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423

G. K. Schalau () · H. A. AliyarPharmaceutics, Dow Corning Corporation, Healthcare Industry, Midland, MI 48686, USAe-mail: [email protected]

Chapter 14Silicone Excipients in Pharmaceutical Drug Delivery Applications

Gerald K. Schalau and Hyder A. Aliyar

Abstract Silicones have been used in medicines, cosmetics and medical devices for over 60 years. Polydimethylsiloxanes (PDMS) are commonly used as an active in many oral antiflatulent remedies and topically applied skin protectant creams, and ointments. The plethora of physical forms and the physio-chemical properties that silicones can display has led to their adoption in a diverse array of healthcare applications in different physical forms including as excipients in topi-cal and transdermal drug delivery systems. Unique characteristics like hydropho-bicity, low surface tension, and aesthetics intrinsically associated with silicones offer function and performance to drug delivery products. Recent research inves-tigations support the use of silicone based pressure sensitive adhesives for their skin-friendliness, and also to enhance the efficacy of the drug in the transdermal drug delivery patch products. Similarly, in topical drug delivery applications, sili-cone based novel excipients have demonstrated their capability in improving drug delivery efficiency. Recent silicone technologies like swollen crosslinked silicone elastomer blend networks, sugar siloxanes, amphiphilic resin linear polymers, and silicone based hybrid pressure sensitive adhesives promise potential performance advantages and improved drug delivery efficacy in topical or transdermal drug delivery systems.

Keywords Adhesives · Cyclomethicone · Dimethicone · Pressure sensitive adhesives · Silicon · Simethicone · Topical drug delivery

Abbreviations

ANDA Abbreviated new drug applicationARL Amphiphilic resin linearEP European PharmacopeiaHEC Hydroxyethyl celluloseHIV Human immunodeficiency virus

© Springer International Publishing Switzerland 2015A. S. Narang, S. HS. Boddu (eds.), Excipient Applications in Formulation Design and Drug Delivery, DOI 10.1007/978-3-319-20206-8_14

424 G. K. Schalau and H. A. Aliyar

IVR Intravaginal ringLog P Octanol–water partition coefficientNF National FormularyNMDA N-methyl-D-aspartateNSAIDs Non-steroidal anti-inflammatory drugsOTC Over-the-counterPDMS Polydimetyl siloxanesPEG Poly(ethylene glycol)PIB PolyisobutylenesPSA Silicone pressure sensitive adhesiveREACh Registration, Evaluation, Authorization and Restriction of ChemicalsSEB Silicone elastomer blendSIS Styrene-isoprene-styrene block copolymersTDDS Transdermal drug delivery systemsTEWL Transepidermal water lossTg Glass transition temperatureUSP United States Pharmacopeia

14.1 Introduction

Silicones are synthetic polymers containing -Si-O siloxanes bonds. The most com-mon silicone polymers are polydimethylsiloxane (PDMS) and its unique position in the silicone industry is a consequence of its structure. Silicones are noted in many industries for their stability in extreme temperatures and other challenging environments, and have found success in many applications requiring water repel-lency, surface wet-ability, high permeability, and resistance to thermal, radiation and chemical degradation. Silicone materials have been used in medicines, cosmet-ics and medical devices for over 60 years. The plethora of physical forms and the physiochemical properties that silicones can display has led to their adoption in a diverse array of healthcare applications. Silicones are used as both pharmaceutical actives (e.g. dimethicone and simethicone as an anti-flatulent) and as excipients in drug delivery applications, appearing most often in transdermal patches, topical semisolid formulations and drug loaded medical devices. Silicones are noted for their low surface tension, high permeability to gases and their non-greasy aesthetics which may be rationale for their use in topical drug delivery applications. It is gen-erally accepted that low molecular weight and lipophilic drugs can readily diffuse through silicone rubber; which may be a contributing factor to silicone’s wide use in drug loaded medical device and in some transdermal drug delivery applications (Robb 1968).

42514 Silicone Excipients in Pharmaceutical Drug Delivery Applications

14.2 Terminology, Structure, and Characteristics

Although the term “silicone” is not used consistently, it is important to avoid the relatively common confusion between the metallic element, silicon (Si), and the polymeric material, silicone. Sometimes “silicone” is used to generically describe all organosilicon compounds containing silicon-oxygen bonds, while at other times it is used as a collective term for all types of organosilicon compounds. While the term “silicone” persists in common vernacular, “polyorganosiloxane” is a more appropriate term and has found acceptance in most scientific literature. This term is based on the Si-O-Si unit as a siloxane. Polyorganosiloxanes are organosilicon polymers containing Si-O-Si bonds, the most common of which are the trimethyl-siloxy- terminated polydimethylsiloxanes (Fig. 14.1; Noll 1968). The simple linear polymer structure can be imagined using the following scheme:

For the purposes of this discussion, we will define “silicones” as those siloxanes that are characterized according to three general structural principles: (1) they are polymeric, (2) they contain Si-O bonds, and (3) they contain hydrocarbon func-tional groups combined directly with silicon (Noll 1968).

Through the use of this definition, we can discriminate silicones from other com-mon silicon-containing materials that are used in healthcare applications like silica, silicates, and silicic acid which will be largely excluded from this discussion. Silica (silicon dioxide) is a common component in silicone materials, especially silicone elastomers (rubber) where it is frequently added as a filler and/or reinforcing agent. Silica is a distinct, inorganic chemical entity and therefore, not included in the definition of silicones used here and will not be explicitly detailed in this work. Similarly, silicates (SiO4) and silicic acid (Si(OH)4) are largely excluded from this discussion except as they relate to building blocks of siloxane polymers.

The name “silicone” was given to this class of materials by Kipping in 1904, at a time when organosilicon chemistry was thought to be fairly analogous to carbon-based chemistry (Thomas 2010). The term “silicone” was adopted by analogy with ketone, since the basic building block of silicone polymers is R2SiO, similar to that of a ketone (R2CO). However, the analogy between silicones and ketones is very limited, in that unlike the carbon-oxygen double bond, the silicon-oxygen double bond is highly unstable (Noll 1968). The instability of the silicone-oxygen double bond is one possible explanation for the tendency of silicon to combine with oxy-gen to yield polymeric compounds with a backbone consisting of Si-O bonds. This

CH3-Si-O-(Si-O)n-Si-CH3CH3

CH3

CH3

CH3

CH3

CH3

n = 0, 1, 2, 3, etc.

Fig. 14.1 Chemical structure of typical polydimethylsiloxanes


helps explain the different behavior of the two elements in nature- while silicon naturally reacts with oxygen to build up crystalline silicate structures with stable polymeric anions as stable end products, carbon compounds are degraded by oxy-gen to gaseous carbon dioxide (Noll 1968).

The silicon in polyorganosiloxanes can be combined with one, two or three organic groups, with the remaining valence(s) satisfied with oxygen. While oth-ers also exist, some of the most common organic groups (represented as R in Fig. 14.2) are –CH3, –CH = CH2 or –H. Five possible siloxane types exist within the regime of siloxanes, beginning with a group consisting of a silicon and only oxygen and ending with a silicon and only hydrocarbon radicals as seen in Fig. 14.2 (Noll 1968).

Through the free valences of the oxygen the functionality of each siloxane unit is determined and hence the siloxane unit is named. The individual siloxane units are named as mono, di, tri, or quaternary structural groups and are thusly named: M, D, T, and Q units. This convention is especially useful when describing very complicated polymers rapidly as exemplified in Fig. 14.3.

Me3Si-O-SiMe3 = M M

Me3Si-O-(Si-O)10-SiMe3 = M D10 M

Me

Me

Me3SiO-Si-O-Si-O-Si-OSiMe3 = M3 Q D T M2Me3SiO

Me3SiO

Me

Me

OSiMe3

Me

Fig. 14.3 Chemical structures corresponding to conventional silicone polymer notations (Me = CH3)

SiO4 SiO3R SiO2R2 SiOR3 SiR4Fig. 14.2 Chemical structure of five possible siloxanes types


Branched silicone structures are possible by substitution of dimethyl siloxane units (e.g. (CH3)2SiO2/2) with those that contain additional Si-O connections (e.g. CH3SiO3/2 or SiO4/2). It is through the fact that different siloxane units can be com-bined with one another in the same molecule that the great variety of silicone com-pounds arises (Noll 1968).

Silicones exhibit an unusual combination of an inorganic backbone chain (Si-O)n and organic, (typically methyl) side groups (Owens 1993). The silicon to oxygen bonds of the backbone are longer and more open than analogous carbon to oxygen bonds allowing for a high degree of flexibility of the siloxane chain. By way of comparison, the rotational energy around a –CH2–CH2 bond is 13.8 kJ/mol, but only 3.3 kJ/mol around a (CH3)2Si–O bond, essentially allowing free rotational movement. This flexibility is responsible for the characteristic low surface tension observed in silicones which allows them to quickly “wet out” and be easily spread onto surfaces including skin (Owens 1993).

In addition to being more flexible, the silicon–oxygen bonds are also stronger than analogous carbon-carbon bonds. The bond energy of a Si-O bond along the backbone of a silicone polymer is 452 kJ/mol while the typical C-C bond of the backbone of an organic polymer is only about 348 kJ/mol (Owens 1993). This back-bone strength of the silicone polymers is at least partly responsible for the inherent chemical stability silicone polymers possess toward moisture, UV degradation, and a wide range of temperatures. This is equally important at very low and very high temperatures, where some types of silicones maintain their characteristic physical properties and utility from − 100 up to 260 °C (Lin et al. 2007).

Silicones in general, are characteristically hydrophobic, with hydrophobicity be-ing defined as having little or no affinity for water. The inherent hydrophobicity of silicones is the primary reason some are used as water repellants in many industrial applications and as skin barriers in diaper creams and similar treatments. Given sili-cone’s acknowledged hydrophobicity, and a common perspective equating hydro-phobicity with lipophilicity, one may anticipate silicones to be extremely lipophilic. However, this convention does not hold in the case of silicones, although they are not hydrophilic, most are also not very lipophilic either. While very small silicones may be classified as lipophilic, because of the relatively high ionic character of the Si-O linkage, the polydimethylsiloxane (PDMS) polymers tend to lose their lipo-philicity and have little to no affinity with lipids beginning at six to eight Me2SiO units and become essentially lipophobic (Liu et al. 2004). Although this behavior is unusual, silicones are not unique in this regard, as fluorocarbons are also known to be hydrophobic but not lipophilic (Riess and Krafft 1998). These hydrophobic and lipophobic properties increase the difficulty of forming silicone emulsions using traditional emulsifiers. It also impacts the ability of silicones to solubilize drugs, oils, botanicals and other traditional active ingredients. However, the relatively poor compatibility of many drugs that make it difficult to solubilize them into a silicone matrix may be used to a positive impact in their release from silicone matrices.

Historically, the “excellent biocompatibility” of silicones has been noted as a key characteristic that led to their acceptance in pharmaceutical and medical device applications, and silicones have been used without incident in numerous healthcare


and pharmaceutical applications (Ulman 1995) . However, using a risk based ap-proach has refined the concept of biocompatibility from one of universal “good” or “bad” to one more specific to the application. This more modern definition high-lights the ability of a material to perform its function with an appropriate host re-sponse in a specific situation (Black 1992; Colas). Given this more modern defini-tion of biocompatibility, and the multitude of substitutions and varieties possible within a given chemistry set, it may be naïve to assume that any class of materials would be biocompatible in every application and form (Colas). While a variety of silicone products and technologies have undergone biocompatibility testing, and have passed every bio-qualification test, some have not. Reasons for the poor results of some silicones in biocompatibility tests are the substitution of the well known methyl groups of the standard PDMS polymer with other functional groups of questionable biocompatibility. Other failing results may be the result of by-prod-ucts from the preparation of the silicone polymers, highlighting the need to consider not only the known and intended composition, but also contributing factors such as the material’s purity that may impact the appropriateness of a material to its in-tended application (Colas). Therefore, it is of utmost importance for the developer to not assume appropriate biocompatibility, but to understand the application, the chemistry, how the material is processed and potential modifications from its basic form before including the material in the formulation. The developer must also be proactive in selecting excipients with known impurity profiles and traceability throughout the manufacturing process (Ulman and Neun 2006).

14.3 Silicones in Compendial Monographs

Compendial monographs provide data about pharmaceutical products, active phar-maceutical ingredients, and excipients. Monographs are usually valid within a specified geography, and help define the product and suggest tests and descriptions that define the compendial material. Compendial information may include identifi-cation tests, assay methods, tests for impurities, known impurity profiles, and other physio-chemical properties and measurements. Using excipients that are described by relevant compendia in a pharmaceutical formulation can help substantiate that the excipient has been adequately and consistently characterized and may provide confidence that potential interactions with other components of the formulation are relatively well known and have also been described. Although a variety of silicone forms and chemistries have been used in medicines, cosmetics and medical devices for some time, relatively few silicones are described by common pharmacopeial monographs. The silicone materials that are described in some of the most common compendia are included in Table 14.1. The silicone elastomers for closures and tubing described by the European Pharmacopoeia (EP) are not excipients per se, but are used in the manufacture and packaging of drug products. These elastomers have a very similar chemical composition to the silicone elastomers that are used as excipients in drug loaded device applications which will be discussed later in the


chapter. Similarly, the materials described by the EP in the monograph for silicone oil as a lubricant are similar enough chemically to those described by the mono-graphs for dimethicone to not warrant a separate discussion.

14.3.1 Dimethicone and Simethicone

Multiple monographs describe a common linear siloxane polymer under different names. The NF monograph for dimethicone, the EP monograph for dimeticonum or dimeticone all describe essentially the same polymer. The United States Pharmaco-poeia (USP) terminology will be adopted for this discussion and this group of poly-mers will be referred to as dimethicone. Dimethicone is chemically defined as being a fully methylated linear siloxane polymer containing repeating units of the formula [–(CH3)2SiO–]n with trimethylsiloxy end block units of the formula [(CH3)3–SiO–]. To comply with the monographs, the number of repeating units must have an aver-age value such that the corresponding specific nominal viscosity of the polymer is between 20 and 12,500 cSt. All of these monographs describe what is likely the most common silicone polymer used in pharmaceutical applications. All dimethi-cone polymers are clear, colorless, immiscible with water and alcohol, but mis-cible with chloroform and ether. Various physio-chemical properties are elucidated for each viscosity within the monographs highlighting the changes expected as the number of repeating siloxane units and hence, the viscosity increases. The polymers with a viscosity greater than 20 cSt are expected to contain less volatile content than those with a viscosity of 20 cSt. Typically, increases in refractive index and specific gravity are also expected as chain length (and viscosity) increase (The United States Pharmacopeia, Vol. 36; National Formulary, Vol. 31 2013).

Like most silicones, dimethicone is hydrophobic and repels water. Dimethicone polymers find utility in many topical formulations (e.g. creams, lotions, etc.) where water resistance is key to performance. Dimethicone is substantive when applied to the skin and forms a barrier to regular soap and water that may last for several hours when exposed to primarily aqueous media, but is a less effective barrier against lip-id soluble agents and synthetic detergents (Allen 2013). Dimethicone is specified in the 2003 United States Food and Drug Administration (US FDA) final monograph describing skin protectant drugs for over-the-counter (OTC) human uses. Therefore topically applied products containing from 1 to 30 % dimethicone can make skin protection claims under this monograph. This is a common usage of dimethicone

Compound Typical application CompendiaDimethicone Skin protectant, coating EP, NFSimethicone Anti-foam, anti-flatulent EP, USPCyclomethicone Volatile carrier NFSilicone oil as lubricant Lubricant EPSilicone elastomers for closures and tubing

Closures and tubing EP

Table 14.1 Silicones in United States Pharmacopoeia (USP), National Formulary (NF) and European Pharma-copoeia (EP)


and it can be incorporated into many final product forms including sticks, creams, lotions and ointments either as the only active, or in combination with others (Allen 2013). Dimethicone is especially prevalent in incontinence barrier products for both adults and children and is also a common ingredient in products intended for the treatment of diaper rash and prickly heat that claim to be non-allergenic and non-sensitizing (Allen 2013; Robert Llewellyn 1986). Dimethicone emulsions as either creams or lotions are also well known in the pharmaceutical industry and the process and general formulary composition is well known and described (Niazi 2004). These silicone emulsions are utilized in the treatment of several indications including acne, fungal diseases and psoriasis and other skin conditions (Colas and Rafidison 2005). While the reason for the use in other conditions is vague, dimethi-cone has long been considered non-comedogenic, which may explain the use in acne remedies (Fulton 1989).

A variety of silicones including dimethicone and dimethicone emulsions in par-ticular are known to be used in siliconization, the lubrication of syringes, plungers, needles and the like by a thin layer of silicone (Colas). It has been noted that silicon-ized needles moved through the skin with less force and caused less pain to patients than uncoated needles. Silicones were first used to coat a glass vial interior in 1950 (Dixit 2013). Today, siliconized needles are widely accepted and most hypodermic needles and syringes are coated and/or lubricated with silicone (Colas). With the recent increase of prefilled syringes for protein based pharmaceuticals, the use of silicones as a syringe lubricant has come under scrutiny. This is in large part due to a tendency of some proteins to exhibit increased aggregation in the presence of polydimethylsiloxane polymers under specific conditions (Jones et al. 2005). How-ever, analysis indicated only marginal changes to protein structure, and detailed investigation failed to provide evidence of large conformational changes or altera-tions in the thermal stability of the proteins studied (Jones et al. 2005). While these observations may have bearing on formulating biologically derived active pharma-ceutical ingredient (API) with silicone excipients, it is important to note that these observations are neither surprising nor unique to silicones. There is a relatively mature literature set that underscores the capacity of a wide variety of chemicals to either stabilize or destabilize (denature) proteins in vitro (Creighton 1995). Solvent systems in general, have a primarily a destabilizing effect on proteins, and so it is not altogether surprising that silicone oil alters the native three dimensional protein structures. Although the mechanism by which silicones denature proteins is less well-studied, protein denaturation by organic solvents is believed to involve altera-tions in the properties of water and the favorable solvation of non-polar groups, thus tipping the free-energy balance from a folded protein to an unfolded, dena-tured protein (Creighton 1991). With these challenges in mind, at least one study has been conducted to investigate if the method of silicone deposition may play a role in reducing the deleterious effects on proteins. This study identified that baked on silicone treatments showed less protein aggregation with the model monoclo-nal antibody than those that were sprayed on (Badkar et al. 2011). A more recent study of the interactions between silicone and proteins concluded that surfactants (specifically Tween® 20) were effective in reducing interfacial protein adsorption


when present as pre-adsorbed species, but surfactants were not effective when in-troduced after the interfacial protein adsorption was complete. This researcher also concluded that it was important to optimize the silicone content in the formula used to siliconize needles thereby avoiding free silicone oil (Dixit 2013). While not ex-haustive, these studies and the suggestions offered may provide a means to develop a biological therapeutic in a prefilled syringe with confidence of even less protein-silicone interaction (Badkar et al. 2011).

A monograph also exists for a silicone active pharmaceutical ingredient. The USP describes Simethicone as a mixture of fully methylated linear siloxane poly-mers containing repeating units of the formula [–(CH3)2SiO–]n stabilized with tri-methylsiloxy end block units of the formula [(CH3)3–SiO–] and between 4 and 7 % silicon dioxide. In addition to a monograph for simethicone raw material, the USP also contains monographs for finished products that utilize simethicone, includ-ing capsules, emulsions and oral suspensions. Simethicone is widely available as the active ingredient, under many brand names, generally as OTC orally ingested antacids (Robert Llewellyn 1986). Simethicone decreases the surface tension of gas bubbles, causing them to combine in the stomach which can be passed away more easily. Simethicone does not reduce the formation of gas. The USP contains the usual characterization and assay tests found in most monographs, but also require confirmation of the de-foaming activity of simethicone— likely because of the typi-cal usage.

Although the monographs describe simethicone as the active ingredient in a va-riety of liquid or solid dosage forms, simethicone has also been described in recent patent literature for other pharmaceutical applications where simethicone was used as a process aid or an intentionally added excipient. The commercial viability of some of these ideas is uncertain, but the following provide a snapshot of potential uses considered worthwhile enough to seek intellectual property protection. Given the widespread use of simethicone as a defoaming agent in anti-flatulent products, it is not surprising to note that researchers have suggested simethicone being used as a defoaming agent in protein fermentation processes to increase yields (Aruna-kumari 2013). Likely due to the inherent lubricity of the silicones in general and the well known pharmaceutical application of simethicone specifically, another group has proposed the use of simethicone as a lubricant to prevent and reduce mold foul-ing in pharmaceutical tablet or lozenge manufacturing (Chen et al. 2011). Many of the most promising new drug molecules are of biological origin and the use of simethicone to reduce shearing of proteins by agitation during the protein producing fermentation process has been described (Arunakumari 2013).

Literature describing non-traditional tablets with specialized drug release have claimed the use of simethicone as a key component of those compositions including enteric tablet coatings (Dansereau and Burgio 2005) and components of quickly disintegrating tablets (Bunick et al. 2011). The inherent lubricity of simethicone has also been noted and described for more traditional tablets, where simethicone has been suggested as an excipient to ease difficulties associated with swallowing (Bilgic 2012). Another group of researchers has claimed the use of simethicone in an orally administered disintegrating film intended to deliver pharmaceutical agents


(Fuisz 2011). Although simethicone has traditionally been used in oral delivery, its selection as an excipient may not be limited to those delivery forms; it has also been suggested as an excipient in topical products including nanoemulsion formulations for topical anti-fungal treatments (Baker 2012) and topically applied skin whiteners (Niki et al. 2011). A recent search of database for inactive ingredients in topical for-mulations found several instances of simethicone in anti-acne products (US-FDA 2014).

14.3.2 Cyclomethicone

Cyclic silicones are a third type of material described by a pharmacopoeial mono-graph, specifically the US National Formulary (NF). They are described as a class including multiple variants in the Cyclomethicone monograph. Chemically, cyclo-methicone is described as a fully methylated cyclic siloxane containing repeating units of [–(CH3)2SiO–]n in which n is 4, 5, or 6, or a mixture of them. The pentamer ( n = 5) is probably the most prominent in usage (The United States Pharmacopeia, Vol. 36; National Formulary, Vol. 31 2013). Cyclomethicones are used in topical products and can provide such benefits as ease of spreading, lubricity, and residue-free volatility (Klimisch 1991). All of the cyclomethicone oligomers possess a char-acteristically low heat of evaporation when compared with non-silicone compo-nents typically used in topical formulations. Despite being of a significantly higher molecular weight, the heats of vaporization of both the tetramer and pentamer cy-clomethicone oligomers are significantly lower than water or ethanol (Table 14.2; Klimisch 1991). In addition to being an interesting curiosity, when cyclomethicones are used in topical formulations, the low heat of vaporization provides a volatile sol-vent that evaporates with a minimum cooling effect on the skin (Aguadisch 1999; Klimisch 1991).

Cyclomethicone has been used historically as a solvent or volatile carrier for var-ious components in color cosmetic, hair conditioning, antiperspirant and sunscreen products. Typical cyclomethicone use levels range from 0.1 to greater than 50 % of the composition(Johnson et al. 2011) and it may assist in fulfilling the application specific need to easily coat the skin (or hair) then evaporate and leave behind a non-tacky surface (Klimisch 1991; Tamarkin et al. 2013; Johnson et al. 2011). More re-cently, cyclomethicones have been integrated as components of disinfectant wipes and skin cleansers, acknowledging the non-cooling and non-stinging properties and to solubilize and deliver the film forming components of substantive barrier films

Material Heat of vaporization (Cal/g)

Water 539Ethanol 210Tetramer oligomer of cyclomethicone 32Pentamer oligomer of cyclomethicone 32

Table 14.2 Heat of vaporization


for skin contact, such as those used on immobile and incontinent patients. (Lam et al. 2010; Vogel et al. 2011; Koenig et al. 2006)

Although these materials are relatively low molecular weight, only minimal per-cutaneous absorption was noted for these materials and the data do not suggest skin irritation and sensitization potential. (Johnson et al. 2011; Final report on the safety assessment of cyclomethicone 1991) The environmental fate of cyclic siloxanes has been subject to extensive research for many years, including recent monitor-ing programs. Although some uses, including pharmaceutical applications may be exempt, cyclic siloxanes have been materials of interest for inclusion in the Reg-istration, Evaluation, Authorization and Restriction of Chemicals (REACh) regu-lation in the European Union (REACH—Registration, Evaluation, Authorisation and Restriction of Chemicals 2013). This regulation is intended to streamline the former legislative framework on chemicals in the member nations and limit the use of some chemicals (REACH—Registration, Evaluation, Authorisation and Restric-tion of Chemicals 2013). A similar work was performed in Canada, and in 2012, the Canadian Environment Minister endorsed the findings of an independent scientific panel, which conducted a comprehensive systematic evaluation to assess all avail-able environmental data for decamethylcyclopentasiloxane (the cyclomethicone pentamer that is colloquially referred to as “Siloxane D5”) and determined that it is safe for the environment. This review followed and overruled an assessment done by Environment Canada in 2008 which at that time identified the substance as pos-sibly warranting environmental measures. The Board’s final report concluded that “… based on the information presented, Siloxane D5 will not pose a danger to the environment or its biological diversity in the future” (Fishlock 2011).

An interesting example of the use of cyclomethicone and other well-known sili-cones in new healthcare applications is the advent and acceptance of silicone based products for the treatment of head lice. Insecticide based treatments for head lice infestations based on permethrin, malathion and other organophosphorus or chlo-rinated organic compounds have been common and effective treatments for many years. However, studies have shown that lice are becoming resistant to this type of chemical treatment. Furthermore, some pesticides may be absorbed transdermal-ly and so, have limits upon their repeated use to minimize toxicological concerns (Heukelbach et al. 2010; Burgess et al. 2005). Topical products for lice infestations consisting of 4 % high molecular weight polydimethylsiloxane polymer carried in a volatile silicone fluid, usually cyclomethicone, have been introduced in recent years (Ansell 2001). These products are typically lotions or gels and act to eliminate lice through a physical mode of action rather than more traditional chemical mode em-ployed by insecticides (Heukelbach et al. 2010). Clinical studies have indicated that silicone based lice treatments are comparably effective to the traditional pesticide based products in the eradication of lice, with similarly successful outcomes for patients (Burgess et al. 2005; Brunton and Burgess 2013). Additional clinical data suggests that the silicone products are successful against eggs and nymphs, which are often difficult to eliminate (Burgess and Burgess 2011).

The mode of action for these silicone treatments was initially thought to be as-phyxiation by way of the polydimethylsiloxane entering the tracheal system of the


louse and preventing the exchange of respiratory gases (Heukelbach et al. 2010; Pearlman 2004). This mechanism was suggested because lice are immediately im-mobilized following treatment with PDMS lotions—which is similar to the effect after immersion of lice in water. However, the lice do not recover as they would after water immersion, making some researchers doubt that the mechanism of ac-tion is suffocation (Burgess 2009). Recent evidence suggests that lice are actually eradicated by occlusion of the louse’s spiracles and tracheal trunks by dimethicone which inhibits the ability to excrete water leading to osmotic stress and ultimately death (Burgess 2009). Although the exact mechanism of action may not be fully agreed upon, it is generally agreed that mode of action is a physical one, which is important as it may greatly reduce the likelihood of lice strains that will develop a resistance to the treatment (Heukelbach et al. 2010).

14.4 Non-compendial Silicone Excipients

Selecting compendial excipients within known formulation concentrations can pro-vide confidence that the drug product contains recognized materials with a well documented history of use. It may also reduce the risk of increased scrutiny about the safety and fit for purpose of the selected excipients. However, at times, a for-mulation or product form requires performance characteristics that may not be pos-sible using only compendial excipients. When non-compendial excipients are se-lected, the regulatory burden for the formulation can be much greater. The process of controlling the quality and consistency of excipients while ensuring they are well characterized, robust and meet regulatory requirements is a critical expectation for excipient suppliers (Ulman and Neun 2006). Upon considering the specific applica-tion, and the history of use of the excipient, the user must at a minimum fully char-acterize the excipient including residual and trace impurities, and assess the impact on health. Because of the extra burden and the time and costs involved, the selection of non-compendial products is often done only if compendial excipients cannot be found that perform a similar function. Still, several non-compendial silicone excipi-ents exist in current commercial pharmaceutical products. Some non-compendial silicones are used in topical therapeutic formulations which can help to carry or solubilize actives, or improve aesthetic properties of a formulation. Silicone elas-tomers (i.e. silicone rubber) are found as the primary polymer in some drug deliv-ery devices. Transdermal drug delivery systems (TDDS), commonly referred to as “patches,” may use multiple silicones, many of which may be non-compendial.

14.4.1 Transdermal Drug Delivery

The commercial era of transdermal drug delivery patches was initiated in 1980 with the introduction of a scopolamine patch to treat motion sickness. Today drug deliv-ery via skin is still an attractive delivery technology as witnessed by the number of


recent transdermal product approvals. The key scientific aspect for this continuing success is the ability of the technology to provide sustained drug blood levels with minimal variation in blood levels of the active via a non-oral, non-injectable route of delivery. The features and other advantages of transdermal delivery include the elimination of first pass metabolism over oral delivery, painless and easy to use compared to hypodermic needles, continuous drug delivery for up to a week is pos-sible via transdermal patches.

Pressure sensitive adhesive (PSA) is a key component of TDDS. Typically three types of adhesives are used in transdermal patches, polyacrylates, silicones and polyisobutylenes (PIB). A family of non-compendial silicone excipients that has become widely accepted is silicone PSA. Silicone adhesives are commonly used as the skin interface that holds the TDDS patch in place and/or acts as the rate control-ling matrix for the active. Medical PSA must provide secure adhesion for the pre-scribed duration and then have the ability to be removed cleanly from skin without causing undue trauma to the wearer (Lin et al. 2009). TDDS that utilize silicone PSA vary in the duration of time that they should be worn, but twice per week and even once per week applications exist. The chain flexibility and open molecular structure with low molecular interactions that are inherent to silicone PSA provide the ability to wet out and conform to the highly variable contours of the skin sur-face and have suitable tack and adhesion for a variety of skin types (Ulman 1995). Adhesives designed for transdermal drug delivery must also show permeability to therapeutic ingredients while displaying minimal interactions that are deleterious to the drug and the other excipients and components of the transdermal device. Therefore, the PSA must maintain sufficient adhesion in the presence of drugs to allow the TDDS to maintain intimate contact with the patient over the duration of the dosage regime (Lin et al. 2009; Ghosh and Pfister 1997). Furthermore, the ad-hesive must also possess enough cohesive characteristics to maintain a consistent geometry (e.g. surface area) in contact with the skin throughout administration of the dosage (Lin et al. 2009; Ghosh and Pfister 1997). Silicone PSAs offer excellent permeability to lipophilic drugs, and can be further modified by formulating with hydrophilic fillers, copolymers, plasticizers, or by modification of the network with silicone-organic copolymers to also allow delivery of hydrophilic drugs (Ulman 1995; Raul et al. 2005).

14.4.1.1 Chemistry of Silicone Pressure Sensitive Adhesives

The silicone PSAs used in TDDS are based on silicone polymer and silicate resin chemistries (Fig. 14.4). The polymers typically used are PDMS with dimethlysi-lanol end-groups, while the resins are three dimensional trimethlysiloxy and hy-droxyl end-blocked silicate structures (Ulman 1995). The resulting material from a simple blend of the resin and polymer will have some pressure sensitive adhesive properties, albeit with poor cohesive characteristics. This lack of cohesion can be overcome through a condensation (or bodying) reaction whereby the respective functional groups create a covalently bonded, crosslinked network (Ulman 1995).


The adhesives created by this bodying reaction retain a relatively high degree of si-lanol (Si–OH) functionality. These adhesives are suitable for many applications, in-cluding drug delivery for some actives, however their utility in TDDS is somewhat limited by high amount of silanol functionality. Many actives, especially amine functional actives will hydrolyze in the presence of silanol by either degrading, or reacting and binding into the silicone matrix. This reaction is akin to hydrolysis that occurs in the analogous alcohols. To minimize this effect, the available silan-ol groups can be reacted with a trimethylsilyl endcapping agent, ((CH3)3–Si) and hence the silanol content can be significantly reduced to provide enhanced chemical compatibility (Ulman 1995; Metovia and Woodard 1987). The resulting adhesives are sometimes referred to as “amine-compatible” since they have improved compat-ibility with amine functional actives. These adhesives have found utility in trans-dermal patch applications because of their increased resistance to reactivity with amine functional drugs (Ulman 1995; Lin et al. 2009; Metovia and Woodard 1987).

The biocompatibility of any component intended to have intimate contact with the skin is important, but when that component will be occluded via an

HO-Si Si-OH +Si-OH

HO-Si

HO-Si

Si-OH

OHSi

OHSi

Si-O-SiHO-Si

HO-Si

Si-OH

OHSi

OHSi

Si-O-Si

Si-OH

HO-Si Si-OH

OHSi

OHSi

Si-O-SiSi-O-Si

Si-O-Si

- H2ONH3

Xylene

(CH3)3Si-O-Si

Si-O-Si Si-O-Si(CH3)3

O-Si(CH3)3Si

O-Si(CH3)3

SiSi-O-Si

Si-O-Si(CH3)3Si-O-Si(CH3)3

O-Si(CH3)3Si

O-Si(CH3)3

Si

Si-O-SiSi-O-Si

Si-O-Si

(CH3)3Si-O-Si

(CH3)3Si-O-Si

NH(Si(CH3)3)2∆

∆

“Standard” PSA

“Amine compatible” PSA

Polymer Resin

- NH3

Fig. 14.4 Schematics showing the preparation of silicone pressure sensitive adhesives (PSA)


impermeable film as in the case of the components of a TDDS, the importance is magnified. The polymeric form of the silicone starting materials and the sequential chemical reactions whereby silicone PSA are produced yield an adhesive polymer essentially devoid of skin irritating and/or sensitizing monomers, initiators and oth-er by-products that are often associated with many non-silicone adhesive technolo-gies (Fisher 1956; Clemmensen 1984). Furthermore, the primary by-product from the ammonia catalyzed condensation reaction whereby silicone PSA are produced is water; resulting in a product technology with appropriate biocompatibility for many TDDS, as evidenced by the nearly 50 years history of silicone PSAs in TDDS applications (Table 14.3; Ulman 1995).

14.4.1.2 Silicone Pressure Sensitive Adhesives for Enhanced Therapeutic Efficiency

Achieving the therapeutically appropriate drug release profile that will support a commercial drug product is ultimately the factor that determines the relevance of a TDDS. Studies have investigated the permeation of many drugs from multiple adhesive matrices through different models and concluded that drug release from silicone matrices is usually higher than those from other tested adhesive matrices. This phenomenon is likely a result of lower interaction between the drug and the silicone PSA polymer compared to other adhesive polymers. The extent of the drug polymer interaction can be estimated by the relationship between the drug con-centrations in the PSA and their diffusion coefficients (Kokubo et al. 1994). One such study investigated the interactions of four different drugs: dipropylphthalate,

Table 14.3 Transdermal drug delivery patches containing silicone adhesiveProduct brand name Company/Manufacturer APITransderm Nitro® Novartis NitroglycerineDuragesic® Janssen Pharma FentanylProStep® Aveva NicotineCombiPatch® Novartis Estradiol/Norethindrone acetateVivelle-Dot® Novartis EstradiolEstradot® Novartis EstradiolFentanyla Mylan FentanylDaytrana® Noven MethylphenidateNeupro® UCB RotigotineFentanyla Lavipharm Labs FentanylMatrifen® Nycomed FentanylExelon® Novartis RivastigmineFentanyla Watson FentanylFentanyla Actavis FentanylQutenza® NeurogesX CapsaicinClonidinea Aveva Clonidine

a ANDA Abbreviated new drug applications


aminopyrine, ketoprofen, and lidocaine in four adhesive matrices, two polyacrylate adhesives with differing functionalities, a PIB and an amine-compatible silicone PSA. Interactions between the polyacrylate adhesives and some drugs were noted, but no drug-polymer interactions were noted with either the PIB or silicone adhe-sives which are composed of mostly non-polar groups (Kokubo et al. 1994). An-other study of a developmental analgesic drug, CNS5161 (a N-methyl-D-aspartate (NMDA) based receptor antagonist), compared the release of this drug from a simi-lar group of adhesive matrices and found that the highest permeation was also from the silicone adhesive matrix (Fig. 14.5; Naruse et al. 2012). A third study identified the permeation of terbinafine, an antifungal drug across porcine hoof membrane and determined that drug permeation from the silicone matrix was the highest of those measured, followed by PIB, polyacrylate adhesives, and styrene block copolymer adhesives (Ahn et al.).

Fentanyl is a potent analgesic that is available in many dosage forms includ-ing transdermal patches. A variety of fentanyl TDDS patch designs and adhesive chemistries are currently available commercially, making the comparison of differ-ent transdermal fentanyl patches possible. One such published survey attempted to characterize fentanyl’s solubility, diffusion coefficient and permeability coefficient with respect to three adhesive types found in fentanyl patches: silicone, polyacrylate and PIB. This study found the fentanyl diffusion coefficient from silicone PSA was the highest among the four adhesives studied. The silicone adhesive patches also provided the highest fentanyl flux through skin as well. This is likely a result of low

Fig. 14.5 Skin permeation of CNS5161 base (N-methyl-D-aspartate) from PSAs containing 10 % CNS5161. Data shown is the cumulative amounts of CNS5161 base, expressed as the mean with the bar shown SD values of four experiments. Key: ● SIS(1), ○ SIS(2), ■ silicone, □ acrylate (OH), ∆ acrylate (COOH). SIS styrene-isoprene-styrene block copolymers. (Reproduced with permission from © 2012 The Pharmaceutical Society of Japan)


drug solubility, high diffusion coefficient and low partition coefficient of fentanyl in the silicone matrix (Roy et al. 1996). A recent survey of commercial fentanyl patches using three different adhesive chemistries, silicone, polyacrylate and PIB concluded that formulators could achieve bioequivalency of the drug dosage by formulating with any of the adhesive types, although with vastly different patch designs. However, commercial patches that made use of silicone or PIB adhesives exhibited more efficient utilization of the loaded drug which was defined as leaving less unused fentanyl in the patch. The efficient use of the drug also impacted the size of the patch- where more efficient drug utilization typically required smaller patch size (equating to a smaller surface area of skin in contact with the patch). This phenomenon was attributed in large measure to the higher solubility of fentanyl in polyacrylate adhesives, which limited the likelihood of the drug passively eluting from the patch. The survey concluded that adhesives with lower drug solubility may provide more efficient delivery attributes and therefore, should be preferentially se-lected when designing patches (Yeoh 2011). While solubility certainly plays a role in efficient release, an inspection of some model drug solubility in three adhesive types indicates that silicones do not always have the lowest drug solubility, yet in the cases cited above had the highest release (Table 14.4; Roy et al. 1996; Webster and West 2002).

Pharmaceutical formulators have utilized the diverse drug and polymer interac-tions inherent to the various adhesive technologies as well as the adhesive’s dis-similar compatibility with drugs to create increasingly sophisticated TDDS designs. These have taken the form of layering various adhesives or other polymers that may act as drug reservoirs, or rate controlling layers within the patch to achieve the desired performance (Jackson and Miller 2005; Yeoh 2011). Other unique and advanced patch designs have been created by blending silicone adhesives with non-silicone adhesives and other polymers with differing drug compatibilities to achieve patches with the desired therapeutic release profiles for a number of actives (Kanios 2001; Kanios and Hartwig 2006).

While variations around the theme are numerous, the construction of TDDS can be broadly grouped into three general categories, and silicones can find utility in all. The three basic design styles are reservoir systems, matrix systems and micro-reservoir systems (see Fig. 14.6) (Ulman 1995; Kandavilli et al. 2002). Reservoir patches are those TDDS where the solubilized drug, typically in an alcoholic gel, is embedded between an impervious backing layer and a rate controlling membrane. In this type of design, a thin layer of drug compatible, hypoallergenic adhesive polymer is applied to the rate controlling membrane and functions to affix the patch to the skin. Two major concerns exist for this design type, especially as it relates to

Table 14.4 Drug solubility (mg/ml) in acrylic, silicone, and Polyisobutylene adhesivesPSA chemistry Fentanyl Aminopyrine Dipropylphthalate Lidocaine KetoprofenAcrylic copolymer 21.9 95.1 223.7 438.6 61.3Silicone 20.0 39.6 1.9 81.0 4.2PIB 0.8 48.3 22.7 62.4 0.8


certain highly potent drugs—leakage of the matrix which can alter the drug dosage, and a relatively high potential for product abuse (Yeoh 2011). It is for these reasons that recently developed TDDS for some opiates, have for the most part adopted the matrix style patches (Yeoh 2011). Matrix TDDS designs can be further delineated to drug-in-adhesive systems and matrix-dispersion systems (Ulman 1995; Kandavilli et al. 2002). In both types of matrix design systems, the drug is dispersed into a polymer matrix which controls the release of the drug directly into the skin. In the case of drug-in-adhesive design, a drug reservoir is formed by dispersing the solu-bilized drug in an adhesive polymer and then coating the polymer onto an occlu-sive, impervious backing layer. In matrix-dispersion systems, the drug is dispersed in a non-adhesive polymer, creating a disk, which is then affixed to the backing substrate. Rather than applying the adhesive directly over the drug reservoir, the adhesive may be spread around the perimeter of the patch to form an adhesive rim that acts to hold the drug containing matrix in intimate contact with the skin (Kan-davilli et al. 2002). While the former is the far more common design, the latter has existed in some commercial patches and may still persist. Microreservoir TDDS

bc

a

ed

fc

a

a

cg

I

II

III

Fig. 14.6 Schematic diagram of typical transdermal drug delivery patch designs. I represents a matrix design, II represents a reservoir design, III represents a microreservoir design. a release liner, b drug + adhesive, c backing, d membrane, e adhesive, f drug reservoir and g drug and poly-mer dispersed in adhesive


designs combine the concepts of both types of previously mentioned patch designs. In a microreservoir system, the drug is suspended in one polymer which is then dispersed homogenously in an adhesive matrix. Usually, the first polymer in which the drug is suspended has minimal compatibility with the adhesive and so will form a multitude of microscopic drug reservoirs which are stabilized via polymerization or other means to prevent the separation of the drug polymer suspensions within the matrix (Kandavilli et al. 2002).

While increased drug delivery efficiency may have an impact on the physical characteristics of a TDDS patch such as its size and shape, some regulatory and sustainability benefits may also be realized through more efficient formulations. A 2010 draft guidance issued by the US FDA provided recommendations to devel-opers and manufacturers of transdermal drug delivery systems, transmucosal drug delivery systems and topical patches to ensure that the residual drug content at the end of the product’s labeled use period is minimized. More efficient delivery as evidenced by higher release rates of drugs from patches is not only aligned with this draft guidance, they may become a regulatory requirement. In recent years, numer-ous reports have noted the presence of pharmaceutical and personal care actives in ground water (Ternes et al. 2004; Phillips et al. 2010). The impact of API on aquatic animal development (Ruiz et al. 2010), and the inability of current waste water and drinking water treatment facilities to remove the API from treated water (Ternes et al. 2002; Vieno et al. 2005) have been reported. In the more efficient drug de-livery formulations detailed above, less active was needed in the TDDS to achieve comparable therapeutic effect, and a higher proportion was utilized, therefore it is likely that less drug may find its way into the environment from these devices.

The use of silicone PSA in the healthcare arena continues to expand in response to specific application needs. A number of publications describe compositions and/or constructions utilizing silicone PSA that have been designed to provide sustained delivery of specific drugs for the treatment of a variety of disease states and im-proved safety through abuse deterrent TDDS dosage forms (Lauterbach and Schol-lmayer 2003; Reder and Goldenheim 1998; Mantelle 2010; Stinchcomb et al. 2011). In addition to traditional transdermal drug delivery applications, silicone PSA are also being considered for other applications too, including sustained release of anti-microbials for wound care devices. In these devices, the innately hydrophobic sili-cone adhesive is modified to increase its hydrophilicity and the compatibility with actives through manipulation and incorporation of other chemical functionalities into the silicone adhesive (Saxena and Joshi 2013). Modification of the physio-chemical properties of silicone PSA have also resulted in a claimed ability to in-crease the adhesion to very wet biological surfaces including mucosa, teeth and even skin submerged in water (Schalau et al. 2007). The ability of these composi-tions to release drugs and deliver tooth whiteners and other oral care actives has also been noted (Schalau et al. 2007; Boyd et al. 2013; Vazales et al. 2013). Silicone PSA that are very similar to those described above and used in TDDS have also recently been specified as structural components of medical devices, owing to the biocom-patibility of the PSA (Vazales et al. 2013). Some academic researchers have even considered silicone PSA as a matrix for an oral dosage tablet with the rationale that


tablets that utilized silicone PSA may avoid the granulation and proceed directly to compression, due to the low glass transition temperature (Tg) and high compress-ibility of the silicone PSA, thereby potentially eliminating the need for glidants, granulating agents and the like (Tolia and Kevin 2012).

14.4.1.3 Soft Skin Silicone Adhesive

A very different type of silicone adhesive technology has garnered much interest in recent years. This second adhesive is cross-linkable and is designed as a multi-part (typically 2 parts) system based on a platinum catalyzed, addition-cure reaction between functional silicone polymers. Although the reaction will occur at room temperature, it is expedited by heat. The crosslinking or curing reaction occurs between a vinyl (Si-Vi) functional PDMS and a silicon-hydride (SiH) functional PDMS (Fig. 14.7). (Lin et al. 2007; Ulman 1995; Lin et al. 2009)

The resulting adhesive is very different from the aforementioned silicone PSA in terms of final properties and consistency. Although prior to curing both parts of the adhesive are typically liquids, after curing, the adhesive, which is sometimes re-ferred to as a “silicone tacky gel” or “Soft Skin Adhesive” in the literature, is a very tacky, elastomeric silicone with a soft, gel-like consistency and with low peel adhe-sion to skin. Since it is a gel, it may be compressed, however it is thermoset, and so resists cold flow whereas the silicone PSA retains some viscoelastic properties. The tacky gels also resist transfer lamination and are typically coated and cured onto the final substrate, while the silicone PSAs are readily transfer laminated.

Silicone tacky gels are regularly used in wound care dressings and as the skin in-terface for scar care devices. The ability of tacky gels for improving the appearance of scars has been well known for some time and confirmed by a meta-study of 27 separate clinical studies. The synopsis of clinical studies concluded that silicone gel sheeting was superior to other occlusive dressings in the treatment and management of scars, even hypertrophic scars (Poston 2000). However, it is the characteristic low peel adhesion to skin that has led to its adoption as the skin contact adhesive in many advanced wound care products (Lin et al. 2009). Dressings prepared with silicone tacky gels have been compared with traditional wound dressings in clini-cal settings, with the conclusion that the dressings prepared with tacky gels dem-onstrated less pain to the patient, and caused less trauma to the patient’s stratum corneum upon dressing removal than other wound dressings (Dykes et al. 2001; Platt et al. 1996).

The trend toward skin-friendlier adhesive alternatives has received some atten-tion in the drug delivery field too where the use of silicone tacky gels to optimize drug delivery devices has been suggested as an alternative to more aggressive

--Si-CH=CH2 + H-Si-- --Si-CH2-CH2-Si—Pt

Fig. 14.7 Schematic for the hydrosilylation reaction


adhesive types. The ability to formulate silicone gels at low temperatures, and their characteristically low removal force from the skin have been noted as positive at-tributes of silicone tacky gels in potential therapeutic and transdermal drug deliv-ery applications (Bruner and Freedman 2006). The potential for this technology in TDDS applications may be limited by the platinum catalyzed addition reaction currently required to achieve the cohesive cured matrix. This cure mechanism is susceptible to inhibition by some classes of chemicals and functionalities that are commonly found in drugs (Raul et al. 2006; Schalau II 2009). Although to date a silicone gel TDDS has not been commercially realized, some in vitro drug release from crosslinked silicone tacky gel matrices has been published demonstrating the release of corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), and anesthetic salts (Raul et al. 2006; Schalau II 2009). Additionally, wound care prod-ucts that utilize silicone tacky gels and are loaded with silver and chlorhexidine gluconate to prevent microbial contamination of the wound, as the skin contact adhesive have received FDA approval (Pedlar 2012). This may be a precursor to the addition of other actives in more advanced therapeutic capacities as these materials gain more commercial acceptance and their history of use in delivery applications becomes more established.

14.4.1.4 Hybrid Silicone Pressure Sensitive Adhesive

As mentioned above, PSA of several chemical families relevant to this chapter are available as materials of construction in TDDS. Two of the most commonly cho-sen adhesive types are the polyacrylate and silicone. Each adhesive chemistry type provides some advantages. Silicone PSA may release many actives more readily, and the polyacrylate PSA may have a greater affinity with more drugs and other common excipients, making formulating more straightforward. However, the con-verse of each advantage may act as a disadvantage. Silicones may be more difficult to formulate due to the poor compatibility with a number of excipients and drugs, while drug release from the polyacrylate matrix is often less efficient, resulting in more drug remaining in the patch, even after its use.

There have been several attempts to combine polyacrylate PSAs and silicone PSAs to gain the advantages of both technologies. Blending two types of PSAs or emulsifying in presence of surfactants generally provides phase separation and stability issues. In this context, the concept of a silicone acrylate hybrid copoly-mer composition that retains the positive attributes of both types of PSA has been put forward. At least two synthetic approaches have been suggested by different research groups through which silicone acrylate hybrid PSA for TDDS can be achieved (Loubert et al. 2012; Yuxia 2012). To date, it is unclear if either approach has been commercially realized as a PSA, let alone used in a pharmaceutical prod-uct. Nonetheless, it is an interesting silicone-based technology that has gained much interest and is potentially on the horizon. The first approach recorded in the litera-ture describes a multi-step process through which a silicone pressure sensitive ad-hesive, much like those described above is prepared and functionalized with a free


radical reactive agent. Acrylate monomer is then added and polymerized to create the hybrid PSA (Loubert et al. 2012). This acrylate polymerization yields an adhe-sive which chemically integrates the advantageous functionalities associated with both polyacrylate and silicone chemistries into one stable PSA that resists phase separation. The second technique to create the silicone acrylate hybrid begins with a pre-polymerized acrylate polymer containing reactive silane groups. This is then combined with the precursors to the silicone PSA and during the final bodying step in the creation of the silicone PSA, the acrylates are grafted to the silicone (Yuxia 2012). Both techniques suggest that during polymerization, the silicone to polyac-rylate ratio, type of monomers chosen, and the ratio of selected monomers may be sufficiently controlled and optimized to achieve desired physical properties (Yuxia 2012; Loubert et al. 2012). Similarly, the balance of silicone to acrylic components can be selectively used to control solubility of an active agent in the hybrid PSA to optimize the rate at which the active agent is released from the system and also the amount of active agent that is ultimately released (Loubert et al. 2012; Evans et al. 2012). While the ultimate commercial utility of this technology is not totally understood today, derivations and applications outside TDDS are already appearing in literature as the non-tacky adaptations of this technology have been suggested as topically applied film forming compositions for both cosmetic and pharmaceutical applications (Thomas and Mitchell 2012).

While much of this discussion of silicone excipients in transdermal drug delivery systems has focused around the use of adhesives, they are not the only place where silicone based technologies exist in transdermal drug delivery systems. Although they are not defined by any known monograph, silicone and fluorosilicone products are regularly used as release liner coatings for transdermal patches due their inher-ent low surface energies (Colas and Rafidison 2005). The release liner covers the adhesive prior to applying the patch on the skin and is the layer that is removed to allow the patch to stick to the skin. Release liners are typically paper or polyolefin films coated with a low surface energy release coating to create a non-stick surface that does not interact with the drug, protects the patch until use and is then discarded (Belosinschi et al. 2012). Ideally, the release liner will remain bonded well enough to the adhesive that it does not accidentally fall off over the patch’s expected shelf life, and then will remove easily enough when needed that it doesn’t remove any adhesive from the patch (Testa 2004). Silicone release coatings are typically based on cross-linked PDMS chemistry and are used with many non-silicone adhesive systems (Belosinschi et al. 2012). Fluorosilicone release coatings too are typically crosslinked silicone materials with fluoro alkyl or fluoro aryl substitution (Hamada and Shimoda 1994). Although the exact surface energy of silicone release coatings can vary, measurements around 22 dyne/cm are not uncommon (Thanawala and Chaudhury 2000). Sometimes, even lower surface energies are required and can be achieved using fluorosilicone release coatings. Surface energy measurements as low as 8 dyne/cm are achievable with fluorosilicone release coatings (Kim et al. 1998). The release coating material required for a TDDS is largely governed by the adhesive chemistry selected for the patch, with fluorocarbon and fluorosilicone coated liners selected for TDDS that utilize silicone adhesives and silicone coated


liners selected for TDDS that utilize polyacrylate and PIB adhesives (Testa 2004). Of course, physical property concerns are not the only consideration when selecting a release liner. To address regulatory concerns and ensure appropriate quality of the release liners, many release liner suppliers in the medical industry provide materials that are manufactured to some critical parameters of Good Manufacturing Practices to ensure their acceptability for healthcare applications (Ulman and Neun 2006; Lin et al. 2009).

14.4.2 Topical Drug Delivery

Topical drug delivery is the localized administration of a drug by non-oral, non-in-jectable method via skin or other mucosal membrane surface. Being large and read-ily accessible, delivery via skin often dominates other routes. The drug delivered through skin could either be intended to dermal layer or sometime to reach systemic circulation, in the later case it may better be referred as transdermal delivery using topical application.

Two of the most common silicone excipients used in topically applied pharma-ceutical applications have already been discussed, dimethicone and cyclomethicone. However, other, non-compendial excipients are also used in topical pharmaceutical applications. A recent estimate is that approximately 55 % of current skin care prod-ucts contain at least one silicone material. The silicones used in these applications are generally recognized as safe and are known for having a variety of aesthetics that may be preferred by consumers. Specific property improvements noted by the addition of silicone into formulations include ease of spreading, less tackiness, and a silkier, “elegant” and more lubricious feel than comparable formulations without silicones (Schalau and Ulman 2009; Sene 2003; Aust et al. 2005). The cosmetic industry has long recognized and understood the importance of aesthetics in the materials applied to skin. However, evidence as to the importance of aesthetics contributing to positive patient compliance and hence positive treatment outcomes of topically applied pharmaceutical products is growing. The impact of patient non-adherence on treatment failure is an area of increasing concern and poor aesthet-ics may be a contributing factor to purposeful patient non-adherence with medical treatment regimes. Because of its chronic nature and historical reliance on topical medications, psoriasis is one condition the dermatological community has studied to understand the causes of patient non-adherence to medication regimes. It has been reported that more than one-third of psoriatic patients are not compliant with their prescribed medication despite the well documented link between adherence to a treatment regime and successful clinical outcomes for psoriatic patients (van et al. 2000; Carroll et al. 2004), While patients expressed frustration with the (lack of) treatment efficacy, research has suggested that vehicle related factors were also im-portant to patients when considering their motivations for intentional non-adherence to their treatment regimes (Brown et al. 2006). Among the important vehicle related factors determining intentional non-adherence rates patients noted aesthetic reasons such as the unpleasant feel of the medication and the time-consuming nature of


application (Brown et al. 2006). Dosing frequency (once vs. twice-daily applica-tion) which is sometimes suggested as having an impact on patient compliance was not a determining factor in patient adherence to a treatment regime (Brown et al. 2006).

In addition to the aesthetic improvements that silicones may provide to a topi-cal formulation, other more objectively measured properties can also be provided. Substantivity is a term referring to the adherent qualities of a topical formulation and its ability to be retained on the skin over time (Stedman 2005). A pharmaceuti-cal product’s substantivity, essentially the resistance to washing off and rubbing off may lead to more prolonged exposure of the drug on the skin surface, which in turn may lead to a greater amount of drug being available, and ultimately having the de-sired therapeutic effect. Silicone gums are very high molecular weight PDMS poly-mers with a similar chemical structure to dimethicone, and a viscosity in excess of 100,000 cSt. Silicone gums, while still liquid by definition, are no longer pourable, and can hold a shape for a short time. Silicone gums are both highly substantive on the skin themselves and have been shown to significantly improve the substantiv-ity of an active on the skin (Aguadisch 1999). One study demonstrated that when silicone gum was dissolved in a volatile silicone fluid (hexamethyldisiloxane) and applied to the skin surface of a human forearm, 25 % of the silicone gum applied, remained after 8 h of routine daily activities (Sene et al. 2002). Consistent with the substantivity of the gum, when a similar measurement was conducted with a ketoprofen loaded silicone gum dispersion, detectable levels of ketoprofen were also observed 6 h after application, as compared to only 40 min in the formulation without the silicone gum (Sene et al. 2002).

Skin hydration via occlusion can also temporarily alter the barrier properties of the stratum corneum to allow an enhanced permeation of both hydrophilic and hy-drophobic drugs. Most PDMS are fairly non-occlusive, but silicone gums as well as organic modified silicones (e.g. alkylmethylsiloxanes that are typically available as waxes) are somewhat occlusive and are known to reduce transepidermal water loss (TEWL) and, therefore, hydrate the epidermis (De Paepe et al. 2014).

The near-perfect barrier properties of the epidermis restricts most transport through the skin to molecules with certain properties that correlate with adequate solubility such as low molecular weight (< 500 Da), moderate lipophilicity (octa-nol–water partition coefficient (logP) between 0.7 and 5.2), and modest melting point (< 200 °C) (Watkinson 2012). Even when an active exhibits such properties, it is usually necessary to find additional means to increase its transport across the skin. Chemical skin penetration enhancers are able to promote the transport of ac-tives substance across the skin barrier by a variety of mechanisms including extrac-tion of lipids from the stratum corneum, altering the vehicle or skin partitioning coefficient, disruption of the lipid bilayer structure, loosening of horny cells and delamination of stratum corneum (Barry 2001; Daniels 2009).

As described earlier, the aesthetic properties of silicones may impact the “feel” of a formulation and thereby compliance to the treatment regimen and silicones can impact physio-chemical properties like substantivity and occlusivity of a for-mulation, which indirectly impact formulation efficacy. However, it is unclear if


unmodified cyclic or linear PDMS could act as chemical penetration enhancers themselves. A Japanese patent application submitted in 1983 claimed that one or more cyclic or low molecular weight linear PDMS can enhance the penetration of medicines through skin when formulated in combination with alcohols. (Sato). However, follow-up studies have not been found that corroborate this claim and a more recent study indicates that PDMS, 100 cSt failed to serve as a penetration enhancer, currently leaving this question without a definitive answer (Leopold and Lippold 1995). A growing body of data has highlighted that a number of modified silicones can serve as chemical penetration enhancers. In one study, at the Cardiff School of Pharmacy in Wales, a number of modified silicones were synthesized and subsequently evaluated. The ensuing European patent application indicated that certain carboxyalkyl and alklylsulphoxide functional siloxanes could serve as penetration enhancers. (Colas et al. 1993). Consistent with the aforementioned pat-ent application, a number of other modified silicones have been reported to serve as penetration enhancers too, including oligodimethylsiloxane containing a gluco-pyranosyl end group, poly(ethylene glycol)/polydimethylsiloxanes (PEG/PDMS) co-polymers, and alkyldisiloxanes (Colas et al. 1993; Akimoto et al. 2001; Akimoto et al. 1997; Nagase et al. 1992; Akimoto and Nagase 2003).

14.4.2.1 Silicone Elastomer Blend Gels

Silicone elastomer blends (SEB) are silicone polymers that are lightly crosslinked three dimensional networks, the network is swollen in an organic or silicone sol-vent to create a gel. The general procedure to prepare the gels includes a platinum catalyzed hydrosilylation reaction of silicon hydride functional and silicone-vinyl functional polymers in the presence of the swelling solvent followed by shearing the gels into discrete particles (Fig. 14.8) (Biggs and Legrow 1996; Lin and Stark-Kasley 2009; Kennan and Messner 2009).

Three general categories of elastomer blend materials are commercially avail-able in the form of semi-solids and utilized in cosmetic and skin care applications where they function as gelants and thickeners of topical products. The unique aes-thetics of the SEB that have been described as silky, smooth, light and powdery are responsible for much of its acceptance in beauty care applications (Rosen 2005; Van 2006). Each type of SEB is available in a variety of organic or silicone solvents that range in volatility and feel. Though the solvent is often referred to as a carrier fluid, the solvent is used in the reaction when preparing the gel network itself and helps to swell the overall gel structure. Hence, silicone elastomer blends are not simply a dispersion of elastomer polymer in a corresponding solvent. Instead it is a crosslinked network of polymers made in the presence of a solvent such that the preparation procedure and subsequent processing methods add to material’s overall characteristics in the finished product (Maxon and Starch 2013).

The first SEB to reach commercial status utilized a simple alkyl crosslinker and maintained the characteristic silicone properties, while the second and third generations make use of propylene oxide and ethylene oxide functionalities in the


crosslinking systems to impart improved compatibility with organic excipients and water, respectively. First-generation silicone elastomers (INCI name: dimethicone crosspolymer and dimethicone/vinyl dimethicone crosspolymer) are compatible with non-polar cosmetic oils such as cyclomethicone, dimethicone, and hydrocar-bons, but polar cosmetic oils such as esters and sunscreen actives are not compatible with them. The second generation materials provide greater compatibility with or-ganic and hydrophobic compounds which allowed the development of novel trans-parent sunscreen formulations (Maxon and Starch 2013). Although the new organ-ic-compatible silicone elastomer blends were designed to improve the compatibility with organic formulation components, they also replicate the excellent aesthetics of the original silicone elastomer blends. The introduction of hydrophilic functionality through the incorporation of pendent ethylene oxide make the third generation SEB compatible with water when aqueous based formulations are desired (Fig. 14.9).

PtCarrier solvent

∆SiH

SiH

SiH

SiH

SiH

SiH

SiH

SiH

SiH

Shear gel with additional carrier solventto form paste

Fig. 14.8 Schematic representation of SEB (Silicone elastomer blend) polymer preparation. The grey color represents the carrier solvent used in the polymerization procedure which functions as a carrier solvent for the swelling of the polymer. The –Si–H polymer and divinyl crosslinker can be substituted for different SEB (Silicone elastomer blend) polymers accordingly


The SEBs described above are widely recognized for their superior aesthetics in skin care formulations and their physical properties that enable production of novel formulations. Utilization of these silicone elastomer blends as topical ex-cipients in delivering small molecular active pharmaceutical ingredients efficiently has also been investigated (Forbes et al. 2011). Development and testing of a non-aqueous silicone elastomer gel formulation using a commercial SEB, Dow Corn-ing® ST Elastomer 10, in the efficient in-vivo vaginal delivery of antiretroviral human immunodeficiency virus (HIV) drug, maraviroc (a CCR5 receptor agonist), has been reported compared to non-silicone based formulation (Fig. 14.10). The silicone formulation also demonstrated no-irritation to mucosal tissue and enhanced mucosal retention for efficiency. The non-aqueous silicone gels may offer several advantages over water based gels for vaginal delivery systems, including better

Si

Si

Si Si

Si Si SiSi

Si

Fig. 14.9 The generalized chemical structure of the silicone elastomer blends


formulation of poorly water-soluble drugs, prolonged pharmacokinetic profiles and greater stability of hydrolytically vulnerable compounds.

While the above research reports the efficient drug release to vaginal mucosal tissues, where the barrier property of stratum corneum does not exist, silicone elas-tomer gel based formulation has also been demonstrated for the in-vitro efficient delivery of ibuprofen across human cadaver skin compared to a commercial product and similar formulations made of non-silicone polymers. The increased ibuprofen

0

5

10

15

20

25

30

0 1 2 3 4 5 6 7 8

Ibup

rofe

n in

blo

od[µ

g/g]

Time [hr]

S1

Benchmark

Fig. 14.11 In vivo delivery of ibuprofen to rats’ blood. Data shown is the comparison of aver-age ibuprofen blood concentration measured in vivo for S1 ( n = 5) and benchmark ( n = 4). S1 is silicone elastomer-based gel formulation and benchmark is a commercial gel product. Both S1 and benchmark contained ibuprofen at 5 %. (Reproduced with permission from © 2014 Wiley Periodicals, Inc., and the American Pharmacists Association)

Fig. 14.10 In vivo delivery of anti-HIV drug maraviroc by silicone and hydroxyethylcellulose (HEC) based gels. Data shown is mean concentration ± SD (ng/mL) of maraviroc measured in the vaginal tissue of rhesus macaques following vaginal administration of a single 4 mL sample of 80/20 silicone elastomer gel or 2.2 % w/w HEC gels containing 33 mg/mL maraviroc (100 mg total dose). (Reproduced with permission from © 2011 Elsevier B.V.)


delivery efficiency was also demonstrated against the commercial product in-vivo using rats (Fig. 14.11) (Aliyar et al. 2014b)

14.4.2.2 Silicone Elastomers for Drug Delivery

Silicone elastomers are well known as materials of construction in the manufacture of medical devices, and since the 1960s have been in many applications includ-ing catheters, drains, shunts, extracorporeal equipment, as well as small joint and aesthetic implants, to name a few (Colas). Silicone elastomer based devices for the treatment of various disorders of the eye have been investigated. These devices include canalicular silicone plugs placed in patient’s tear ducts to prevent tear drain-age in those with severe dry eyes associated with trachoma- a bacterial eye infec-tion (Guzey et al. 2001). The use of silicone elastomers has been described as the controlled release matrix for pharmaceutical products, including the release of an-tibiotics (Bhatt and Raul 1995; Aguadisch 1999). One manifestation appeared as a small silicone rubber rod with protrusions to anchor it in place after insertion in the upper or lower fornix (Bhatt and Raul 1995; Darougar et al. 1999). The use of con-tact lenses as an ophthalmic drug delivery has been proposed for decades (Lesher and Gunderson 1993; Jain 1988; Smolen et al. 1975). However, clinical approach-es have occurred recently (Schultz et al. 2009; Ciolino et al. 2009; Jacobs et al. 2009; Kapoor et al. 2009; Pitt et al. 2012; Peng et al. 2012). While contact lenses made of non-silicone material are also in use, silicone based contact lens are often considered due to their higher oxygen permeability than other materials. Loading and release of 1,2-dimyristoyl-n-glycero-3-phosphocholine (DMPC) from silicone contact lenses has recently been reported (Pitt et al. 2012). Though DMPC is not considered a therapeutic drug, a lack of such phospholipids in tears is sometimes implicated in destabilization of the tear film, rapid evaporation, distortion of the tear induced smooth ocular surface, and decreased lubrication. These events may lead to eye discomfort. Decreased availability of phospholipids is sometimes attributed to dysfunction of the phospholipid secreting Meibomian gland or possibly to wearing contact lenses, which are shown to absorb a small amount of phospholipid. Thus, a phospholipid eluting contact lens might be used in a beneficial manner to increase the amount of phospholipids in the tear, thereby enhancing eye comfort.

Similarly, commercially available silicone hydrogel contact lenses loaded with cysteamine, has been reported for the treatment of corneal manifestations of cysti-nosis acting to reduce the accumulation of cystine crystals (Peng et al. 2012). Deliv-ery of topical anesthetics, post-operative pain control after corneal surgery and vi-tamin E as a potential treatment for glaucoma from silicone hydrogel contact lenses have also been reported (Hsu et al.). In these applications, the contact lens acts to keep the active in the eye longer (which is a known and ongoing issue with ocular drug delivery) and act as a diffusion barrier to increase the duration of release.

Contraceptive diaphragms are among the many medical devices created from silicones, so perhaps it is not too surprising that silicone drug delivery devices have


also been developed for female reproductive health. Among the first intravaginal ring (IVR) drug delivery devices studied in the early 1970s were those that utilized a silicone elastomer as the material of construction to deliver hormones for a contra-ceptive effect, representing a major advancement in both vaginal drug delivery and the drug delivery field as a whole (Mishell and Lumkin 1970; Mishell et al. 1970; Johansson and Sitruk-Ware 2004). Although these devices were among the first to take advantage of the mechanistic understanding of controlled drug release from solid implants, curiously, these devices received little commercial attention until relatively recently (Kiser et al. 2012). Today, at least five IVR are commercially available. Of these, three are recommended for contraception (Progering®, Fertir-ing®, and NuvaRing®) and two others are prescribed for hormone replacement therapies (Femring® and Estring®) (Johnson 2012). Of those, all but NuvaRing utilize silicone as the primary polymer and material of construction (Johnson 2012).

Intravaginal and intrauterine devices are not the only silicone containing con-traceptive devices that have been commercialized. While IVR are designed to be inserted and removed at regular intervals, at least two drug eluting, implantable contraceptive devices based on silicone elastomer technologies have also been marketed in selected geographies (Polly 1998). Both Norplant® (which may no longer be available in most geographies) and Jadelle® (sometimes referred to as Norplant-II) offer long term contraceptive efficacy, via subdermal implantation in the woman’s upper arm for up to 5 years. Both products provide the controlled re-lease of the hormone levongestrel, but function by way of fairly different product designs (Polly 1998). The Norplant design featured a series of six small, hormone containing silicone capsules located within an outer sheath, while Jadelle features two small drug containing, silicone rods inside a larger sheath that elute the drug over time (Polly 1998).

Recently, silicone elastomeric polymer materials have been investigated in vagi-nally implanted ring segments for the long-term, controlled vaginal release of mi-crobicidal agents like TMC120 (dapivarine) a potent non-nucleoside reverse-tran-scriptase inhibitor and UC781 for the prevention of HIV (Kiser et al. 2012; Johnson 2012; Malcolm et al. 2005). Silicone intravaginal rings with internal reservoirs of API have been constructed and investigated with and without the addition of poly-mers to modify controlled release characteristics (Friend 2011; Moss et al. 2012). Some of these constructions are progressing though the pre-clinical investigation process. The sophistication and complexity of IVR investigation continues to in-crease. Historically, most research has focused on anti-HIV devices that contain a single anti-retroviral compound; however, there is clinical rationale for combining antiretroviral drugs with different modes of action to increase the breadth of protec-tion and limit the rise of resistant strains (Fetherston et al. 2013). With this in mind, a silicone IVR with a reservoir that contains both and Tenofir and Acyclovir is un-der investigation (Moss et al. 2012), as well as a silicone elastomer ring with both dapivirine, and maraviroc in the matrix (Fetherston et al. 2013). This object of study has shown enough promise to progress into Phase I clinical testing (Fetherston et al. 2013; Rohan and Sassi 2009; Gupta et al. 2008; Woolfson et al. 2006).


Similar silicone elastomer technologies have been put to use in veterinary medi-cine. Intrauterine devices made of silicone elastomer impregnated with progester-one have been developed and are widely used to control and synchronize animal estrus for breeding or artificial insemination (Heredia et al. 2008; Rathbone et al. 1997).

14.5 The Future of Silicone Excipients

Given the wide variety of silicone forms and applications, it is difficult to foresee which if any of the current materials may find utility in pharmaceutical applica-tions. However, current uses in other life science related industries, combined with surveys of technical literature and recently developed technologies in which intel-lectual property protection has been sought may yield some hints about which tech-nologies may play roles in the future of silicone excipients.

Recent advancement in the development of innovative technologies and materi-als has opened new avenues of applications in different areas. The entry of these new materials into pharmaceutical applications may be slow due to the regulatory and toxicological hurdles associated with new materials. However, investigation of well differentiated products and novel applications is always in progress by both academia and industry. Due to the lower regulatory hurdles in other industries, these new materials often demonstrate their uniqueness in other applications and indus-tries like personal care or color cosmetics before finding acceptance in pharmaceu-tical applications. Portrayed below are a few such technologies and materials along with the latest investigation related to pharmaceutical applications that may become the next generation

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