Topical cream formulation

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A container with cream E45Tub.JPG
A container with cream

Topical cream formulation is an emulsion semisolid dosage form that is used for skin external application. Most of the topical cream formulations contain more than 20 per cent of water and volatiles and/or less than 50 per cent of hydrocarbons, waxes, or polyethylene glycols as the vehicle for external skin application. [1] In a topical cream formulation, ingredients are dissolved or dispersed in either a water-in-oil (W/O) emulsion or an oil-in-water (O/W) emulsion. [2] The topical cream formulation has a higher content of oily substance than gel, but a lower content of oily ingredient than ointment. Therefore, the viscosity of topical cream formulation lies between gel and ointment. [1] The pharmacological effect of the topical cream formulation is confined to the skin surface or within the skin. [3] Topical cream formulation penetrates through the skin by transcellular route, intercellular route, or trans-appendageal route. [4] Topical cream formulation is used for a wide range of diseases and conditions, including atopic dermatitis (eczema), psoriasis, skin infection, acne, and wart. [5] Excipients found in a topical cream formulation include thickeners, emulsifying agents, preservatives, antioxidants, and buffer agents. [6] [7] Steps required to manufacture a topical cream formulation include excipient dissolution, phase mixing, introduction of active substances, and homogenization of the product mixture. [2] [8]

Contents

Pharmacology

A diagram showing different skin layers Skin.png
A diagram showing different skin layers

Human skin can be divided, from outside to inside, into the stratum corneum, viable epidermis, dermis, and underlying hypodermis. [9]

Stratum corneum

The stratum corneum is typically 10–20 μm thick and consists of extracellular lipid-surrounded corneocytes. The lipophilic environment of the stratum corneum can serve as a reservoir for certain highly lipophilic molecules. Keratin found in the stratum corneum may provide great affinity with certain drugs. Both of these interactions can play a role in drug accumulation in the stratum corneum and the local drug action on skin disease. [4]

Viable epidermis

Below the stratum corneum is the viable epidermis. The viable epidermis is usually 50–100 μm thick. It includes immunologically sensitive cells (e.g. Langerhans cells), and metabolically active cells (e.g. keratinocytes, melanocytes, merkel cells). Melanocytes are involved in melanoma pathogenesis. As a result, drugs treating melanoma need to be administered to the lower epidermis.

Dermis

The dermis lies next to the epidermis. It is a 1–2 mm layer mainly composed of fibroblasts and immune cells (e.g. dermal dendritic cells, macrophages, T cells, mast cells) in a collagen and elastic fiber extracellular matrix. [5] These immune cells play important roles in parasitic infections, psoriasis induction, tumor progression, dermal inflammation, angiogenesis, wound healing, tissue remodeling, skin sensitization, and tolerance. [10] Therefore, the regional accumulation of drugs in the dermis is necessary for the prevention and treatment of these local skin diseases.

The hair follicle is an invagination of epidermis cells deep into the dermis. The follicular route is critical in the topical delivery of particle-based formulations and hydrophilic, high-molecular-weight drugs. The follicular route provides benefits such as deeper penetration, prolonged residence duration, faster entry into the skin, and site-specific targeting. [11]

Hypodermis

Beneath these layers lies the hypodermis, which is composed of adipose tissue, fascia, as well as larger lymphatic and blood vessels. For joint and muscle disease treatment, topically applied drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) can penetrate the subcutaneous tissue or even deeper tissues in the hypodermis. [12] Drugs are primarily delivered into the underlying muscle by direct penetration without prior entry into the systemic circulation to prevent unintended side effects.

Routes for topical drug administration

In general, there are three possible routes for drug administration into or across the skin. The first one is the transcellular route, where the drugs are required to pass through both lipid matrix and dead corneocytes of the stratum corneum. The second one is the intercellular route, where the drugs only have to pass through lipid domains between corneocytes. The third one is the trans-appendageal route, where the drugs are transported by hair follicles, sebaceous glands, or sweat glands. [4]

The most common route for drug delivery into the skin is the intercellular route. Multiple steps are involved. [13]

  1. Dissolution and release from the formulation
  2. Partitioning into the stratum corneum
  3. Diffusion through the stratum corneum
  4. Partitioning into the aqueous viable epidermis
  5. Diffusion into the dermis [14]

Excipient

Excipient has a significant impact on the final product performance, manufacturability, and stability. Therefore, the selection of excipients has to be carefully considered during topical cream formulation design.

Oily compounds

In topical cream formulations, oily compounds act as active substance carriers. They also serve as skin penetration enhancers and consistency or viscosity modifiers. The oily excipients may influence cream viscosity, drug solubility, physical stability, drug release performance, and transport into the skin. Oily compounds commonly used in cream formulations include saturated and unsaturated fatty acids/fatty acid esters, hydrocarbons, and polyols.

Thickeners and Emulsifying agents

Topical cream formulations consist of the oily phase and water phase. As the two phases are immiscible, in the absence of thickeners and emulsifying agents, molecules in the topical cream formulation will form droplets. Rapid aggregation of droplets within each phase will eventually lead to phase separation. Physical stability is determined by the mitigation ability to these physical instability phenomena.

Thickeners increase cream viscosity and thus reduce dispersed droplets' mobility. They hinder the separation of phases, thereby increases the physical stability of the cream. For example, the inclusion of methylcellulose and paraffin reduces dispersed droplets' mobility in an oil-in-water emulsion and water-in-oil emulsion respectively.

Emulsifying agents can reduce the interfacial tension between the two phases, thus retards phase separation. Ionic surfactants are used in oil-in-water emulsions, whereas nonionic surfactants are used in both oil-in-water and water-in-oil formulations. [6]

Preservatives and Antioxidants

Oils and fats used in topical cream formulations are susceptible to oxidation by atmospheric oxygen or microorganism action. The stability against oxidation can be enhanced by the introduction of antioxidants. The selection of antioxidants and their concentration can only be determined by testing their effectiveness on the final product, according to pharmacopoeial information. The efficiency of antioxidants depends on their compatibility with other excipients and oil/water partition coefficient.

Oxidations from microbiological source influence the physicochemical properties of the emulsion, resulting in color and odor changes, fat and oil hydrolysis, pH changes in the aqueous phase, or phase separation of the cream. Oil-in-water creams are more susceptible to microbial contamination. Therefore, preservatives are included to prevent any microorganism growth. Preservatives suitable for topical cream formulations must present a broad spectrum of bactericidal activity, low logP, compatibility with other excipients, stability, and effectiveness over a wide range of pH and temperatures.

Buffer agents

By buffering any potential pH change, buffer agents can provide chemical stability and ensure the physical compatibility of the topical cream formulation. They ensure that the formulation can deliver the correct amount of drug to the therapeutic application site, is free from microbial contamination, and physically unchanged since the manufacturing day. Nonetheless, buffer agents need to be carefully added to avoid undesirable effects on physical stability. For example, buffer agents may influence the rheological behavior. [15]

Manufacturing

During the production of the topical cream formulation, the first step is to dissolve excipients in the phase in which they are soluble. The initial mixing temperature of both phases should be high enough to ensure intimate liquid mixing and avoid premature solidification of the oily phase by the colder water. The aqueous phase should be warmed to a temperature slightly higher than the oily phase.

The second step is the mixing of both the aqueous phase and the oily phase by adding either the dispersed phase to the continuous phase, or the continuous phase to the dispersed phase. The effect of the addition order and the addition rate on the drug product quality should be evaluated during process development.

The third step is the introduction of the active substances into the mixture. Some active pharmaceutical ingredients can be dissolved at high temperatures but recrystallize during the cooling stage after mixing. To prevent recrystallization, the active substances can be carried to the cooled down cream base via a powder induction system or through slurry addition. The active substances are simultaneously mixed into the cream base.

The last step is the homogenization stage. Agitators, mechanical mixers, rotor stators, homogenizers, or ultrasonic devices can be employed to ensure uniform excipient dispersion and droplet size reduction. Critical variables of the homogenization equipment include time, temperature, and mechanical energy. Critical parameters must be controlled to produce products of consistent quality. [2] [15]

Medical uses

A wide spectrum of drugs is available as topical cream formulations. Therefore, topical cream formulations are used to treat many skin diseases.

A tube of hydrocortisone cream Tube of hydrocortisone cream.jpg
A tube of hydrocortisone cream
Drugs available as topical cream formulations and their medical uses
Drug classExamples of drugApplications
Glucocorticoids Hydrocortisone
Retinoids Tretinoin, Tazarotene, Adapalene
Vitamin D Analogues Calcipotriene Psoriasis
Antimicrobial Agents Azelaic acid, Erythromycin, Metronidazole Acne and Rosacea
Neomycin, Mupirocin, Silver sulfadiazine Infection
Antiviral Agents Acyclovir, Docosanol, Penciclovir
Cytotoxic, Immunosuppressant,

and Immunomodulatory Agents

5-Fluorouracil
Imiquimod
  • Actinic keratoses
  • Superficial basal cell carcinoma
  • Genital warts
Pimecrolimus
  • Psoriasis
  • Atopic dermatitis
  • Other inflammatory skin diseases
Targeted Immunotherapies PDE4 inhibitors; Jak inhibitors
  • Psoriasis
  • Atopic dermatitis (off label) [5]

Comparison with gel and ointment

Cream, together with gel and ointment, are semisolid dosage forms intended for topical application. [16] They have different appearances, advantages, disadvantages, and applications.

Definitions, properties, and areas of application for cream, gel, and ointment
DefinitionFormulationAppearance and feelAdvantagesDisadvantagesAreas of Application
CreamAn emulsion semisolid dosage form used for external application on the skin. There are two forms of cream, including oil-in-water cream with water as the continuous phase and  water-in-oil cream with oil as the continuous phase [17] Contains >20% water and volatiles and/or <50% of hydrocarbons, waxes, or polyethylene glycols as the intermedia [18] Opaque, viscous, and ranges from non-greasy to mildly greasy; tends to mostly evaporate or be absorbed when rubbed onto the skin
  • Moistening and emollient properties
  • More spreadable and less greasy than ointments
  • Less hydrating than ointments
  • Can be used in all areas
  • Especially effective in:
    • Areas with dry and exudative skin conditions, especially if there is a serous exudate
    • Flexural and genital areas
GelA semisolid dosage form that contains a gelling agent to provide stiffness to the solution or colloidal dispersion. It is used for external application on the skin. A gel may contain suspense particlesUsually contains an aqueous or alcoholic vehicle and a gelling agent such as starch, cellulose derivatives, carbomers, nathan gum, colloidal silica, magnesium-aluminium silicates, aluminium or zinc soapsThick, non-greasy with a clear or translucent appearance in a single-phase system; provides a cooling sensation when applied to the skin
  • Dry as a greaseless non-occlusive film
  • Cosmetically elegant
  • Easy to apply and wash off, especially to a hair-bearing area
  • Non-greasy
  • Provide cooling sensation
  • Not an occlusive or emolliating vehicle
  • Perspiration may remove the gel
  • No occlusive effects and little skin hydration
  • May be challenging to wash off an oily gel from hair-bearing areas
  • Hair-bearing areas, such as the scalp
  • Oily areas, such as the face
OintmentA suspension or emulsion semisolid dosage form that is used for external application on the skinContains <20% water and volatiles and >50% of hydrocarbons, waxes, or polyethylene glycols as the intermedia [18] Opaque or translucent, viscous, greasy; tends not to evaporate or be absorbed when rubbed onto the skin [19]
  • Increase hydration and temperature of the skin

Related Research Articles

An emulsion is a mixture of two or more liquids that are normally immiscible owing to liquid-liquid phase separation. Emulsions are part of a more general class of two-phase systems of matter called colloids. Although the terms colloid and emulsion are sometimes used interchangeably, emulsion should be used when both phases, dispersed and continuous, are liquids. In an emulsion, one liquid is dispersed in the other. Examples of emulsions include vinaigrettes, homogenized milk, liquid biomolecular condensates, and some cutting fluids for metal working.

<span class="mw-page-title-main">Skin</span> Soft outer covering organ of vertebrates

Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation.

<span class="mw-page-title-main">Integumentary system</span> Skin and other protective organs

The integumentary system is the set of organs forming the outermost layer of an animal's body. It comprises the skin and its appendages, which act as a physical barrier between the external environment and the internal environment that it serves to protect and maintain the body of the animal. Mainly it is the body's outer skin.

<span class="mw-page-title-main">Epidermis</span> Outermost of the three layers that make up the skin

The epidermis is the outermost of the three layers that comprise the skin, the inner layers being the dermis and hypodermis. The epidermis layer provides a barrier to infection from environmental pathogens and regulates the amount of water released from the body into the atmosphere through transepidermal water loss.

<span class="mw-page-title-main">Topical medication</span> Medication applied to body surfaces

A topical medication is a medication that is applied to a particular place on or in the body. Most often topical medication means application to body surfaces such as the skin or mucous membranes to treat ailments via a large range of classes including creams, foams, gels, lotions, and ointments. Many topical medications are epicutaneous, meaning that they are applied directly to the skin. Topical medications may also be inhalational, such as asthma medications, or applied to the surface of tissues other than the skin, such as eye drops applied to the conjunctiva, or ear drops placed in the ear, or medications applied to the surface of a tooth. The word topical derives from Greek τοπικόςtopikos, "of a place".

<span class="mw-page-title-main">Stratum corneum</span> Outermost layer of the epidermis

The stratum corneum is the outermost layer of the epidermis. The human stratum corneum comprises several levels of flattened corneocytes that are divided into two layers: the stratum disjunctum and stratum compactum. The skin's protective acid mantle and lipid barrier sit on top of the stratum disjunctum. The stratum disjunctum is the uppermost and loosest layer of skin. The stratum compactum is the comparatively deeper, more compacted and more cohesive part of the stratum corneum. The corneocytes of the stratum disjunctum are larger, more rigid and more hydrophobic than that of the stratum compactum.

<span class="mw-page-title-main">Moisturizer</span> Type of cosmetics

A moisturizer, or emollient, is a cosmetic preparation used for protecting, moisturizing, and lubricating the skin. These functions are normally performed by sebum produced by healthy skin. The word "emollient" is derived from the Latin verb mollire, to soften.

<span class="mw-page-title-main">Cream (pharmacy)</span> Preparation for application to the skin or mucous membranes

A cream is a preparation usually for application to the skin. Creams for application to mucous membranes such as those of the rectum or vagina are also used. Creams may be considered pharmaceutical products as even cosmetic creams are based on techniques developed by pharmacy and unmedicated creams are highly used in a variety of skin conditions (dermatoses). The use of the finger tip unit concept may be helpful in guiding how much topical cream is required to cover different areas.

<span class="mw-page-title-main">Lotion</span> Skin treatment preparation

Lotion is a low-viscosity topical preparation intended for application to the skin. By contrast, creams and gels have higher viscosity, typically due to lower water content. Lotions are applied to external skin with bare hands, a brush, a clean cloth, or cotton wool.

Sonophoresis is a method that utilizes ultrasound to enhance the delivery of topical medications through the stratum corneum, to the epidermis and dermis. Sonophoresis allows for the enhancement of the permeability of the skin along with other modalities, such as iontophoresis, to deliver drugs with lesser side effects. Currently, sonophoresis is used widely in transdermal drug delivery, but has potential applications in other sectors of drug delivery, such as the delivery of drugs to the eye and brain.

Dosage forms are pharmaceutical drug products in the form in which they are marketed for use, with a specific mixture of active ingredients and inactive components (excipients), in a particular configuration, and apportioned into a particular dose. For example, two products may both be amoxicillin, but one is in 500 mg capsules and another is in 250 mg chewable tablets. The term unit dose can also sometimes encompass non-reusable packaging as well, although the FDA distinguishes that by unit-dose "packaging" or "dispensing". Depending on the context, multi(ple) unit dose can refer to distinct drug products packaged together, or to a single drug product containing multiple drugs and/or doses. The term dosage form can also sometimes refer only to the pharmaceutical formulation of a drug product's constituent drug substance(s) and any blends involved, without considering matters beyond that. Because of the somewhat vague boundaries and unclear overlap of these terms and certain variants and qualifiers within the pharmaceutical industry, caution is often advisable when conversing with someone who may be unfamiliar with another person's use of the term.

Skin absorption is a route by which substances can enter the body through the skin. Along with inhalation, ingestion and injection, dermal absorption is a route of exposure for toxic substances and route of administration for medication. Absorption of substances through the skin depends on a number of factors, the most important of which are concentration, duration of contact, solubility of medication, and physical condition of the skin and part of the body exposed.

Pharmaceutical formulation, in pharmaceutics, is the process in which different chemical substances, including the active drug, are combined to produce a final medicinal product. The word formulation is often used in a way that includes dosage form.

<span class="mw-page-title-main">Human skin</span> Outer covering of the body

The human skin is the outer covering of the body and is the largest organ of the integumentary system. The skin has up to seven layers of ectodermal tissue guarding muscles, bones, ligaments and internal organs. Human skin is similar to most of the other mammals' skin, and it is very similar to pig skin. Though nearly all human skin is covered with hair follicles, it can appear hairless. There are two general types of skin, hairy and glabrous skin (hairless). The adjective cutaneous literally means "of the skin".

<span class="mw-page-title-main">Transdermal</span>

Transdermal is a route of administration wherein active ingredients are delivered across the skin for systemic distribution. Examples include transdermal patches used for medicine delivery. The drug is administered in the form of a patch or ointment that delivers the drug into the circulation for systemic effect.

<span class="mw-page-title-main">Fungal folliculitis</span> Inflammation of hair follicles due to fungal infection

Majocchi's granuloma is a skin condition characterized by deep, pustular plaques, and is a form of tinea corporis. It is a localized form of fungal folliculitis. Lesions often have a pink and scaly central component with pustules or folliculocentric papules at the periphery. The name comes from Domenico Majocchi, who discovered the disorder in 1883. Majocchi was a professor of dermatology at the University of Parma and later the University of Bologna. The most common dermatophyte is called Trichophyton rubrum.

Topical drug delivery (TDD) is a route of drug administration that allows the topical formulation to be delivered across the skin upon application, hence producing a localized effect to treat skin disorders like eczema. The formulation of topical drugs can be classified into corticosteroids, antibiotics, antiseptics, and anti-fungal. The mechanism of topical delivery includes the diffusion and metabolism of drugs in the skin. Historically, topical route was the first route of medication used to deliver drugs in humans in ancient Egyptian and Babylonian in 3000 BCE. In these ancient cities, topical medications like ointments and potions were used on the skin. The delivery of topical drugs needs to pass through multiple skin layers and undergo pharmacokinetics, hence factor like dermal diseases minimize the bioavailability of the topical drugs. The wide use of topical drugs leads to the advancement in topical drug delivery. These advancements are used to enhance the delivery of topical medications to the skin by using chemical and physical agents. For chemical agents, carriers like liposomes and nanotechnologies are used to enhance the absorption of topical drugs. On the other hand, physical agents, like micro-needles is other approach for enhancement ofabsorption. Besides using carriers, other factors such as pH, lipophilicity, and drug molecule size govern the effectiveness of topical formulation.

Topical gels are a topical drug delivery dosage form commonly used in cosmetics and treatments for skin diseases because of their advantages over cream and ointment. They are formed from a mixture of gelator, solvent, active drug, and other excipients, and can be classified into organogels and hydrogels. Drug formulation and preparation methods depend on the properties of the gelators, solvents, drug and excipients used.

<span class="mw-page-title-main">Invasomes</span> Drug delivery method, transdermal drug delivery

An invasome are a type of artificial vesicle nanocarrier that transport substances through the skin, the most superficial biological barrier. Vesicles are small particles surrounded by a lipid layer that can carry substances into and out of the cell. Artificial vesicles can be engineered to deliver drugs within the cell, with specific applications within transdermal drug delivery. However, the skin proves to be a barrier to effective penetration and delivery of drug therapies. Thus, invasomes are a new generation of vesicle with added structural components to assist with skin penetration.

Laser-assisted drug delivery (LADD) is a drug delivery technique commonly used in the dermatology field that involves lasers. As skin acts as a protective barrier to the environment, the absorption of topical products through the epidermis is limited; thus, different drug delivery modalities have been employed to improve the efficacy of these treatments. The use of lasers in LADD has been shown to enhance the penetration of drugs transdermal, leading to a higher absorption rate, limited systemic effects, and reduced duration of treatment. Although this technique has evolved in the past decade due to its efficacy through scientific research and clinical practice, there remain some limitations regarding the safety aspect that needs to be taken into consideration.

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