Ointments/Creams/Gels Summary
Two Worlds of Dermal Delivery
Local (Topical) Drug Delivery: Medications are applied directly to the skin surface to exert their effects primarily at the site of application. The goal is to maximize drug concentration in the desired skin layer while minimizing systemic absorption. Examples include anti-inflammatory creams for eczema, antifungal ointments for athlete's foot, and sunscreens for UV protection.
Systemic Drug Delivery via Skin (Transdermal): Drugs are delivered through the skin to reach the systemic circulation and exert effects throughout the body. This approach bypasses first-pass metabolism in the liver, offers sustained drug release, and can improve patient compliance. Examples include nicotine patches for smoking cessation, hormone replacement therapy patches, and pain relief patches.
Skin care requires extensive knowledge from pharmacists due to its complex barrier function, diverse pathological conditions that affect the skin, the wide range of dosage forms available, and the potential for drug interactions or adverse effects when treating sensitive skin.
Objectives of Lecture
Describe properties of various topical dosage forms, including ointments, creams, gels, and pastes. Understanding these properties is crucial for selecting the appropriate formulation for a specific therapeutic need.
Classify topical dosage forms and discuss their advantages and disadvantages, considering factors like occlusivity, washability, and drug release profile.
Discuss the composition and general compounding principles of topical products, including the roles of active pharmaceutical ingredients (APIs), excipients, and different types of bases.
Topical Dosage Forms
Used to deliver medications (e.g., corticosteroids for inflammation, antibiotics for skin infections), protect/heal skin (e.g., barrier creams, wound healing ointments), and moisturize the skin (e.g., emollients for dry skin, humectants).
Transdermal systems are specialized topical systems designed to facilitate systemic effects by allowing a controlled amount of drug to penetrate the skin barrier and enter the bloodstream over an extended period. These systems often utilize patches for convenience and adherence.
Structure of the Skin
Skin: The body's largest and heaviest organ, comprising approximately 15% of total body weight, and consisting of three primary layers, each with distinct functions crucial for drug absorption:
Epidermis: The outermost protective layer, primarily composed of keratinocytes, which forms the stratum corneum (SC). The SC is the main barrier to drug penetration due to its compact, brick-and-mortar structure of corneocytes embedded in a lipid matrix.
Dermis: Located beneath the epidermis, it is a connective tissue layer containing blood vessels, lymphatic vessels, nerves, hair follicles, and sweat glands. Drugs reaching the dermis are absorbed into the systemic circulation.
Hypodermis (Subcutis): The innermost layer, consisting of adipose tissue and loose connective tissue, providing insulation and shock absorption.
Drug penetration routes: The pathways through which drugs traverse the skin barrier to reach their site of action or the systemic circulation. These include:
Transcellular route (across cells): Involves the drug passing directly through the corneocytes and their lipid envelopes in the stratum corneum. This route is typically favored by small, lipophilic molecules.
Paracellular route (between cells): Involves the drug diffusing through the lipid matrix between the corneocytes in the stratum corneum. This is generally considered the predominant pathway for most topical drugs.
Transappendageal route (via hair follicles, sweat glands, and sebaceous glands): Utilizes the shunts provided by skin appendages. While these routes offer less resistance to diffusion, they represent a very small percentage of the total skin surface area, making them less significant for overall drug permeation compared to the stratum corneum pathways, though they can be important for certain drugs or formulations.
Drug Penetration Factors
Governed primarily by passive diffusion, a process where drug molecules move from an area of high concentration (e.g., formulation on the skin surface) to an area of low concentration (e.g., deeper skin layers or systemic circulation) without the expenditure of cellular energy. This process adheres to Fick's Law of Diffusion, where the rate of diffusion is proportional to the concentration gradient and the surface area, and inversely proportional to the path length.
Influencing factors crucial for effective drug delivery include:
Partition coefficient (Kp): The ratio of a drug's solubility in oil to its solubility in water. An optimal Kp (neither too lipophilic nor too hydrophilic) is required for a drug to partition out of the vehicle and into the stratum corneum lipids.
Skin moisture/hydration: Increased skin hydration swells the corneocytes and loosens the lipid matrix of the stratum corneum, enhancing drug penetration. Occlusive dressings or vehicles can significantly increase skin moisture.
Physical state of skin: Intact skin provides an effective barrier. Damaged, diseased, or abraded skin (e.g., in psoriasis, eczema, burns) has a compromised barrier function, leading to increased drug penetration and potential for systemic absorption or irritation.
Drug concentration: Higher drug concentrations in the applied product generally lead to a greater concentration gradient, thus increasing the rate and extent of penetration.
Molecular size: Smaller molecules (generally < 500 Da) tend to penetrate the skin more readily than larger molecules.
Vehicle composition: The base or vehicle in which the drug is formulated plays a critical role by affecting drug solubility, release rate, and interaction with the skin (e.g., hydration, occlusion).
Topical Dosage Forms Classification
The FDA recognizes various forms suitable for topical application, each with distinct physical properties and therapeutic uses: solutions, lotions (suspensions or emulsions), suspensions, ointments, creams, gels, and pastes. These forms are chosen based on the desired site of action, patient preference, and specific drug properties.
Ointments, creams, gels, and pastes are particularly important semisolid formulations, each offering specific rheological and application properties tailored for different skin conditions and penetration needs.
Semisolid Dosage Forms
Intended for topical application to the skin or mucous membranes (e.g., rectal, vaginal, nasal, ophthalmic). They provide localized drug action, protect the skin, and can exert emollient or lubricating effects. Their consistency allows them to remain on the skin surface for an extended period, facilitating drug release.
Ideal Properties of Semisolid Dosage Forms
Physical Properties
Smooth texture: Ensures even spreading and patient comfort.
Non-dehydrating: Prevents excessive drying of the skin, especially important for compromised skin barriers.
Non-greasy/cosmetically acceptable: Enhances patient adherence and satisfaction, particularly for products applied to visible areas of the body.
Physically and chemically stable: Maintains integrity and drug potency over its shelf life.
Good viscosity and spreadability: Allows easy application and retention at the application site.
Physiological Properties
Non-irritating, non-sensitizing: Does not cause redness, itching, burning, or allergic reactions on the skin.
Biocompatible: Compatible with the skin's natural functions and components, avoiding adverse interactions.
Easy to apply and remove: User-friendly application promotes compliance.
Non-toxic: Safe for human use, even with prolonged application.
Ointments and Creams
Ointments: Defined as semisolid preparations for external application to the skin or mucous membranes. They are typically anhydrous or contain very little water, resulting in an oleaginous (greasy) and occlusive character. Ointments are effective at preventing moisture loss and enhancing drug absorption.
Creams: Semisolid forms consisting of drug substances dissolved or dispersed in suitable bases. They are distinguished from ointments by their higher water content, leading to a lighter, less greasy texture. Creams are typically classified as either oil-in-water (O/W) emulsions or water-in-oil (W/O) emulsions.
Bases for Ointments and Creams
The rate and extent of drug penetration are significantly affected by the nature of the base and its affinity for the drug. The base serves as a vehicle, influencing drug release, skin hydration, and occlusivity.
Categories of ointment and cream bases:
Hydrocarbon Bases (Oleaginous Bases): Anhydrous, occlusive, and greasy. They protect the skin from moisture loss and are generally immiscible with water. Examples: Petrolatum (Vaseline), White Ointment. They are useful for their emollient effect and for retaining skin moisture.
Absorption Bases: Primarily water-in-oil (W/O) emulsions or anhydrous bases capable of absorbing significant amounts of water. They are less occlusive than hydrocarbon bases and can incorporate aqueous solutions. Examples: Hydrophilic Petrolatum, Lanolin.
W/O Emulsion Bases (Water-in-Oil Emulsion Bases): Contain a significant amount of water dispersed as droplets within an oil phase. They are greasy, occlusive, and absorb additional water. Examples: Cold Cream, Lanolin (hydrous).
Water-removable Bases (Oil-in-Water Emulsion Bases): Also known as creams, these are O/W emulsions. They are non-greasy, washable, and non-occlusive, making them aesthetically more appealing and easier to remove from the skin. They allow for evaporation of water, contributing to a cooling sensation. Examples: Hydrophilic Ointment, Vanishing Cream.
Water-soluble Bases: Typically anhydrous formulations that contain only water-soluble components, such as polyethylene glycols (PEGs). They are non-greasy, readily washed off, and contain no oleaginous components. They absorb water but do not contain it inherently, and can dehydrate the skin. Examples: Polyethylene Glycol Ointment.
Absorption Bases
These bases are either anhydrous (e.g., Hydrophilic Petrolatum) designed to become W/O emulsions upon the addition of water, or they are already W/O emulsions (e.g., Lanolin). They are effective emollients and are useful for incorporating aqueous solutions of drugs into oily vehicles. They are moderately occlusive and retain skin moisture well.
Water-removable Bases
These are oil-in-water (O/W) emulsions, meaning oil droplets are dispersed in a continuous water phase. Their significant advantages include being easy to wash off with water, being non-greasy, and having a less occlusive effect compared to hydrocarbon or absorption bases. This enhances drug release and patient acceptance. They can also provide a cooling effect as water evaporates from the skin.
Water-soluble Bases
Primarily composed of polyethylene glycols (PEGs) of various molecular weights, which can be blended to achieve desired consistencies. They are non-occlusive, absorb water, and are readily dissolved in water. They are typically anhydrous but can incorporate some aqueous solutions. A key consideration is that high-molecular-weight PEG bases can sometimes dehydrate the skin if applied to highly exudative lesions, as they draw water from the skin.
Selection of Base
Factors guiding the choice of a suitable base are critical for therapeutic success and patient comfort:
Desired action: Whether an occlusive, emollient, hydrating, or drying effect is needed.
Area of application: Different bases are preferred for hairy areas (gels, lotions) versus intertriginous areas (creams, drying pastes) or dry, scaly lesions (ointments).
Drug release rate: The base significantly impacts how quickly and efficiently the drug is released and penetrates the skin.
Patient acceptance: Cosmetically appealing bases (e.g., non-greasy, easily washable) lead to better patient compliance.
Compatibility: The base must be chemically and physically compatible with the active pharmaceutical ingredient (API) and other additives to ensure stability and efficacy.
Stability: The base should not degrade or react with the drug over time.
Preparation Methods of Ointments
Fusion Method
This method involves melting the components (especially the base) with the highest melting points first, followed by adding ingredients with lower melting points, typically in ascending order of melting points. All components are gently mixed while maintaining a controlled temperature (usually over a water bath or on a hot plate) until a uniform, liquid mixture is obtained. The mixture is then allowed to cool slowly to ensure an even texture, with continuous stirring to prevent separation or crystallization during solidification. This method is suitable for bases containing waxes, paraffins, and high-molecular-weight PEGs.
Levigation
A critical step for incorporating insoluble solid substances (e.g., finely powdered drugs) into an ointment base to ensure a smooth, homogeneous dispersion and prevent grittiness. It involves reducing the particle size of the powder and wetting it by triturating it with a small amount of a chemically and physically compatible liquid (the levigating agent). The levigating agent should be viscous and miscible with the base but un-reactive with the drug. Common levigating agents include mineral oil (for oil-based ointments) and glycerin (for water-soluble ointments). After levigation, the smoothed paste is incorporated into the main bulk of the ointment base.
Additives in Ointments
Various additives are incorporated to enhance product stability, aesthetics, or therapeutic properties:
Perfumes/Fragrances: Used to mask unpleasant odors of certain ingredients or to make the product more appealing, though they can sometimes cause sensitivity.
Antioxidants: Prevent oxidative degradation of oils, fats, and drug substances. Examples: Butylated hydroxytoluene (BHT), alpha-tocopherol (Vitamin E).
Preservatives: Inhibit microbial growth in formulations containing water, thus extending shelf life and preventing contamination. Examples: Parabens (methylparaben, propylparaben), benzyl alcohol, sorbic acid.
Chelating agents: Bind to metal ions that can catalyze oxidation reactions, thereby improving stability. Example: Ethylenediaminetetraacetic acid (EDTA).
Humectants: Attract and hold water, improving skin hydration. Examples: Glycerin, propylene glycol, urea.
Emollients: Soften and smooth the skin by filling spaces between desquamating corneocytes. Examples: Lanolin, petrolatum, mineral oil.
Evaluation of Ointments
Comprehensive evaluation ensures quality, safety, and efficacy:
Drug penetration studies: In vitro (e.g., Franz diffusion cells) and in vivo methods to assess the rate and extent of drug absorption into and through the skin.
Drug release rate: Measures how quickly the active ingredient is released from the formulation and becomes available for absorption.
Irritant effect/Sensitization potential: Clinical tests (e.g., patch tests) to evaluate primary skin irritation and allergenic potential.
Blood absorption/Systemic exposure: Measuring drug levels in the bloodstream after topical application to assess the extent of systemic absorption, especially for transdermal products or when minimizing systemic side effects is crucial.
Homogeneity: Visual inspection or microscopic analysis to ensure uniform distribution of the drug in the base.
Rheological properties: Measurement of viscosity and spreadability.
Physical stability: Assessing changes in appearance, consistency, phase separation, or odor over time and under different storage conditions.
Microbial limits: Testing to ensure that the product meets specified limits for microbial contamination.
Creams
Creams generally have a lower viscosity and are less greasy than ointments, making them easier to spread and remove. This is largely due to their higher water content. They are broadly classified into:
Oil-in-Water (O/W) creams: The oil phase is dispersed in a continuous water phase. These are more common, non-greasy, and easily washable. They are suitable for weeping or moist skin lesions as they allow water evaporation.
Water-in-Oil (W/O) creams: The water phase is dispersed in a continuous oil phase. These are more emollient, occlusive, and greasy, providing better hydration and protection, similar to ointments but typically with a softer consistency. They are suitable for dry skin conditions.
Forms of Gels and Pastes
Gels: Semisolid systems consisting of a dispersion of small or large molecules in an aqueous or alcoholic liquid vehicle, rendered semisolid by the presence of a gelling agent (e.g., carbomers, cellulose derivatives). They have a low solid content, are non-greasy, transparent (often), and spread easily. They can provide a cooling sensation upon evaporation of the vehicle and are preferred for application to hairy areas or oozing lesions. Gels exhibit thixotropy, meaning they become fluid upon shaking or stirring and then re-solidify.
Pastes: Stiffer than ointments, containing a high proportion of finely dispersed solid materials (typically 20-50% or more) within an ointment base. The high solid content makes them very viscous, less greasy (as the powder absorbs secretions), and highly protective. Pastes are excellent at providing a protective barrier, absorbing exudates, and offering a strong localized action, making them suitable for heavily weeping lesions or as protective barriers (e.g., zinc oxide paste for diaper rash).
Topical Product Applications
Cosmetic products: Moisturizers, anti-aging creams, foundations intended to improve appearance or feel of skin.
Diaper rash ointments: Formulations containing zinc oxide or petrolatum to protect and heal irritated skin.
Sunscreens: Creams, lotions, or gels containing UV filters (physical or chemical) to protect against sun damage.
Antiseptics and disinfectants: Topically applied agents to reduce microbial load on skin (e.g., iodine, chlorhexidine preparations).
Insect repellants: Sprays or creams containing active ingredients like DEET or picaridin.
Emollients: Products designed to soften and moisturize dry, rough, or flaky skin (e.g., paraffin-based creams for eczema).
Deodorants and antiperspirants: Applied to reduce body odor and sweating in axillary regions.
Topical corticosteroids: Anti-inflammatory agents for conditions like eczema, psoriasis, and dermatitis.
Local anesthetics: Creams or gels (e.g., lidocaine) to numb skin before minor procedures.