of Delivery Systems Examples of Delivery Systems 1. Liposomes. 2. Elastic Vesicles 3. Particulate Systems 4. Molecular Systems: Dendrimers Topical Applications : Examples 1. Reduction of Melanin Synthesis by Inhibiting Tyrosinase Activity 2. Reducing the Appearance of Wrinkles by Affecting the Collagen- elastin 3. Improvement of Acne Condition and Intrafollicular Delivery 4. Improving the Appearance of Skin Imperfections and Superficial Delivery

26. DESIGN OF DELIVERY SYSTEM LIPOSOME ELASTIC VESICLES PARTICULATE SYSTEMS MOLECULAR SYSTEMS: DENDRIMER

27. Topical Applications : Examples Reduction of Melanin Synthesis by Inhibiting Tyrosinase Activity Reducing the Appearance of Wrinkles by Affecting the Collagen-elastin Improvement of Acne Condition and Intrafollicular Delivery Improving the Appearance of Skin Imperfections and Superficial Delivery

28. 2. Crossing the Lipid Barrier with the EchoDerm™ Delivery System ( A Skin-Mimicking, Lamellar Matrix System)

29. 3. An All Natural Delivery System Adjuvant