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Topical formulations Alton Chapter 6 and 38 The skin:its function • Thick skin • Thin skin • • Mechanical protection (dermis) Changes over time The outer layer of skin should contain 10-20% water to have the proper elasticity Protection from Bacteria and viruses, foreign substances Dehydration, radiation Temperature regulation Production of vitamin D 1 The skin:Anatomy • Epidermis Stratum corneum Sebaceous glands Dermis Sweat glands • • • • The heaviest organ in the body Epidermis Stratum corneum Viable epidermis Dermis Subcutaneous fat tissue Appendages of the skin Sweat glands • Eccrine sweat glands • Apocrine sweat glands Hair follicles Sebaceous glands Passage through the skin effects of the route • The appendages Two types • hair follicles • sweat ducts Low available surface area 0.1% Can be important for ions and large hydrophilic molecules such as in immunization through the skin Colloidal particles such as liposomes or small crystals of 3-10µm size can be used to target the appendages • Epidermis Main transport barrier stratum corneum • 10 mm in dry state, Swells in water • Intracellular matrix of lipids and proteins The viable layer has some enzymatic activity The dermis is strongly vascular and often functions as a perfect sink 2 Stratum corneum • • • Dead cells: no-active transport Network of lipids and proteins giving two possible “transport canals” Organized like a brick wall Bricks (Corneocytes) • Dense layer of dead cells containing keratin (protein) ¬ Mortar • Lipids and some water (bilayer), ceramides, fatty acids, cholesterol • The layer where most substances are transported Passage through the skin-Interactions, reactions and other problems Partition Diffusion Binding in depot Metabolic site Binding to receptors Binding in depot Binding in depot • Binding of active substance to skin components such as dead tissue, to cell receptors and to fat tissue • Precipitation when partitioning from a lipidrich to a water-rich environment • Metabolism by the cells • Fast clearance in the dermis • Rediffusion 3 Passage through the skin - effects of biological factors • • • Age of the skin Higher penetration for children and elderly Condition of the skin Disease can cause increased thickness or damage to the skin Damaged skin show enhanced permeability 3 days needed to obtain a protective layer Regional skin sites Hands- feet - eyelids scrotum Evaluation of uptake and dissolution Dissolution • • Release without use of a ratelimiting membrane Release with use of a rate-limiting membrane Types of membrane • Simulated skin: cellulose acetate, silicone rubber • Natural skin: stratum corneum, whole skin Uptake • Franz Bronaugh No good animal models - pig best 4 Strategies for delivery • Local treatment Surface treatment • Bacteria and fungal creams • Deodorants • Insect repellents Stratum corneum • Moisturizing agents Skin appendages • Antiperspirants such as aluminium • Treatment of acne • Antibiotics and Antifungals Viable epidermis and dermis • Anti-inflammatory • Anaesthetics • Antiprutric • Antihistamines • Transcutaneous immunization (in the development stage) • Systematic treatment Often depot formulations • Testosterone, Estrogens • Nicotine • Nitroglycerine Factors affecting development of a formulation • Patients’ compliance Products that are easy to transfer from the container to the skin Products that spread easily and evenly Products that leave no visible residues on the skin Products that do not feel tacky or sticky Products that do not sting • Safety Need of dose accuracy Microbiological safety • Enhancement of drug penetration Drug properties • Prodrugs • Ion pairs Hydration of the skin • Moistering • Occlusion Chemical activity and solubility of the drug • Supersaturation • Lipophilic or hydrophilic drug vehicle Adding excipients that enhance penetration 5 Penetration enhancers Definition A substance that temporarily diminishes the impermeability of the skin • Example of enhancers DMSO Pyrrolidols Surfactants Azone (Water) The ideal enhancer • • • • • • • • • • Pharmacologically inert Non-toxic, non-irritating Immediate effect Full recovery Compatible with the drug Good solvent for the drug Not causing loss of water, ions etc Having a acceptable look, taste, texture and odour Inexpensive In reality, it is difficult to find enhancers that are safe and that are accepted by authorities Formulations that affect skin hydration Vehicle Examples Occlusive dressings Lipophilic Waterproof plaster Waxes, oils Effects on hydration Preventing water loss, full hydration Preventing water loss, might give full hydration Absorption Anh. Lipids + Prevent water loss, base W/O emulsifier marked hydration Emulsion Anh. Lipids + Prevent water loss, base O/W emulsifier marked hydration W/O Oily creams Reduce water loss, emulsions increased hydration O/W Aqueous creams May donate water, slight emulsions increase in hydration Humecant Glycerol May withdraw water Powders Clay, Topical Aiding evaporation of powders water Effects on permeability ++ ++ ++ ++ + (+) (-) -/0 6 Requirements on an ideal formulation for local treatment • Low penetration of the active substance to avoid systemic delivery • Non irritating • Broad therapeutic window • Not harming clothes and other things that comes in contact with the formulation • Good cosmetic properties Requirements placed on formulations for systemic delivery • Usually a low daily dose, <20 mg/day • An active substance that can penetrate the skin • Low molecular weight < 600 Daltons • A partitioning coefficient high enough to ensure penetration through the lipid layers in the stratum corneum but not so high that it risks precipitation in the dermis • A non-charged species passes through the skin more easilly • A low melting temperature leads to high intrinsic solubility • Not causing irritation or sensitisation of the skin • Easy to apply the correct dose - (transdermal patches) 7 Special Quality considerations • Stability of excipients, especially of Preservatives Penetration enhancers Lipids • • • • • Rheology Water content Phase changes Particle and drop size pH • Test conditions Problems at elevated temperatures • Typical problems Volatile solvents can evaporate Risk of oxidation of the lipid components pH measurements are difficult in complex systems Tests of dissolution especially from plasters Type of formulations • Solutions (viscose or liquid) Liniments Lotions Tinctures • • • • • • • Solution aerosols Powders Ointments Pastes and ointment that contains as much as than 50% solid material Gels Creams and semi solid emulsions Depot formulations such as plasters 8 Ointments • Character Greasy, sticky, semisolid products normally containing a hydrophobic component such as oil, fat, hydrocarbons or silicone • Example of products Bactroban Nasal - local treatment of Staphylococcus aureus infection Iodosorb® - Treatment of open infected wounds, also as a powder • Advantages Increases hydration of the skin Good chemical stability if no water present • Disadvantages Poor cosmetic properties Formulation of ointments • Base Hydrocarbons • Paraffin • Plastibases (polyethylene in hydrocarbons) Fats and fixed-oils bases • Semisolid vegetable oils Silicones • Water-repellent Water-soluble • Polyethylene glycols • Non-occlusive Absorption base • Contain excipients that create o/w emulsions upon adsorption of water Emulsifying base • Self-emulsifing systems that are mixable with water • Other Excipients Usually low in water content thus bacteriosides are only needed in special cases Antioxidants may be needed especially for Fats and fixed-oils bases 9 Gels • Characteristics Two phase semisolids system rich in liquids containing a continuous structure • Examples of products Divigel®- Oestrogen for systemic treatment Oftagel - tear substitute local treatment of the eye Crinone - a progesterone replacement formulated as a vaginal gel Basiron® - local treatment of acne • Advantages Good cosmetic properties Good release of substances High water content can hydrate the skin slightly • Disadvantages Low chemical stability of some excipients due to high water content Low microbiological stability What defines a gel A gel is a two-phase semisolid product. A gel consists of a network that entraps the liquid phase. A gel has viscoelastic properties and is characterised by losing its elastic properties at high stress. There is a has high mobility of molecules in the liquid phase low amount of dispersed phase (>1%) still provides rigidity • Uses of gels Topical formulations Stabilising foams, emulsions and dispersions “Cosmetic” factors • Easy to handle • Easy to spread Entrapment of active substances to achieve controlled release 10 Formulation of gels • The gel-forming component • Lyophilic sols Entangled networks • Polyvinyl alcohols • Cellulous derivates Covalent coupled • Carbomers Ion-birding • Alginic acid An aggregating structure • Gelatin • Carrageenan • The solvent Water Additives to increase vaporization -ethanol Buffers to control pH • Other additives Antioxidants Perfumes, colour Bactericide and preservatives Moisterises • Flocculated lyophobic sols Clay and Bentonite Magnesium hydroxide Types of networks Networks can consist of Flocculated systems • Normal hydrophobic solids • “Card house” flocks of special crystal particles Polymeric networks • Covalent linked networks • Entangled networks • Physically linked networks 11 Creams • Characteristics Semisolid emulsions for topical use. O/W emulsions and W/O emulsions • Examples of products Garamycin® for Local treatment of virus infection Daktacort® for Local treatment of fungal infection EMLA- local treatment of pain • Advantages Good cosmetic properties Evaporation of the liquid gives a soothing feeling When O/W emulsions are rubbed into the skin the water evaporates An effective formulation for hydrophobic substances • Disadvantages Can be unstable systems Show complex release patterns Formulation of creams • Contain all the ingredients of gels and of emulsions • It is sometimes not necessary to stabilize the emulsion by the use of a gel. Especially if the formulation contains high amounts of the dispersed phase for example Nivea • Surfactants are needed to stabilize the emulsion component of the gel • O/W creams Used for vanishing creams as the oil is rubbed into the skin Can increase the amount of watersoluble substances in the skin • W/O creams Spread better than ointments but are not occlusive 12 Transdermal Therapeutic systems TTS ”Plasters” Occlusive or nonocclusive • Advantage Possible controlled release Easy to remove No peak concentration Avoiding the variability seen in the gastrointestinal systems Backing membrane Can be combined Drug reservoir Dissolution control • Disadvantages Contact adhesive Low permeability Risk of skin irritation Only applicable for potent drugs < 2 mg/day “Plasters”- things to consider • Site of application Buccal plasters Special locations on the body • Duration of a unit 1-3 days • Types of release control Polymeric membrane Rate-controlling adhesive layer Polymeric matrix Microreservoir system • • • • • Interactions with excipients and the control system Penetration enhancers Effect on occlusion of the skin Hydration Effect of adhesive on the skin Irritation Easy to remove Long-term changes in the matrix system Temperature- and light. stability of the matrix system 13 Plasters- Example of products • Nicotine plasters Nicotine passes easily through the skin • • • • Steroid hormones Testosterone - Atmos® Oestrogen - Evorel® Motion sickness Scopolamine Scopoderm® Angina pectoris Nitroglycerine Hypertension Clonidine • Joint formulation development between big pharma and drug formulation companies (patent holder) are common 3M Alza Iontophorecic drug delivery • • + - • • Molecules are transported through the skin by the mean of an electric current Transport mainly through the skin appendages, which have the lowest impedance of any of the skin components Neutral molecules transported due to low flow of water - electro-osmosis Other types of “external” induced uptakes Phonophoresis - Ultrasound Electroporations Needle arrays 14 Terms to know from today's lecture • • • • • • • • • • Epidermis: the outer layer of the skin contains Stratum corneum. the protective layer of the, skin containing dead cells and a lipid matrix Dermis; the lower parts of the skin which contains blood vessels The appendages of the sin, sweat glands, hair follicles and sebaceous glands Penetration enhancers: excipients that increase penetration of the epithelial cells or the skin Ointments: topical formulations containing low amounts of water, often lipophilic bases Pasts: ointments with high particle content Gels: Two phase semisolids system rich in liquid can be used for topical formulations Creams: semisolid emulsion for topical use. Transdermal Therapeutic systems TTS - ”Plasters containing active drug for slow release formulations 15