Topical formulations

Alton Chapter 6 and 38

The skin:its function

• Mechanical protection (dermis) Thick skin  Changes over time  The outer layer of skin should contain 10-20% water to have the proper elasticity • Protection from  Bacteria and viruses, Thin skin foreign substances  Dehydration, radiation • Temperature regulation • Production of vitamin D

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The skin:Anatomy

• The heaviest organ in the Stratum corneum body Epidermis • Epidermis  Stratum corneum  Viable epidermis Sebaceous • Dermis glands • Subcutaneous fat tissue Dermis • Appendages of the skin  Sweat glands • Eccrine sweat glands Sweat glands • Apocrine sweat glands  Hair follicles  Sebaceous glands

Passage through the skin - effects of the route

• The appendages • Epidermis  Two types  Main transport barrier - • hair follicles stratum corneum • sweat ducts • 10 mm in dry state,  Low available surface Swells in water area 0.1% • Intracellular matrix of  Can be important for ions lipids and proteins and large hydrophilic  The viable layer has some molecules such as in enzymatic activity immunization through the  skin The dermis is strongly vascular and often  Colloidal particles such as liposomes or small functions as a perfect crystals of 3-10µm size sink can be used to target the appendages

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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

Diffusion Partition • Binding of active substance to skin Binding components such as dead in depot tissue, to cell receptors Metabolic Binding to and to fat tissue site receptors • Precipitation when partitioning from a lipid- Binding rich to a water-rich in depot environment • Metabolism by the cells • Fast clearance in the dermis Binding in depot • Rediffusion

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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 rate- Franz limiting 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 Bronaugh • No good animal models - pig best

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Strategies for delivery

• Local treatment  Viable epidermis and  Surface treatment dermis • Bacteria and fungal • Anti-inflammatory creams • Anaesthetics • Deodorants • Antiprutric • Insect repellents • Antihistamines  Stratum corneum • Transcutaneous immunization • Moisturizing agents (in the development stage)  Skin appendages • Systematic treatment • Antiperspirants such  Often depot formulations as aluminium • Testosterone, • Treatment of acne Estrogens • Antibiotics and • Nicotine Antifungals • Nitroglycerine

Factors affecting development of a formulation • Patients’ compliance • Enhancement of drug  Products that are easy to penetration transfer from the container to  Drug properties the skin  Products that spread easily • Prodrugs and evenly • Ion pairs  Products that leave no visible  Hydration of the skin residues on the skin • Moistering  Products that do not feel tacky or sticky • Occlusion  Products that do not sting  Chemical activity and • Safety solubility of the drug  Need of dose accuracy • Supersaturation  Microbiological safety • Lipophilic or hydrophilic drug vehicle  Adding excipients that enhance penetration

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Penetration enhancers

Definition The ideal enhancer A substance that • Pharmacologically inert temporarily diminishes the • Non-toxic, non-irritating impermeability of the skin • Immediate effect • Full recovery • Example of enhancers • Compatible with the drug  DMSO • Good solvent for the drug  Pyrrolidols • Not causing loss of water, ions  Surfactants etc  Azone • Having a acceptable look, taste, texture and odour  (Water) • 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 Effects on hydration Effects on permeability Occlusive Waterproof Preventing water loss, full ++ dressings plaster hydration Lipophilic Waxes, oils 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 -/0 powders water

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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)

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Special Quality considerations

• Stability of excipients, • Test conditions especially of  Problems at elevated  Preservatives temperatures  Penetration enhancers • Typical problems  Lipids  Volatile solvents can • Rheology evaporate  Risk of oxidation of the lipid • Water content components • Phase changes  pH measurements are • Particle and drop size difficult in complex systems • pH  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

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Ointments

• Character • Advantages Greasy, sticky, semisolid  Increases hydration of products normally containing a hydrophobic component the skin such as oil, fat, hydrocarbons  Good chemical stability or silicone if no water present • Example of products  Bactroban Nasal - local • Disadvantages treatment of  Poor cosmetic Staphylococcus aureus properties infection  Iodosorb® - Treatment of open infected wounds, also as a powder

Formulation of ointments

• Base  Absorption base  Hydrocarbons • Contain excipients that create o/w emulsions • Paraffin upon adsorption of water • Plastibases (polyethylene in  Emulsifying base hydrocarbons) • Self-emulsifing systems  Fats and fixed-oils bases that are mixable with water • Semisolid vegetable oils • Other Excipients  Silicones  Usually low in water content thus • Water-repellent bacteriosides are only  Water-soluble needed in special cases • Polyethylene glycols  Antioxidants may be • Non-occlusive needed especially for Fats and fixed-oils bases

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Gels

• Characteristics • Advantages Two phase semisolids system  Good cosmetic properties rich in liquids containing a continuous structure  Good release of substances • Examples of products  High water content can  Divigel®- Oestrogen for systemic treatment hydrate the skin slightly  Oftagel - tear substitute • Disadvantages local treatment of the eye  Low chemical stability of  Crinone - a progesterone some excipients due to replacement formulated high water content as a vaginal gel  Basiron® - local treatment  Low microbiological of acne stability

What defines a gel

A gel is a two-phase • Uses of gels semisolid product.  Topical formulations A gel consists of a network that entraps the liquid phase.  Stabilising foams, A gel has viscoelastic emulsions and properties and is dispersions characterised by losing its  “Cosmetic” factors elastic properties at high • Easy to handle stress. There is a has high mobility • Easy to spread of molecules in the liquid  Entrapment of active phase substances to achieve low amount of dispersed controlled release phase (>1%) still provides rigidity

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Formulation of gels

• The gel-forming component • The solvent • Lyophilic sols  Water  Entangled networks  Additives to increase • Polyvinyl alcohols vaporization -ethanol • Cellulous derivates  Buffers to control pH  Covalent coupled • Other additives • Carbomers  Antioxidants  Ion-birding  Perfumes, colour • Alginic acid  Bactericide and  An aggregating structure preservatives • Gelatin  Moisterises • Carrageenan • 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

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Creams

• Characteristics • Advantages Semisolid emulsions for  Good cosmetic properties topical use. O/W emulsions  Evaporation of the liquid and W/O emulsions gives a soothing feeling • Examples of products  When O/W emulsions are rubbed into the skin the  Garamycin® for Local water evaporates treatment of virus infection  An effective formulation for hydrophobic  Daktacort® for Local substances treatment of fungal infection • Disadvantages  EMLA- local treatment of  Can be unstable systems pain  Show complex release patterns

Formulation of creams

• Contain all the ingredients • O/W creams of gels and of emulsions  Used for vanishing • It is sometimes not creams as the oil is necessary to stabilize the rubbed into the skin emulsion by the use of a  Can increase the gel. Especially if the amount of water- formulation contains high soluble substances in amounts of the dispersed the skin phase for example Nivea • Surfactants are needed to • W/O creams stabilize the emulsion  Spread better than component of the gel ointments but are not occlusive

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Transdermal Therapeutic systems TTS ”Plasters” Occlusive or nonocclusive • Advantage  Possible controlled release  Easy to remove Backing membrane  No peak concentration  Avoiding the variability Can be Drug reservoir seen in the combined gastrointestinal systems Dissolution control • Disadvantages  Low permeability Contact adhesive  Risk of skin irritation  Only applicable for potent drugs < 2 mg/day

“Plasters”- things to consider

• Site of application • Interactions with excipients  Buccal plasters and the control system  Penetration enhancers  Special locations on the body • Effect on occlusion of the skin • Duration of a unit  Hydration  1-3 days • Effect of adhesive on the skin • Types of release control  Irritation  Polymeric membrane  Easy to remove  Rate-controlling • Long-term changes in the adhesive layer matrix system  Polymeric matrix • Temperature- and light. stability of the matrix system  Microreservoir system

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Plasters- Example of products

• Nicotine plasters • Joint formulation  Nicotine passes easily development between big through the skin pharma and drug • Steroid hormones formulation companies  Testosterone - Atmos® (patent holder) are  Oestrogen - Evorel® common • Motion sickness  Scopolamine -  3M Scopoderm®  Alza • Angina pectoris  Nitroglycerine • Hypertension  Clonidine

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

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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

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