External Preparations 1

• The skin


  The largest and the most visible organ in the body
• The skin


  • Along with the mucosal linings of the urogenital, digestive, and respiratory tracts, it protects the internal body structure from hostile environment of temperature, humidity and radiation
  • The skin is the most easily accessible organ and at the same the most abused
• The delivery of drugs into and through the skin requires good knowledge of skin and the transport process across the skin
• The skin


  It is a multilayered tissue extending over an area of approximately 20,000 sq. cm and weighing about 4 Kg. in an average human adult
• The skin


  • It is mainly a protective covering for the inner and more delicate cell layers and acts as a barrier against physical, chemical and microbiological invasions
  • It regulates the body temperature and also has a role in regulation of blood pressure
• The layers of tissues constituting the skin

  • the epidermis
  • dermis
  • subcutaneous fatty layer
• The outermost covering


  horny layer or stratum corneum consisting of dead and compacted keratinised cells with a density of 1.55
• The skin is well supplied with

  • sweat glands
  • hair follicles
  • blood vessels
  • nerves
• The horny layer


  • Acts as a barrier to percutaneous absorption of many substances including drugs
• The other layers below the horny layer

  • stratum lucidum
  • stratum granulosum
  • stratum spinosum
  • stratum germinativum
• The Stratum Corneum (SC)


  • Cornified multilayered epidermis 0.8mm-0.006mm
  • Consists of 75 – 85% protein, 10 – 15% lipids
  • Cells are loose at the surface and tightly knit in lower layer
  • Metabollically inactive "dead"
  • Barrier to permeation
• Viable Epidermis


  • Consist of irregular scattered cells with large intercellular spaces
  • Made up of carbohydrates, low protein and lipids
  • Hydrophilic layer, devoid of blood vessels (avascular)
  • Polar drugs will enter
• The Dermis (the true skin)

  • About 0.3 cm thick
  • Located between the epidermis and subcutaneous fatty layer
  • Composed of network of the sensory nerve
  • Entire microcirculation (capillaries) that serve the skin
  • Consists of watery, gelatinous ground substance mostly collagen fibres
• The Skin Circulatory System

  • Local circulation can be turned off and on by vasoconstrictors and vasodilators respectively
  • Network provides supply to the hair follicles, the glandular skin appendages, the subcutaneous fat and the dermis
• The Skin Appendages


  • Hair follicles (originate in the dermis and subcutaneous layers)
  • Sebaceous glands and sweat glands. (located in the subcutaneous tissue)
• The passage of drugs through the skin compared to mucous membrane is very slow
• Slow diffusion of drugs through the skin can be attributed to its high keratin and low moisture contents
• Microbiological barrier


  • The stratum corneum provides a microbiological barrier
  • The sloughing of groups of corneocytes (squames), with their adhering microorganisms, aids the protective mechanism
  • Microbes penetrate superficial cracks and damaged stratum corneum may allow access to the lower tissues, where infection may develop
  • The so-called acid mantle (produced by sebaceous and eccrine secretions, at ( pH 4.2-5.6) probably does not defend the skin against bacteria via its acidity
  • Skin glands also secrete short-chain fatty acids that inhibit bacterial and fungal growth
• Microbiological barrier


  • Nitric oxide, produced from nitrates in sweat, may help to prevent infections from skin pathogens, just as acidified nitrite has an antimicrobial action in the oral and gastrointestinal tracts
  • Bacteria are unlikely to enter the tiny opening of the inner duct of the eccrine gland; the entrances to the apocrine gland and the hair follicle are much wider, and these appendages may become infected
• Chemical barrier


  • An important function of human skin is to bar the entry of unwanted molecules from outside while controlling the loss of water, electrolytes and other endogenous constituents
  • The horny layer is very impermeable to most chemicals and usually contributes the rate-limiting step in transdermal absorption
  • The intact skin is a very effective barricade because the diffusional resistance of the horny layer is large and the permeable appendageal shunt route provides only a small fractional area (about 0.1%)
• Sun-damaged skin


  • May produce solar keratoses, progressing to a squamous cell carcinoma
  • Bowen's disease, malignant and basal cell carinnoma carcinoma may evolve
• Heat barrier and temperature regulation

  • The stratum corneum is so thin over most body areas that it does not effectively protect the underlying living tissues from extremes of cold and heat; it is not an efficient heat insulator
  • The skin, however, is the organ primarily responsible for maintaining the body at 37°C
• Radiation barrier


  • For skin exposed to sunlight, ultraviolet light of 290-400 nm is the most damaging
  • Three main acute reactions follow irradiation: erythema, pigmenation and epidermal thickening
  • Ultraviolet light stimulates melanocytes to produce melanin, which partially protects the skin
  • In a severe photosensitive disease such as xeroderma pigmentosum, sunlight may induce changes even in patients whose intense racial pigmentation makes them less susceptible to sunburn
  • Chronic reactions to sunlight include skin 'ageing', premalignancy and malignancy
• Heat barrier and temperature regulation cont'd.

  • To conserve heat, the peripheral circulation shuts down to minimize surface heat loss; shivering generates energy when chilling is severe
  • To lose heat, blood vessels dilate, eccrine sweat glands pour out their dilute saline secretion, water evaporates, and removal of the heat of vaporization cools the body
• Percutaneous Absorption


  The absorption of substances from outside the skin to layers beneath the skin surface and into the blood stream
• Percutaneous absorption depends on a number of factors

  • The physical and chemical properties of the drug substance
  • The behaviour of the drug when placed in the pharmaceutical vehicle
  • The condition of the skin
  • The presence of moisture
• Factors Affecting Percutaneous Absorption

  • Drug Concentration
  • Surface Area
  • Physiochemical attraction of drug substance
  • Characteristics of vehicle
  • Hydration of the skin
  • Inunction
  • Thickness
  • Duration of contact
  • Multiple application
• Emollients


  Products that can increase the moisture content of the skin
• Astringent


  A hygroscopic material or to a lesser extent, a dusting powder that can remove excess moisture from the skin
• Three main ways to attack the problem of formulating a successful topical dosage form


  • We can manipulate the barrier function of the skin
  • We can direct drugs to the viable skin tissues without using oral, systemic or other routes of therapy
  • The third approach uses skin delivery for systemic treatment
• Dermatologists aim at five main target regions

  • skin surface
  • horny layer
  • viable epidermis and upper dermis
  • skin glands
  • systemic circulation
• Surface treatment


  Skin care for the surface mainly by using a simple camouflage or cosmetic application by forming a protective layer
• Surface treatment


  • protective films, sunscreens, and barriers that hinder moisture loss and so avert chapping
  • Topical antibiotics, antiseptics and deodorant
• Effective surface bioavailability requires that the formulation should release the antimicrobial so it can penetrate the surface skin fissures and reach the organisms
• Skin appendage treatment


  • We may reduce hyper-hydrosis of the sweat glands with antiperspirants such as aluminium or other metal salts
  • Topical exfoliants used for acne such as salicylic acid, tretinoin (retinoic acid) or isotretinoin and benzoyl peroxide and antibiotics such as erythromycin and clindamycin
  • Topical antibiotics applied in skin treatment include Framycetin and neomycin sulphates, Fusidic acid, polymyxins and mupirocin
  • Depilatories usually contain strontium or barium Sulphides, or Thioglycolates
  • Male pattern baldness may be treated with Minoxidil and Finasteride
• Delivering the medicament to the diseased site is a problem with appendage treatment
• For example, it is difficult to achieve a high antibiotic concentration in a sebaceous gland when, as in acne, a horny plug blocks the follicle
• When delivered through the skin, the drug may not be sufficiently hydrophobic to partition from the water-rich viable epidermis and dermis into the sebum-filled gland
• Viable epidermis and dermis treatment

  • Many diseases can be treated if the formulation delivers drug to the receptor efficiently
  • Many potentially valuable drugs cannot be used topically as they do not readily cross the stratum corneum
  • Addition of penetration enhancers to diminish this layer's barrier function
  • Another approach develops prodrugs, which reach the biological receptor and release the pharmacologically active fragment
  • The efficacy of many topical steroids depends partly on molecular groups that promote percutaneous absorption, but which may not enhance drug-receptor binding
• Therapy for treating skin cancer

  • Topical steroidal and non-steroidal anti-inflammatory agents
  • Antibiotics include those listed above
  • Anaesthetic drugs - benzocaine, amethocaine and lignocaine reduce pain
  • Antipruritic and Antihistamines - alleviate itch, but they may cause sensitization
  • Topical 5-fluorouracil and methotrexate eradicate premalignant and some malignant skin tumours and treat psoriasis
  • The Psoralens (particularly in conjunction with ultraviolet light - PUVA therapy) mitigate psoriasis