Pharmaceutical Sciences: Topical Preparations

Topical Preparations

• Topical preparations are a discipline of pharmaceutical sciences.
• Human skin has three tissue layers: epidermis, dermis, and subcutaneous tissue.

Anatomy of the Skin

• Epidermis:
  • Composed of 5 layers: stratum corneum, stratum lucidum, stratum granulosum, stratum malphigi, and stratum germinativum.
  • Thickness varies by location: face (0.1mm), hand-palm (0.8-1mm), eyelids (0.006mm).
  • Stratum corneum forms a keratin phospholipid complex, acting as a barrier to water and foreign bodies.
  • No blood vessels or lymphatics.
  • pH of skin is 5-6.
• Dermis:
  • Connective tissue matrix of fibrous proteins (collagen, elastin, reticulin).
  • Contains nerves, blood vessels, and lymphatics.
  • Skin appendages (eccrine, sweat glands, apocrine glands, and pilosabaceous units) penetrate it.
  • Requires efficient blood supply to transport nutrients, remove waste, regulate temperature, and mobilize defenses.
• Subcutaneous Tissue:
  • Layer of fat providing a cushion against external injury and acting as a thermal barrier.
  • Synthesizes and stores high-energy chemicals.

Absorption

• Skin condition affects absorption degree.
• Absorption through skin is a passive process happening in two ways:
  • 1. Transepidermal: high surface area facilitates rapid penetration.
  • 2. Transappendageal: absorption through glands and hair follicles.

Factors Affecting Absorption

• Vehicle: must mix with sebum; animal/vegetable oils are better than mineral oils; oily bases create moisture barriers.
• Occlusion: Hydration changes due to bandaging; non-occlusive applications enhance absorption.
• Rubbing: Increases absorption as it increases blood flow; longer periods of rubbing lead to higher absorption.
• Contact Time: Increased contact time leads to increased absorption.
• Drug Release: Rate of drug release determines absorption rate; partition coefficient, drug form, and drug size affect this.
• Lipid Layers of Skin: Drugs may be stored in outer/deeper layers; lipids act as barriers.
• pH of Skin: Skin secretions (pH 5-6) affect drug penetration and absorption; unionized drugs penetrate stratum corneum more readily.
• Skin Location: Thicker skin leads to slower absorption; slowest absorption is on the sole of the foot, and fastest behind the ear.
• Hydration: Water diffusion to epidermal layers or perspiration affects penetration rates. Water-soluble substances (e.g., amino acids, urea) influence hydration.
• Temperature: Higher temperature increases diffusion rate.
• Hpyeremia: increased blood flow increases drug removal and absorption rate.
• Content of Drug: Higher drug concentration leads to higher absorption.

Types of Topical Preparations

• Topical preparations are categorized into powders, liquids, and semi-solids.
• Preparations may contain an active ingredient (e.g., antihistamines, corticosteroids), or no active ingredient (used as a barrier).

Topical Powder Preparations

• Used to absorb moisture from the skin to keep it dry.
• Contain starch, bacteriostatics, or bacteriocides/antiseptics.
• Dusting powders are used for body surfaces, not open wounds (unless sterilized).

Topical Liquid Preparations

• Solutions: Liniments formulated with alcoholic or oily vehicles are rubbed into unbroken skin. counter-irritants are substances that, when applied to the skin, create a mild inflammatory response that distracts the body from the underlying pain or discomfort. They work by increasing blood flow to the area, which can help to alleviate deeper muscle or joint pain. analgesic, warming effects)
  • Liniments must contain a preservative.
• Lotions: Applied to unbroken skin without friction. Vehicle can be alcoholic/acetone to aid rapid evaporation.
• Paints: Applied to skin with a brush. Solvent of H2O or organic for rapid evaporation.
• Suspensions: Lotions containing suspended solids; evaporation can create a cooling effect.. Thickening agents in suspensions form a strong, non-sticky film. May require preservatives when applied to broken skin.
• Liquid Emulsions: Formulated as liniments and lotions; must contain preservatives.

Topical Semi-Solid Preparations

• Creams: Viscous semi-solids, may be o/w or w/o.
• Ointments: The emollient effect refers to the ability of certain substances to soften and soothe the skin. .; used to protect lesions and administer topical medications.
• Pastes: Contain finely ground solids; excellent emollients but absorb exudates from wounds effectively.; often used for chronic infections.
• Gels: Water-soluble bases from natural gums (e.g., alginates); can act as dermatologicals or lubricants.

Preservation of Topical Preparations

• Plastic containers can absorb preservatives, reducing effectiveness.
• Preservatives can irritate mucous membranes (e.g., parabens more than QACs).
• Interactions of preservatives with actives or excipients in storage can reduce preservative effectiveness.
• The effectiveness of preservatives is influenced by their concentration in the aqueous phase, as higher concentrations typically enhance antimicrobial action.

Evaluation of Semi-Solid Topical Systems-

• Testing includes dissolution testing (similar to tablet testing), using a cellulose acetate phthalate membrane in a water bath at 37°C. Samples taken at intervals to assess drug concentration and release rate.
• Stability tests are performed by storing the preparation for an extended time at normal temperatures to assess emulsion-type preparations and semi-solid preparations.
• Rheological properties are measured by means of a viscometer; this determines the consistency of the preparation and potential phase separation issues.

Ointments

• Semi-solid preparations often anhydrous; medicaments are sometimes dissolved and dispersed into the base.
• Ideal ointment bases: non-irritant, smooth, odourless, chemically stable, compatible with a wide range of medicaments; must not retard healing.

Rheology

• Ointments are viscoelastic materials, softening and spreading easily with shearing stress.
• Flow properties are significantly influenced by the specific types of constituents present, as well as their relative quantities. For example, wax contributes to the overall structure and rigidity of a formulation, whereas fats and oils impart increased flexibility and fluidity, essential for varied applications.

Classification of Ointment Bases

• Four groups based on the USP and Pharmaceutical Codex:
• hydrocarbon,
• absorption,
• water-miscible,
• water-soluble.

Hydrocarbon Bases

• Immiscible with water,. Are not absorbed by the skin, and absorb little water.
• Examples include soft paraffin, hard paraffin, liquid paraffin, paraffin substitutes and
• Paraffin ointment BP is a specific formulation outlined in the British Pharmacopoeia, commonly used in various pharmaceutical applications for its emollient properties. It serves as a base for many topical medicinal preparations.

Absorption Bases

• These emulsions typically consist of small droplets of water dispersed throughout a continuous oil phase, leading to unique texture and application properties.
• Examples include wool fat, wool alcohols, and beeswax and cholesterol.

Water-miscible Bases

• Easily washable; this property makes them practical for various cleaning applications, as they can be easily rinsed away without leaving significant residues. Additionally, they can emulsify large amounts of water, allowing for the effective mixing of oil and water; however, they are not miscible with excess water. This means that while they can work with certain proportions, too much water will prevent proper emulsification, highlighting the importance of maintaining an optimal balance for desired results.
• Examples include emulsifying wax, white soft paraffin, and liquid paraffin.

Water-soluble Bases

• Developed from macrogols/polyethylene oxide mixtures; completely water-soluble
• These bases possess a finite ability to uptake water while maintaining their structural integrity, which allows them to retain their original composition without undergoing significant alterations in texture or consistency. (eg Solidify between 40-60°C.)
• This formulation is frequently employed in ophthalmic preparations due to its ability to provide lubrication and protection.

Penetration Enhancers

• These substances create a short-term alteration in the skin's barrier function, enhancing the absorption of therapeutic agents through the dermis.
• Ideal enhancers are non-toxic, non-irritating, and non-allergenic; immediate action; skin recovery after removal; compatible with various drugs and excipients.

Other Excipients

• Antioxidants: (eg. BHA, BHT, EDTA), crucial for preventing oxidation of ingredients.
• Preservatives: Parabens, organics, and QACs(eg. quarternary ammonium compounds) are often needed, particularly in aqueous preparations. They are often absent in completely anhydrous ointments.

Compounding of Ointments & Pastes

• Methods of formulating ointments and pastes encompass several critical steps, including accurate weighing of ingredients, precise measurement of liquids, size reduction through grinding or milling to achieve the desired texture, and thorough mixing to ensure uniformity and stability.
• Mixing Methods:
• Mixing by fusion involves heating ingredients until they melt and blend, forming a homogenous mixture.
• Trituration, a process involving the mechanical breakdown and integration of substances, is commonly used to achieve a fine powder consistency in pharmaceutical preparations. This method is essential for ensuring uniformity in the dispersion of active ingredients within a formulation, enhancing the bioavailability and effectiveness of the final product.

Other Excipients

• Vegetable Oils: (e.g., arachis, castor, coconut, olive); these natural oils are commonly utilized as emollients due to their ability to smooth and hydrate the skin. However, they may also have drawbacks, such as potential for clogged pores or allergic reactions.
• Synthetic Esters Of Fatty Acids: (eg. isopropyl myristate, palmitate-stearate); consistent compositions, resistant to oxidation, and used as substitutes for vegetable oils.
• Higher Fatty Alcohols: (eg. cetostearyl alcohol); have good emollient properties, are non-greasy, and ensure that the ingredients remain stable and safe.
• Silicones: (eg. dimethicones, dimethyl polysiloxanes); used in barrier ointments to protect skin.
• Propylene Glycol: This compound acts as a solvent and humectant, allowing for even distribution of active ingredients within an ointment base. Its properties enhance skin absorption, improving the effectiveness of the medication while also maintaining moisture within the formulation.

Cosmetic Criteria

• The ideal feel of ointments and pastes is characterized by a non-greasy and smooth texture, which enhances user comfort during application.
• Utilizing synthetic bases and waxy materials contributes to a this process enhances the product's usability and handling., ensuring a more pleasant experience for users when applying these formulations on the skin.