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While the skin offers an alternative route of administration for local and systemic drug delivery, developing semi-solid dosage forms can be a challenge.
Matthias Springfelter, senior formulation scientist at Recipharm Pharmaceutical Development AB, Solna, Sweden, spoke to Pharmaceutical Technology about the advantages and the key considerations in developing topical formulations.
AdvantagesPharmTech: What advantages do topical formulations offer compared to other dosage forms?
Springfelter: Perhaps the most obvious advantage is that topical formulations allow for local treatment of a number of dermatological conditions with very little systemic exposure. A high drug load can be applied on the actual site where the drug is required, with a reduced risk of unwanted side effects. Topical products are easy for the patient to apply and the moisturizing effect of topical formulations, such as creams and ointments, may also be beneficial for several skin conditions.
Transdermal delivery systems offer an alternative route for systemic administration of various drugs with the benefit of a reduced risk of loss of potency or unwanted variability due to first-pass metabolism. Transdermal delivery systems can be designed to offer prolonged and controlled-release absorption of certain drugs, which can be convenient for pain relief drugs, nicotine, and hormone products.
Drug absorptionPharmTech: Can you tell us more about the mechanisms of drug absorption across the skin barrier and how they affect the development of topical drug products?
Springfelter: The human skin functions as an efficient barrier against the outside environment. Achieving sufficient drug absorption can, therefore, prove challenging for many molecules. For a drug to reach its target site or to be absorbed into the blood stream, a sufficient amount has to pass through the outer part of the epidermis, the stratum corneum, and the epidermis. Even though there are some passages, such as the hair follicles, sweat glands, and active transportation mechanisms, the most important mechanism for drug absorption is by passive diffusion. The rate of diffusion will, to a large extent, depend on the properties of the drug molecule itself. However, formulators can use a number of methods to optimize drug absorption.
In general, small-sized and relatively lipophilic molecules are most likely to be readily absorbed through the skin, and this aspect must be considered when selecting a drug candidate. Sometimes, it is possible to modify the drug properties or alternatively, choose a pro-drug that is delivered in inactive form and that better matches these criteria. The choice of vehicle depends on the properties of the drug substance, such as the solubility profile and partition coefficient, so that the chemical potential of the drug is maximized. The permeability of the skin is also an important factor--the penetration rate could be increased by an increase in skin hydration, for example, by choosing an occlusive vehicle or patch. A number of penetration enhancers that increase the absorption of a drug by temporarily increasing the permeability of the skin have been evaluated, but there are limitations because of skin irritation or toxicity concerns.
PharmTech: What are the main components of a topical formulation?
Springfelter: The components of a topical product will depend on the type of formulation. It could be as simple as an active ingredient dissolved in a solvent with suitable additives such as pH-buffers, co-solvent, and preservatives to achieve adequate solubility and stability for the formulation. In a topical gel, viscosity modifiers such as cellulose-based or synthetic polymers are added to achieve the desired rheological properties. Ointments are semi-solid preparations of a drug substance dissolved or dispersed in a semisolid ointment base made of paraffin or other hydrocarbons. Emulsions are somewhat more complex because they consist of two liquid phases, one of which is dispersed within the other, usually oil droplets dispersed in water. A number of excipients are often necessary to achieve a physically and chemically stable emulsion. Water and one or more organic compounds, such as mineral or vegetable oils, make up the two liquid phases, and one or more emulsifying agents will be needed to keep the phases apart. The stability of the emulsion can be further improved by the addition of polymers to increase the viscosity of the water phase. Additional excipients such as pH-buffers, antioxidants, and preservatives are usually added as well.
Considerations in formulation developmentPharmTech: What are the key considerations when designing a formulation for topical drug delivery?
Springfelter: First of all, the choice of formulation must be made based on the disease or condition to be treated, the type of skin upon which it is to be applied, and the properties of the drug substance. After that, one has to ensure that sufficient amount of the drug reaches its site of action, whether it is on the skin layer, or systemically. The drug absorption may have to be optimized, for example by adjusting the vehicle or adding penetration enhancers. It is also important to ensure that skin irritation and toxicity are minimized.
As always in formulation development, the physicochemical properties of the drug product must be well controlled. The stability of the active ingredients and other functional excipients, such as preservatives or antioxidants, will have to be monitored. Phase changes, such as separation or bleeding, must be prevented in emulsions and ointments. The microbial quality control of the drug product needs to be considered, especially in water-rich formulations; in this case, it is often necessary to add preservatives. The viscosity and rheological behavior should be adjusted to fit the type of application and the overall cosmetic properties should be acceptable.
Vehicle selectionPharmTech: Can you elaborate more on the selection of a vehicle for topical formulations and how drug properties will affect the choice of a vehicle?
Springfelter: The selection of a vehicle for a topical formulation is based on several factors, ranging from stability and compatibility, the type of disease and skin to be applied on, to biopharmaceutical considerations.
In general, the lipophilic type of vehicles, such as ointments and emulsions, are preferred for conditions that involve dry skin. Ointment vehicles are commonly used as they provide a moisturizing effect on dry and flaky skin due to their occlusive properties. In addition, the increase in hydration of the skin can also improve the absorption of the drug. Ointments are also less irritating to sensitive skin than water-based formulations, but they have a greasy feel that patients tend to dislike.
Emulsion-type vehicles, such as oil-in-water creams, are often preferred for their improved cosmetic properties because they are easy to apply and are less viscous and greasy. Achieving a stable emulsion, however, can prove to be challenging in some cases. Liquid vehicles such as solutions or gels are convenient for application on hairy skin areas such as the scalp and are sometimes preferred in dermal conditions for which a drying effect is desired. For transdermal applications, a suitable patch or other device would have to be evaluated together with the formulation.
Testing drug release and drug absorptionPharmTech: How do you test drug release and drug absorption?
Springfelter: A number of methods are available for the evaluation of the drug release and absorption of dermal and transdermal products. There is, however, no gold standard and the method used will vary from case to case.
Some in-vitro methods are particularly useful for early studies and screening purposes. For transdermal patches, the paddle-over-disc method described in the United States Pharmacopeia and the European Pharmacopoeia is a reliable test to determine the in-vitro dissolution rate. For semi-solids, no compendial methods are available, but the diffusion cell systems, such as Franz or In-Line cells, are widely used and may be fitted with various artificial or animal skin membranes, or even excised human skin. Diffusion cell systems can provide useful information and guidance, for example, when choosing the vehicle for a topical product, but as always, caution should be taken when extrapolating into more complex in-vivo conditions. New in-vitro models and methods are also being developed, and are becoming more useful in the characterization of topical products. In-vivo studies in different species of animals are often performed, but as animal skin differs from human skin, results should be extrapolated with caution.
PharmTech: As the pharmaceutical landscape becomes increasingly competitive, drug developers are now focusing more on patient centricity and formulation for specific populations. In your opinion, what is the future outlook for semi-solid drug products and do you expect demand for this type of dosage form to increase?
Springfelter: We have seen increased interest in semi-solid products in recent years and there may be several reasons for this trend. Where, several years ago, the focus was on blockbuster products, today there is a move toward more niche applications. As demand for personalized products increases, topical administration is gaining popularity. Another key driver is the increasing interest in new products that use existing drug substances. New topical formulations using drugs that were previously administered in another dosage form can offer significant benefits, not only therapeutic benefits, but financial ones, as they reduce development cost and risk.
Article DetailsPharmaceutical Technology
Vol. 39, No. 3
Citation: When referring to this article, please cite it as A. Siew, “Semi-Solid Dosage Forms,” Pharmaceutical Technology39 (3) 2015.