Silicone Excipients in Drug Development

A versatile ingredient works in excipient applications

By Gerald K. Schalau II and Katherine L. Ulman

Silicones have a range of applications in the pharmaceutical industry, from active ingredients in antacids to tubing used in drug processing. They also are used as excipients in topical pharmaceutical creams, ointments and lotions. These applications depend on the versatility and distinctive physicochemical and performance properties of silicone fluids, gums, and gels, which can offer combinations of formulating solutions not available with other ingredients. Low surface tension, improved aesthetics, substantivity, high permeability, nonstaining properties, and the ability to protect and deliver active ingredients allow contract manufacturers expanded formulating opportunities to meet the evolving needs of their customers.

An Expanding Role for Silicones

As the functional properties of excipients become more critical to the performance of pharmaceutical products — for example, their impact on bioavailability of drugs — contract manufacturers can benefit from considering excipients with versatility to fill a number of roles. Although silicones can function as active ingredients, they are more often used as excipients. Examples include siliconization (lubrication of syringe barrels, pistons, needles or stoppers), skin adhesives in transdermal patches (based on their adaptability for drug permeability), volatile or nonvolatile agents to improve spreading and aesthetic properties, or carriers for active ingredients. With silicone excipients, a key factor for success is selecting from a range of materials to provide specific functionalities and performance characteristics throughout the shelf life of the drug product.

The use of silicones to improve a pharmaceutical application or its aesthetics might be considered a form of technology transfer from the personal care industry. Silicones have been incorporated into skin care products since the early 1950s, and today at least 50% of newly launched skin care products contain at least one silicone. However, many silicones also have been used in healthcare applications, as evidenced by the number of silicone materials listed on the FDA’s inactive ingredient list. The silicones used in healthcare applications are among the most extensively tested materials for safety, and they are known to provide a pleasant silky, nongreasy and dry feel on skin.

Aiding Patient Compliance

The sensory properties of silicone excipients can be important factors in assisting patients who do not comply with treatment regimens because their prescribed medications have poor aesthetics. Poor patient compliance and its impact on treatment failure is a growing concern. A recent publication estimated the economic impact in the U.S. at $100 billion annually due to excessive use of healthcare resources in response to medication noncompliance¹. Because of its chronic nature and the need for topical treatments, psoriasis has been a focus of the dermatology community in an effort to understand the causes of medication noncompliance. It has been reported that more than one-third of psoriatic patients are not compliant with their prescribed medication².

Another study of psoriatic patients links medication compliance and successful patient outcomes³. The vehicle-related factor that the “medication felt unpleasant” was rated as important, while the “medication stained clothing” factor and the convenience of application (“application was time-consuming”) factor were rated as some of the most important issues. The authors stated, “Choosing a fast-drying vehicle that is easy to apply may improve usage in patients concerned about inconvenience of application.” Of note, the authors indicated that compliance did not vary with prescribed application frequency (once- versus twice-daily application), nor was there a significant difference between high-potency steroid use compared to medium and low-potency steroids.

Versatile Options

Whether selection of excipients focuses primarily on patient compliance or on other functional issues, the distinctive chemical and structural characteristics of silicones play a significant role. The silicones used in healthcare applications are typically based on the polydimethylsiloxane (PDMS) polymer, with its silicon-oxygen backbone and attached methyl pendants. Based on the requirements of individual applications, chain length, cross-linking or substitution by various functional groups can result in a variety of useful materials. Among the most important silicone forms in healthcare applications are volatile and nonvolatile silicone fluids, waxes, emulsifiers, or polymer blends such as elastomers and gums.

Volatile silicone fluids are used in a variety of personal care applications because of their easy spreading, fast evaporation rates, nonstaining properties, smooth and nongreasy feel, noncooling and nonstinging characteristics, and their safety profile. The chemical characteristics of these high purity fluids also make them useful in topical pharmaceutical products. They are compatible with a broad range of lipophilic products such as mineral oil, petrolatum, esters, and lipophilic sun filters, and can be incorporated into the oil phase of emulsions and easily dispersed into hydrogels. Some volatile silicones can be used as volatile excipients in spray pump systems for topical applications. Their low surface tension improves skin coverage and may increase bioavailability of active ingredients, while the low heat of vaporization allows films to dry quickly.

Nonvolatile silicone fluids offer high water repellency through nonocclusive films, good lubrication characteristics and low surface tension for improved spreading. They can also provide substantivity and lubrication, while reducing tackiness and residue on the skin.

As hydrophobic lubricants, nonvolatile silicone fluids can serve as emollients to improve the aesthetics of lotions and creams, and as excipients in transdermal drug delivery systems. At use levels of 1% to 30%, some silicone fluids, depending upon viscosity, appear as active ingredients with skin protectant claims. These products fit the description of “a drug product that temporarily protects injured or exposed skin or mucous membrane surfaces from harmful or annoying stimuli, and may help provide relief to such surfaces,” as described in the FDA skin protectant monograph⁴.

Figure 1 illustrates the use of two viscosities of PDMS delivered at 5% from an isododecane carrier and measured on the skin using a wash-off simulator. After three washes, results show the higher viscosity material has a higher level of substantivity.

Figure 1: Substantivity of 5% PDMS in isododecane on skin after three washings.

Silicone elastomer blends, a mixture of fluid and cross-linked nonfunctional silicone elastomer, can also be used to improve the substantivity of topical pharmaceutical formulations. They provide a more matte appearance on the skin compared to silicone fluids and leave a drier and more powdery feel — an effect that is enhanced by their ability to absorb oil and sebum. In formulations, they can act as rheology modifiers to offer distinctive sensory and textural effects, and recent studies show they can function as carriers for the release of active ingredients⁵. They also offer enhanced delivery and stabilization of volatile or unstable ingredients such as vitamins and pharmaceutical actives. Silicone elastomers can aid in the formation of emulsions or anhydrous gels, and they are optimum thickeners for silicone-based formulations. Upon application, their shear-thinning properties translate to smooth, even application for good coverage, and a “rebuild” of viscosity to remain substantive on the skin.

Figure 2 shows results of sensory evaluations of two ointments, one containing 100% petrolatum, and the other containing 70% petrolatum, 15% volatile silicone and 15% silicone elastomer. The ointment containing silicone was easier to spread and less tacky before and after application than the 100% petrolatum ointment. After application, a perceptible film was present on the skin for both formulations, but the silicone-containing ointment was less greasy, silkier and more slippery (showing better lubrication) than the ointment containing petrolatum. The perception of higher wetness for the silicone formulation was attributed to its lower oiliness.

Figure 2: Sensory evaluation (paired comparison) of an all-petrolatum ointment versus an ointment containing petrolatum and silicones. Percentages indicate level of confidence, and the ratings for absorption were based on panelists’ perceptions, not biological skin absorption.

The addition of silicones to petrolatum resulted in a net improvement in the sensory profile of the ointment. This improvement is important in the case of ointments, which traditionally are linked to poor patient compliance due to their lack of spreadability and their tacky and greasy feel.

Silicone gums are high molecular weight silicone polymers that may be linear or branched and can be delivered onto the skin in volatile or nonvolatile silicone fluids. Like nonvolatile silicone fluids, these materials can enhance film cohesion on the skin, for greater substantivity and prolonged effectiveness of active ingredients. Improved substantivity of UV sunscreens on the skin has been demonstrated in the presence of very high molecular weight (Mw = 700,000) silicone gums⁶.

Silicone gums have been shown to improve substantivity of ketoprofen, a nonsteroidal anti-inflammatory drug, on skin when dispensed from a volatile-based silicone spray⁷. After eight hours, the presence of ketoprofen was detected on the skin surface using formulations containing a silicone gum, while ketoprofen was no longer detected in the control after six hours. It is not clear if the improved substantivity was a result of improved abrasion resistance or whether the gum had an influence on the skin penetration rate by acting as a reservoir to delay penetration. Abrasion resistance was certainly improved. Consecutive attempts to remove the film with adhesive tape immediately after spraying indicated the presence of silicone gum made removal more difficult, and drug-loaded films were even more resistant to removal⁷.

Silicone gums are very substantive on their own.In one evaluation, more than 25% of the silicone gum tested remained on the skin after eight hours⁷. Improved substantivity was observed even when very low concentrations of silicone gum (1% to 3% by weight) were used, thus providing a low viscosity formulation that could easily be applied by spraying, and which would not unreasonably increase drying time⁷.

Silicone waxes improve the aesthetic properties of topical pharmaceutical formulations, allowing application of very thin occlusive to semi-occlusive films that are neither too oily, tacky, nor dry. While silicones such as these are used for their biocompatibility and aesthetic benefits, studies also suggest they may improve the bioavailability of active ingredients over less occlusive formulations. Silicone waxes can also be used to impart moisturization, reduce tackiness and increase the viscosity of emulsions, and they have good compatibility with organic ingredients. Figure 3 shows the thickening effect of a silicone wax on three emulsion types.

Figure 3: Viscosity of emulsions with and without silicone wax.

While PDMS materials are highly permeable to moisture, some silicones such as stearoxytrimethylsilane wax display occlusive properties while still maintaining the silky feel usually associated with silicones. The following listcompares the occlusivity of oil-in-water petrolatum and stearoxytrimethylsilane wax emulsions on gelatin membranes.

Comparison of Oil-in-Water Emulsion Occlusivity

Oily Ingredient / Occlusivity (%)

Petrolatum Emulsion:93.4

Petrolatum/Silicone Wax, 50:50 Emulsion:84.7

Silicone Wax Emulsion:72.9

Silicone emulsifiers are designed for preparation of water-in-oil and water-in-silicone emulsions with excellent stability, flexibility and aesthetics. They are completely soluble in the water phase and dispersible in water solutions, but soluble in detergent systems. The presence of electrolytes (e.g., NaCl, or MgSO4 at 0.7% to 2%) helps reduce the interfacial surface and so reduce particle size, while increasing viscosity, stability and freeze resistance. At levels of 1% to 3%, silicone emulsifiers deliver the benefits of skin protection and water resistance, and they allow formulation of creams and lotions at room temperature, resulting in lower processing costs and faster processing times.

Product Registration Support

When selecting a silicone excipient, the source of the excipients may be in question, and compendial monographs do not exist to describe all potential silicone excipients. It may be preferable to select excipients that are manufactured, packaged, or tested in a dedicated facility that is registered and inspected by the FDA, or similar agencies in other geographies, that apply appropriate GMPs or similar standards for the intended healthcare applications.

Many of the silicone chemistries discussed in this article have already been used in such applications and are listed on the FDA’s Inactive Ingredient List. Using materials on this list may expedite product registration times and reduce costs. The flexibility of silicone excipient options can also be enhanced by selecting a supplier who can provide documentation to help expedite and simplify the regulatory approval process and support customer requests. Filings with global authorities may include Drug Master Files (in the U.S.) and Technical Files (in Europe) or similar filings in other geographies. Other assistance may include Letters of Authorization that provide customer access to Drug Master Files without disclosing proprietary information, while FDA inspection reports can show how well suppliers are conforming to regulatory requirements.

Access to filings of this type can expedite the regulatory application process. In addition, if a contract manufacturer has access to toxicologists and toxicological data via its excipient supplier, the process of determining suitability of silicone excipients for specific applications can go more smoothly. In effect, the expertise of the supplier can help serve as a screening process for potential excipients.

As a complement to regulatory support, availability of formulation expertise to illustrate prototype formulations in a variety of product forms can help contract manufacturers screen multiple formulations without the need to develop them from scratch. This may in turn support their customers by speeding the process for getting products to market.

Silicones have a history of more than 50 years of safety and efficiency in healthcare-related applications, and polydimethylsiloxanes are globally recognized both for their proven biocompatibility as well as for being one of the most tested materials for their safety.

As excipients, many of the unique properties of PDMS have been capitalized upon in controlled release drug delivery systems due to their chemical stability, high level of purity, ease of use and high permeability to many active drugs. Because of their distinctive physicochemical properties, silicones are especially suitable for providing aesthetics and bioavailability of actives for topical formulations.

References

1 R. Balkrishnan, C.L. Carroll, F.T. Camancho and S.R. Feldman, J. Am. Acad. Dermatol., 49, 651-4 (2003).

2 P.C. van de Kerkhof, D. de Hoop, J. De Korte, S.A. Cobelens, and M.V. Kuipers, Dermatology, 200, 292-8 (2000).

3 C.L. Carroll, S.R. Feldman, F.T. Camancho and R. Balkrishnan, Br. J. Dermatol., 151, 895-7 (2004).

4 Skin Protectant Drug Products for Over-the-Counter Human Use; Final Monograph, FDA Monograph 21 CRF Part 347, June 4, 2003.

5 A. Etienne and L. Aguadisch, EP 0 475 664 (1992).

6 G. Chandra and H. Klimisch, J. Soc. Cosmet Chem., 37:2 73 (1986).

7 L. Aguadisch et al., EP 0 966 972 (1999)