As discussed in Chapter 2, there are potential advantages for the use of topical medications to treat pain indications, including provision of local, regional, and systemic therapeutic effects, as well as the potential for better safety profiles than oral medications.1 Owing in part to their clinical potential, topical medications are one of the most commonly compounded preparations in the United States (HHS OIG, 2016; McPherson et al., 2016). The term topical refers to all preparations and products that are intended for application on the skin, mucous membranes, or external body cavities (e.g., mouth, nose, vagina).2 The term cream is used to designate any semisolid preparation (e.g., cream, ointment, gel, lotion), typically with a relatively soft and spreadable consistency, that is intended for external application to the skin.
To explore how the science of compounded topical pain creams affects their safety and effectiveness, this chapter begins with an overview of the art and science of compounding, which highlights the overall complexity involved in formulating safe and effective compounded preparations. This section is followed by a description of the dermal absorption of drugs, including the basic structure and properties of the skin that affect absorption and potential variation in skin absorption among individuals. Subsequent sections describe factors affecting drug delivery and dose, including
2 Transdermal patches use a more complex topical delivery system that is designed to deliver drugs intended for systemic absorption; however, such systems are outside of the study’s scope.
3 This chapter draws on a paper commissioned by the Committee on the Assessment of the Available Scientific Data Regarding the Safety and Effectiveness of Ingredients Used in Compounded Topical Pain Creams titled “Topical Dosage Form Development and Evaluation,” by S. Narasimha Murthy (see Appendix C).
Formulation science is critical in the development, manufacturing, and testing of chemical—including pharmaceutical—products and preparations. Individuals experienced in this area of expertise are able to make difficult determinations regarding the proper combination of active and inactive ingredients, in consideration of the quality, stability, and effectiveness of compounded preparations, including topical pain creams (American Chemical Society, 2020). It is important to note that compounding pharmacists often follow formulations provided by compounding supply companies or published in journals or textbooks (Birnie, 2004; Dooms and Carvalho, 2018); however, they are still individually responsible for assessing the quality, stability, and effectiveness of every compounded preparation they dispense. Of critical importance, a compounding pharmacist often does not have the same training or experience as a formulation scientist, nor access to the same data for evaluation and determination of quality, stability, and effectiveness. See Box 5-2 for an overview of selected considerations for formulation scientists.
Finally, given that compounding is an extemporaneous process, compounded topical pain creams are formulated based on unique prescriptions filled by individual pharmacies. As a result, compounded topical pain creams are more susceptible to modifications in process variables than manufactured drug products that are made by a single drug maker with detailed, U.S. Food and Drug Administration (FDA)-approved manufacturing protocols (Gudeman et al., 2013). Furthermore, the process by which a preparation is compounded is subject to interpharmacist and interpharmacy variations, so a patient may receive a compounded topical pain cream that
has distinct skin permeation and bioavailability profiles depending on who fills the prescription or where it is filled.
At the committee’s public meeting in May 2019, invited speaker Dr. S. Narasimha Murthy discussed how the process by which a formulation is compounded is critical to the attributes and performance of any drug. He concluded that changing even one variable in the compounding process—such as amount of time homogenizing the mixture, or the sequence in which drugs are added—will change the formulation microstructure, even if identical quantities of the same ingredients are used (Murthy, 2019). These changes in microstructure lead to notable differences in the characteristics and performance of the formulation and, ultimately, to differences in the absorption and bioavailability of the drug (Chang et al., 2013).
Dermal absorption is a critical consideration in the science of compounded topical pain creams. The clinical benefits and potential harms of topically applied medications relate to the rate and extent of a drug’s absorption into the skin and beyond. Topically absorbed drugs first penetrate the outer barrier of dead skin cells (stratum corneum), then move through the viable layers of the epidermis to reach the vascularized dermis layer of the skin (see Figure 5-1). Skin cells (keratinocytes) are produced in the lower basal layer of the epidermis and then migrate upward, forming the epidermal skin. Specialized cells (melanocytes) in the epidermis produce melanin, which is taken up by keratinocytes to protect the skin from ultraviolet (UV) radiation; other cells have immunological functions (e.g., Langerhans cells, dendritic cells, memory T cells) (Richmond and Harris, 2014). Nerve endings extend from the dermis toward the epidermis like root fibers (Sewell et al., 2018).
In addition to having blood vessels, the dermis is primarily composed of extracellular matrix proteins that provide structure and elasticity, while also allowing free movement of immune cells (Richmond and Harris, 2014). The skin thus maintains high immunological surveillance and activity to ward off pathogenic and foreign substances. However, this process may also contribute to allergenic reactions to active ingredients or excipients.
Local, Regional, and Systemic Effects
Once a drug ingredient has crossed the outer layer of skin (stratum corneum), topical preparations such as pain creams can have local, regional, and/or systemic effects. Local effects of a drug ingredient occur primarily in the viable layers of skin, including the nerve endings in the epidermis and dermis (Ruela et al., 2016). Regional-area effects in muscles or joints occur
through subsequent diffusion of the drug ingredient through the skin and fatty layer—which also has nerve endings (Richmond and Harris, 2014)—to nearby tissues. Systemic effects occur throughout the body caused by uptake of the drug ingredient by blood or lymphatic vessels in the dermis; the ingredient ultimately travels to the central circulation (Ruela et al., 2016).
In theory, pharmaceuticals intended to treat local or regional pain act on nerves in the skin or in underlying muscles or joints by blocking nerve signals, reducing inflammation, relaxing muscle spasms, or potentiating the effects of other substances (Cline and Turrentine, 2016; Leppert et al., 2018). Distal responses to topical applications can also occur that, whether intended or not, can affect a medication’s safety and effectiveness profile. Systemic action is also an important consideration in reviewing potential drug–drug interactions. As an example, consider a patient who is prescribed the maximum oral amount of a nonsteroidal anti-inflammatory drug (NSAID) and then uses a topical gel formulated with another NSAID.
If the systemic contribution of the topically applied NSAID is sufficient, it will contribute to an excess of NSAIDs in the blood stream and create the potential for severe adverse reactions.
Today, most commercially manufactured FDA-approved creams are intended for local action, while patches are intended for systemic activity. However, there are exceptions in both cases. For example, nitroglycerin cream has long been used for its systemic effect (Fougera Pharmaceuticals, 2019), while lidocaine patches are generally used for regional analgesic effect in muscle tissue (Leppert et al., 2018). Of note, many compounded pain creams are marketed as transdermal (Swidan and Mohamed, 2016) and are intended to deliver the drug to tissues below the skin or into systemic circulation. For systemic activity, the transdermal patches or cream formulations deliver the drug into the systemic circulation through uptake in blood vessels in the dermis (Benson, 2005). (See Figure 5-2 for an illustrative example of the systemic absorption of a topical active ingredient.)
The physical and chemical properties of skin are modified by factors relating to age, gender, and ethnicity, and these factors affect the dermal absorption of topical drugs. Physiochemical properties of active pharmaceutical ingredients (APIs) and features of the drug’s delivery mechanisms also contribute to the success of absorption through the skin (for more details, see Law et al., 2020). These considerations are discussed in greater detail in the sections below.
The Properties of Skin
When topical formulations are applied, the drug (e.g., the API) is released from the formulation and crosses several skin barriers—each with different physical and chemical properties that affect drug diffusion—to reach deeper sites for its pharmacological activity (Chang et al., 2013). The stratum corneum is the main barrier to external agents (Law et al., 2020). This layer is made up of tightly packed dead cells (corneocytes) in a lipid (fat) matrix, resulting in a relatively impermeable, mostly lipophilic layer (van Logtestijn et al., 2015) (see Figure 5-3). Moderately lipophilic (i.e., fat- or oil-soluble) drugs are able to pass the stratum corneum more readily than those that are hydrophilic (i.e., water soluble) or highly lipophilic. Skin also typically contains 10–20 percent water by weight, much of which is associated with hydrated corneocytes (Forslind, 1994; Singh and Morris, 2011). The lipid layer between corneocytes is composed of approximately equal molar amounts of free fatty acids, ceramide (waxy lipids), and cholesterol organized in a bilayer lamellar pattern, with more polar groups on the outer layers and long-chain fatty acids (waxlike) and cholesterol in the interior (Boncheva, 2014) (see Figure 5-3).
Pathways of Substances Through the Outer Barrier of Skin
Pathways of substances through the stratum corneum include diffusion through the lipid layer around skin cells (paracellular or intercellular), passage through the skin cells (transcellular), and entry through sweat or sebaceous glands or hair follicles (transappendageal) (Dabrowska et al., 2018) (see Figure 5-4). Substances that are soluble in oil or fats are able to penetrate the outer layer of skin though the lipid matrix around skin cells. Hydrating the skin, however, can increase the moisture content by 20-fold and may enhance the passage of substances that are more water soluble (Singh and Morris, 2011). Transcellular passage through skin cells is a more selective route that requires lipophilic and hydrophilic properties to cross the lipophilic cell membrane and the hydrophilic cellular contents.
Compared to the stratum corneum, the underlying viable epidermis and the dermis below that layer are more hydrophilic (i.e., more soluble in water) (Perrie et al., 2012), thereby favoring diffusion of hydrophilic substances. However, the lower fatty layer below the dermis favors diffusion of more lipophilic substances to adjacent tissues (see Figure 5-4).
The transappendageal pathway through skin pores and hair follicles is a means of entry for large or hydrophilic substances (Ruela et al., 2016). This could be considered a less important pathway, because pores represent only 0.1 percent of the surface area of the body (Dabrowska et al., 2018). In addition, although these pores extend below the skin layers into the dermis, substances must then penetrate the cellular barrier lining the pores. It has been reported that hair on the faces of men increases the permeability of the facial skin of men compared to women (Dabrowska et al., 2018).
Regional Differences in Skin Absorption on the Body
Regional differences in skin absorption on the body occur as a function of thickness of the outer stratum corneum layer, differences in skin lipid content (including those attributable to variation in sebaceous glands), hydration state, and amount of physical contact (Guzzo et al., 1996). Skin penetration is thus greater on the face, in the genital area, and in skin areas that contact or rub against each other; less penetration occurs on the trunk,
Individual Differences in Metabolic Enzyme Activity
Individual differences in metabolic enzyme activity also play a role. Unlike the oral administration of drugs, the dermal route of exposure avoids the gastrointestinal tract and the first-pass metabolism process in the liver. Still, the skin is estimated to have about 10 percent of the capacity of the liver to metabolize drugs to either inactive or active forms, depending on the drug and enzymes (Singh and Morris, 2011). Therefore, individual differences in metabolic enzyme activity may also have an effect on topical dosing.5
Integrity of the Skin
Integrity of the skin is another important factor. Dermal penetration is increased in skin that is denuded or compromised (e.g., skin that is burned, abraded, or dry). Therefore, dermal penetration is affected by diseases that disrupt the skin—such as psoriasis or atopic dermatitis—or by health conditions such as hypothyroidism (Dabrowska et al., 2018).6 In general, enhancement of absorption through damaged or diseased skin is greater for substances that are more water soluble than for substances that are fat soluble (Law et al., 2020). Increased absorption through compromised skin could increase the effectiveness of topical treatments, but it may also enhance potential systemic absorption and increased the risk of toxicity (Law et al., 2020).
Effect of Age
Age can have effects on the skin that may alter dermal absorption.7 Preterm infants have a thinner epidermis and stratum corneum than adults,
5 For drugs that reach viable layers and systemic circulation, elimination from the body occurs through urinary or biliary excretion routes, either metabolized or unmetabolized (Feldmann and Maibach, 1969). For more information on the metabolism of drugs in skin, see Bronaugh et al., 2005.
6 Note that for the purposes of this report, the committee maintained an explicit focus on the use of topical creams on intact skin. There remains a substantial literature base that reviews the safety, effectiveness, and use of topical pain creams on membrane and mucosal surfaces. However, this evidence was not explicitly reviewed or discussed in this report.
thus higher permeability is expected (Oranges et al., 2015). Before 30 weeks of gestation, infants have 100- to 1,000-fold greater skin permeability than term infants (Barker et al., 1987), while full-term infants have skin permeability that is 3-fold to 4-fold greater than adults (Fernandez et al., 2011). Higher permeability in neonates is thought to be related to incomplete maturation of the skin barrier (Singh and Morris, 2011). Full-term neonates have similar epidermal thickness and lipid composition as adults. However, in the first few months of life, surface pH decreases while sloughing of the outer layer of skin cells (desquamation) increases. In the first week after birth, sebum (lipid) secretion increases, and in the first 14–17 weeks after birth, capillary loops and cutaneous blood flow develop in the dermis (Ramos-e-Silva et al., 2012).
In adults, skin changes that occur with aging result in increasing dryness of the stratum corneum (Ramos-e-Silva et al., 2012) as well as thinning of the epidermis and dermis (Singh and Morris, 2011). Evidence suggests that drying of the stratum corneum with age is associated with less active sebaceous glands and lower surface lipid content—along with atrophy of the cutaneous capillaries—thereby reducing drug delivery through viable layers (Perrie et al., 2012; Ramos-e-Silva et al., 2012). Skin penetration by more hydrophilic drugs has been reported to decrease with age, whereas lipophilic drugs were not similarly affected (Perrie et al., 2012; Singh and Morris, 2011).
Compared to men, infants, children, and many women have larger surface areas relative to their body size and relatively larger volumes of drug distribution. As a result, they absorb a larger internal dose from an application to a proportionally similar skin area. For example, a study using stable isotopes of nanosized zinc oxide particles (19 nm) in sunscreen measured higher zinc isotope blood levels in women than in men, even though a smaller amount of sunscreen per area (g/cm2) was applied to the backs of women than to the backs of men (Gulson et al., 2010). The study was unable to distinguish the form of zinc absorbed, but it may have been soluble ionic zinc.
Difference Among Genders
Compared to women, men have longer keratinocytes, larger pores, more active sebaceous and sweat glands, and lower skin pH (Singh and Morris, 2011). However, the few studies that have examined gender differences in dermal absorption have found little difference in dermal absorption between men and women (Singh and Morris, 2011).
Racial and Ethnic Differences
Ethnic differences in skin properties that may potentially affect dermal absorption have been described in the literature, with some conflicting reports. Several studies report that compared to Caucasians, African Americans or Afro-Caribbeans have higher transepidermal water loss (see Muizzuddin et al., 2010), a thicker and more cohesive stratum corneum with more cell layers, and lower dermal penetration (Dabrowska et al., 2018; Muizzuddin et al., 2010; Singh and Morris, 2011). Higher levels of natural moisturizing factors in the stratum corneum have been reported in Chinese compared to Caucasians or African Americans; however, other studies report no significant differences in skin hydration among ethnic groups (Dabrowska et al., 2018).
A small experimental study compared dermal penetration of radio-labeled benzoic acid, caffeine, or acetyl-salicylic acid in Asian, African American, and Caucasian volunteers (6–9 per group). The vehicles (i.e., carrier substances) used for each of the three compounds to form the topical cream or gel were optimized for the compound’s properties; absorption was measured analyzing urine and skin tape strips. The study found no statistically significant differences among the three racial groups (Lotte et al., 1993). Another study measured percutaneous absorption using methyl nicotinate in four lipophilic vehicles in four ethnic groups (12 subjects per group; subjects aged 20–60 years). The study reported the order of increasing rate of absorption among the groups as Blacks < Asians < Caucasians < Hispanics (Leopold and Maibach, 1996). Considerable individual variation was observed within these groups, but the only statistically significant difference was lower skin absorption in Blacks compared to Hispanics (Leopold and Maibach, 1996). Absorption rates were more similar among racial groups than among vehicles, with vehicles showing consistent rank order of absorption rate for all four racial groups.
A larger study involving 73 African Americans, 119 Caucasians, and 149 East Asians reported the following racial differences in stratum corneum properties, in order of lowest to highest (Muizzuddin et al., 2010):
- Transepidermal water loss: African Americans < East Asians < Caucasians
- Skin barrier strength: East Asians < Caucasians < African Americans
- Stratum corneum cohesion (protein content): East Asians and Caucasians < African Americans
- Ceramides (lipid lamellae in the stratum corneum): African Americans < East Asians and Caucasians
- Maturation index: East Asians < Caucasians < African Americans
- Proteolytic enzymes8: African Americans < East Asians and Caucasians
Overall, the understanding of racial differences in skin properties and penetration of drugs is limited by the small number of studies, small numbers of study participants in most of those studies, and high levels of individual variation (Dabrowska et al., 2018). This work is further limited by the likelihood of great individual-level variability, which may be affected by diet and nutrition, health and diseases, genetic and environmental factors, socioeconomic status, and age. Furthermore, comparisons among skin types with different amounts of pigmentation may be confounded by greater UV damage in those with less pigmentation, particularly in older adults (Singh and Morris, 2011).
Physiochemical Properties of the Active Pharmaceutical Ingredient
The physiochemical properties of a drug’s active ingredients play a substantial role in the drug’s absorption. For example, a drug’s ability to be absorbed into the skin is affected by whether its substances are lipophilic (soluble in oil) or hydrophilic (soluble in water), as well as whether its substances are acidic or basic (i.e., pH). The surface of the skin is acidic in nature, while the inner layers have a more neutral physiological pH (Ohman and Vahlquist, 1994). The pH gradient across the different layers prevents microorganisms from penetrating into deeper layers of skin (Schmid-Wendtner and Korting, 2006), but it also poses challenges for drug absorption. In addition, the skin tissue contains enzymes to break down substances, which constitute a metabolic barrier (Pyo and Maibach, 2019). Therefore, drug properties that increase dermal absorption include
- low molecular weight, generally less than 400–500 Daltons;
- moderately lipophilic properties;
- a melting point below 200°C;
- both lipophilic and hydrophilic properties; and
- a high partition coefficient, so the drug will partition from the vehicle to the skin.
In addition to the above properties, a drug’s acid dissociation constant or acid ionization constant (pKa) is another important factor determining
8 Enzymes that help in the breakdown of skin protein as part of the turnover (sloughing) of the outer layer of skin.
dermal absorption. At an ambient pH that is equal to a drug’s pKa, half of the drug will be in the ionized form and half will be in the un-ionized form. At pH levels greater than the pKa, more of the drug will be in the ionized form. Therefore, a drug with a lower pKa will be in a more un-ionized state at skin pH (4–5) or neutral to basic pH. As noted in Appendix C, un-ionized forms are more extensively absorbed through nonpolar transdermal pathways through the skin than ionized forms are absorbed by polar pathways through the skin. In addition, oppositely charged drugs may form neutral ion pairs that, in turn, enhances their skin absorption (Hadgraft and Valenta, 2000). This complexity is critical to consider in selecting the appropriate APIs to compound together within a given formulation.
As an example of the considerations to be made, Table 5-1 provides a summary of select physiochemical properties of APIs commonly used in compounded topical pain creams. As outlined in the table, each ingredient, regardless of drug class, has unique considerations for the formulation process. Additional layers of complexity need to be considered in cases where multiple APIs (each with different pKAs) are combined with multiple ingredients within an excipient into a single formulation. See Box 5-3 for an illustrative example of considerations related to the absorption of compounded topical formulations with multiple APIs. For an additional discussion of these complex considerations, see Naik et al. (2000), Ng (2018), Prausnitz et al. (2012), Sewell et al. (2018), and Appendix C in this report.
Evidence to Evaluate Topical Absorption
There is limited clinical evidence available to evaluate the extent of topical absorption or potential transdermal penetration of ingredients commonly used in compounded topical pain creams. In vitro skin permeation testing using Franz diffusion cells is one method used by researchers to examine a drug’s potential permeability through animal or human skin (see Appendix C for an additional description of the assay). Research using these types of in vitro studies to examine the permeability of topical analgesics indicate that out of the reviewed drugs, ketamine has the highest flux, or rate of permeation over a specified area of human cadaver skin. In addition, there is a relatively high percent of drug absorbed for ketamine, diclofenac, and pentoxifylline with lower absorption for baclofen, bupivacaine, orphenadrine, clonidine, and gabapentin (Bassani and Banov, 2016; Wang and Black, 2013) (see Tables 5-2 and 5-3). However, these studies did not report the mass balance of applied and recovered drugs, an important quality-control measure for testing of percutaneous absorption (Kluxen et al., 2019). Therefore, it is not possible to thoroughly evaluate the methodological procedures used in the studies, nor is it possible to make conclusive statements about the drugs’ absorption.
|Drug||Molecular Weight (g/mol)||Log P (oct-water)||Melting Point (°C)||pKa|
|Baclofen*||213.66||1.3||207||9.62 and 3.67|
|Gabapentin||171.24||–1.1||166||3.68 and 10.70|
|Lidocaine hydrochloride||270.80||< 0||77||7.9|
NOTES: To add an additional layer of complexity of physiochemical properties that affect dermal absorption, certain drugs have chemical functional groups on the drug molecule with different pKa values, such as baclofen (pKa of 9.62 for the amino group and 3.67 for the carboxyl group) and gabapentin (pKa of 10.70 for the primary amine and 3.68 for carboxylic acid group). octwater = octanolwater partition coefficient; pKa = acid ionization constant.
* Zwitterionic in nature.
SOURCES: DrugBank, 2020; Expert Committee on Drug Dependence, 2017; Plumley et al., 2009; PubChem, 2020.
Given the limitations of in vitro data for many topical drugs, mathematical models are often used for predicting skin permeability. Skin permeability resulting in an absorbed dose can be modeled as a flux rate—a function of partition and diffusion coefficients over a length of the path to the target site, and the applied concentration—resulting in an amount of
drug reaching this site per time (Keurentjes and Maibach, 2019; Prausnitz et al., 2012) (see also Appendix C for additional discussion). Models of flux rate based on a compound’s octanol-water partition coefficient and size (molecular weight) have been reported to more accurately predict in vivo skin permeability than more complex models involving more parameters (Lian et al., 2008).
Nevertheless, a study recently evaluated three such simple models used to calculate fluxes of 17 drugs used in FDA-approved transdermal delivery systems. For more than two-thirds of these drugs, researchers found
|Active Pharmaceutical Ingredient||Percent of Applied Drug Dose Absorbed Across the Cadaver Skin|
|Reference Cream||Versatile Cream|
|Bupivacaine||0.277 ± 0.108||0.441 ± 0.175|
|Diclofenac||0.846 ± 0.223||1.96 ± 0.896|
|Gabapentin||0.381 ± 0.429||0.30 ± 0.237|
|Ketamine||1.03 ± 0.317||1.45 ± 0.591|
|Orphenadrine||0.130 ± 0.0495||0.191 ± 0.0613|
|Pentoxifylline||1.51 ± 0.451||3.63 ± 1.78|
NOTE: Versatile cream is a base commonly used in formulations for compounded topical creams.
SOURCE: Wang and Black, 2013.
|Active Pharmaceutical Ingredient||Percent of Applied Drug Dose Absorbed Across the Cadaver Skin|
|Baclofen||0.27 ± 0.27||0.10 ± 0.08|
|Clonidine||3.955 ± 2.60||4.38 ± 0.95|
|Gabapentin||0.41 ± 0.34||0.19 ± 0.08|
|Ketamine||35.48 ± 9.03||45.52 ± 2.42|
NOTE: Lipoderm and Lipoderm ActiveMax are two bases commonly used in formulations for compounded topical creams.
SOURCE: Bassani and Banov, 2016.
overestimation or underestimation by 10 to 100 times compared to experimental in vivo data. Although the model predictions were correlated with the in vivo results, the models underpredicted the rate flux for more than half of the drugs. There were several major limitations of the models: the models had uncertainties in their parameter databases, and the in vivo data were based on studies in the literature that used different study designs, sample sizes, and analytical methods (Keurentjes and Maibach, 2019). Overall, many factors limit the ability to predict skin absorption for many topically applied drugs.
Considerations for Active Ingredients
Not all drugs are absorbed in the skin to the same degree or at the same rate. In fact, some drugs may not be absorbed by the skin at all. Compounding pharmacists and other individuals who compound must consider not only physiochemical properties of active ingredients, but also how dose affects drug absorption, mechanisms of action of APIs, and selection of excipients. The sections below provide a brief overview of select critical factors that affect drug delivery through the skin.
Applied and Absorbed Dose of the Active Pharmaceutical Ingredient
Dose can refer the amount of drug administered to the individual (applied dose) or taken into the body (absorbed dose). For topical pain cream ingredients, the relevant dose for efficacy is the mass of drug delivered to the site of action. Key determinants of dose for a topical formulation involve (1) the concentration of the drug in the cream formulation, (2) the amount of cream applied, (3) the surface area of application on the body relative to body weight, and (4) the frequency of application (Law et al., 2020). Based on simple diffusion, the magnitude of the applied dose represents the driving force for dermal absorption (Prausnitz et al., 2012). Although the amount of drug applied to the skin is easily determined, the amount of absorption and the effective internal dose may vary depending on factors related to the drug or formulation, the application (including the vehicle), and properties of the skin and underlying tissues (Guzzo et al., 1996).
Furthermore, absorption through the skin is not necessarily constant for a given applied dose. For example, a large amount of cream applied to a smaller area versus a smaller amount of cream applied to a larger area may have the same applied dose. However, an excessive amount of cream over a small area may not allow all of the drug in the cream to contact the skin for absorption before it is rubbed off, adsorbed to clothing, or washed off.9
Similarly, the amount of drug that is solubilized in the vehicle is the available concentration for absorption, meaning that increasing the concentration of a drug in a cream will only increase the dose being delivered if the drug is solubilized (Prausnitz et al., 2012). Depending on drug properties and the vehicle, drugs may also penetrate the stratum corneum and either reside as a reservoir in skin layers or more readily reach systemic circulation
9 Of note, drug removal from the stratum corneum may also occur either by exfoliation (Law et al., 2020) or by washing, which is dependent on the nature of the drug and the solvent (Chan et al., 2013).
(Guzzo et al., 1996; Prausnitz et al., 2012). Another important consideration affecting the dose of a drug that penetrates the skin is frequency of application. Though data are sparse, multiple doses of topically applied drug have been shown to deliver more drug through the skin than single doses (Wester and Maibach, 2005). For example, 1 gram of cream applied twice daily may deliver more drug than 2 grams of cream applied once daily.
Insufficient dermal penetration for some drugs may reduce the internal dose to below the therapeutic range (Yamamoto et al., 2017). On the other hand, a slower rate of entry via skin absorption may achieve a more constant systemic dose rather than the peaks—which could result in toxicity for more sensitive individuals—and valleys that might occur by intravenous injection or oral ingestion (Brown et al., 2006; Prausnitz et al., 2012). For some substances that have low absorption by the oral route (e.g., CBD oil), dermal application with or without skin penetration enhancers has been reported to be an effective means of systemic drug delivery (Lodzki et al., 2003; Paudel et al., 2010a). This is particularly the case for substances that are greatly metabolized by the first-pass effect of the liver from the oral route of administration (Paudel et al., 2010b).
Mechanisms of Action of Active Ingredients
The local, regional, or systemic location where a drug is intended to exert its pharmacological effect is informed largely by the mechanism of action of that drug (Schenone et al., 2013). For example, a drug that blocks sodium channels would need to reach nerve cells, which contain sodium channels that mediate stimuli such as pain (Bhattacharya et al., 2009). Details on the mechanisms of actions for the drugs reviewed within this report can be found in Chapter 6.
Excipients (“Inactive” Ingredients)
A wide range of bases, vehicles, and solvents are used to formulate topical pain creams. These would generally be classified as excipients, which constitute a wide range of materials that influence the quality attributes of topical products, physicochemical characteristics of the drug, and sensorial characteristics (i.e., taste, smell, texture) of the formulation. Excipients are frequently called “inactive” ingredients. However, it is important to note that excipients will ultimately affect the final performance of the compounded preparation by affecting properties such as solubility, stability, release of the active ingredient, and skin penetration. In some cases, patients are allergic to certain excipients; this requires preparations to be specially compounded without these allergens. Specific bases, vehicles, and solvents may be used in compounding to avoid certain allergenic excipients used in
commercial products (e.g., peanut oil) or to support patient compliance by adding flavoring to a medication for a young child (McBane et al., 2019). Excipients are critical components of a topical pain cream formulation and play a number of roles, including
- enhancing the solubility of the active drug,
- modifying the viscosity of the cream,
- emulsifying the formulation,
- enhancing drug penetration,
- stabilizing the formulation,
- extending the shelf life of a cream, and
- modifying the sensorial properties of the cream.
The United States Pharmacopeia (USP) provides a list of excipients as well as instructions to verify their identity and purity. USP <795> advises that all excipients in compounded preparations should meet compendial standards or otherwise be evaluated for safety and purity (USP, 2018). Table 5-4 contains a partial list of excipients found within published monographs from the USP-National Formulary, which outline quality standards for each listing. A second list of more than 1,700 unique excipients are published online in FDA’s inactive ingredient database, which also describes the maximum potencies of excipients in FDA-approved products (FDA, 2019). These lists were developed over years of study to identify inactive ingredients that have been shown to be generally safe for inclusion in compounded preparations and commercial drug products. As such, they serve
|Functional Categories of Excipients (number)||Listing of Excipients|
|Emollient (35)||Alkyl (c1215) benzoate; almond oil; aluminum monostearate; canola oil; castor oil; cetostearyl alcohol; cholesterol; coconut oil; cyclomethicone dimethicone; ethylene glycol stearates; glycerin; glyceryl monooleate; glyceryl monostearate; hydrogenated lanolin; isopropyl isostearate; isopropyl myristate; isopropyl palmitate; isostearyl isostearate; lecithin; mineral oil; mineral oil, light; myristyl alcohol; octyldodecanol; oleyl alcohol; oleyl oleate; petrolatum; polydecene, hydrogenated; propylene glycol dilaurate; propylene glycol monolaurate; safflower oil; soybean oil, hydrogenated; sunflower oil; wax, cetyl esters; xylitol; zinc acetate|
|Functional Categories of Excipients (number)||Listing of Excipients|
|Ointment base (24)||Caprylocaproyl polyoxylglycerides; coconut oil; diethylene glycol monoethyl ether; lanolin; lanolin, hydrogenated; lanolin alcohols; lauroyl polyoxylglycerides; linoleoyl polyoxylglycerides; ointment, hydrophilic; ointment, white; ointment, yellow; oleoyl polyoxylglycerides; paraffin; petrolatum; petrolatum, hydrophilic; petrolatum, white; polydecene, hydrogenated; polyethylene glycol; polyethylene glycol 3350; polyethylene glycol monomethyl ether; polyglyceryl 3 diisostearate; rose water ointment; squalane; stearoyl polyoxylglycerides; vegetable oil, hydrogenated, type II; vitamin E polyethylene glycol succinate|
|Stiffening agent (18)||Alphalactalbumin; castor oil, hydrogenated; cetostearyl alcohol; cetyl alcohol; cetyl palmitate; dextrin; hard fat; paraffin; paraffin, synthetic; rapeseed oil, fully hydrogenated; rapeseed oil, superglycerinated fully hydrogenated; sodium stearate; stearyl alcohol; wax, cetyl esters; wax, emulsifying; wax, microcrystalline; wax, white; wax, yellow|
|Suppository base (6)||Agar; cocoa butter; hard fat; palm kernel oil; polyethylene glycol; polyethylene glycol 3350|
|Suspending and/or viscosityincreasing agent (89)||Acacia; agar; alamic acid; alginic acid; alphalactalbumin; aluminum monostearate; attapulgite, activated; attapulgite, colloidal activated; bentonite; bentonite, purified; bentonite magma; carbomer 910; carbomer 934; carbomer 934p; carbomer 940; carbomer 941; carbomer 1342; carbomer copolymer; carbomer homopolymer; carbomer interpolymer; carboxymethylcellulose calcium; carboxymethylcellulose sodium; carboxymethylcellulose sodium 12; carboxymethylcellulose sodium, enzymatically hydrolyzed; carmellose; carrageenan; cellulose, microcrystalline; cellulose, microcrystalline, and carboxymethylcellulose sodium; cellulose, powdered; cetostearyl alcohol; chitosan; corn starch, pregelatinized hydroxypropyl corn; corn syrup; corn syrup solids; cyclomethicone; dextrin; egg phospholipids; ethylcellulose; gelatin; gellan gum; glyceryl behenate; glyceryl dibehenate; guar gum; hydroxyethyl cellulose; hydroxypropyl cellulose; hypromellose; isomalt; kaolin; magnesium aluminum silicate; maltitol solution; maltodextrin; mediumchain triglycerides methylcellulose; pectin; polycarbophil polydextrose; polydextrose, hydrogenated; polyethylene oxide; polysorbate 20; polysorbate 40; polysorbate 60; polysorbate 80; polyvinyl alcohol; potassium alginate; povidone; propylene glycol alginate; pullulan; silica, dentaltype; silica, hydrophobic colloidal; silicon dioxide; silicon dioxide, colloidal; sodium alginate; sorbitan monolaurate; sorbitan monooleate; sorbitan monopalmitate; sorbitan monostearate; sorbitan sesquioleate; sorbitan trioleate starch, corn; starch, hydroxypropyl; starch, hydroxypropyl pea; starch, hydroxypropyl potato; starch, pea; starch, potato; starch, pregelatinized hydroxypropyl pea; starch, pregelatinized hydroxypropyl potato; starch, tapioca; starch, wheat; sucrose; sucrose palmitatel tragacanth; vitamin E polyethylene glycol succinate; xanthan gum|
SOURCE: USP, 1999.
Of particular concern for compounded topical formulations is the marketing and use of excipients that do not have quality standards established by USP or have not been evaluated by FDA. Consequently, those excipients have limited (if any) available evidence of quality, safety, and functionality for their use in compounded preparations. Even in the case of excipients that have been reviewed for use in one commercial topical product, their effect on dermal delivery and absorption may not be the same when the excipients are used for another formulation. Understanding the effects of individual ingredients is further confounded when multiple inactive and active ingredients are incorporated into formulations.
Composition and Safety Profiles of Ingredients Used in Excipients
A review of topical formulations in the Journal of Pharmaceutical Sciences explains that individuals who compound should consider “intended dosage form, route of administration, safety profile, manufacturing process, and regulatory aspects” when selecting excipients (Simoes et al., 2018). Of course, excipients that cause degradation of the API are undesirable, thus part of the formulation development process involves verifying that excipients do not cause API degradation. Changing ratios of components or substituting excipients can dramatically affect product quality or alter product performance.
Additionally, when designing a formulation, it is important to understand which excipients have the potential to interact with each other by way of synergistic or opposing excipient–excipient interactions (Beraldode-Araújo et al., 2019; Karande and Mitragotri, 2009). For example, an excipient used to decrease viscosity may affect the performance of a permeation enhancer, thus inadvertently increasing the absorbed dose of drug delivered to the tissues below (Osborne and Musakhanian, 2018). On the other hand, if inappropriately formulated, the effects of excipients may have actions that oppose one another (Karande and Mitragotri, 2009). For example, the inclusion of certain preservatives may decrease the effect of an emulsifying agent. As an important consequence, the use of proprietary bases that do not disclose the composition makes it difficult for even the most experienced formulation scientist to evaluate how the ingredients may affect product quality and performance.
In a search for publically available formulations of compounded topical pain creams, the committee identified three examples that listed excipients
|Select Excipients||Active Pharmaceutical Ingredients in Select Compounded Topical Pain Creams||Listed Excipients|
Amitriptyline HCl 2%
Ketamine HCl 5%
|Ethoxy diglycol reagent|
Clonidine HCl 0.2%
Ketamine HCl 5%
Amitriptyline HCl 2%,
Clonidine HCl 0.01%
SOURCE: FDA, 2018.
(see Table 5-5). It is important to note that after reviewing these excipients, the committee determined the following:
- The rationale for the selection of the chemicals in the formulations is unclear.
- It is unclear whether the excipients selected for these pain creams were selected based on guidance from the FDA and USP lists.
- It is unclear whether any of the ingredients that are not on the FDA or USP lists could be unsafe individually or in combination.
- No information is available about whether these ingredients cause instability in the API or interact unfavorably with each other.
Among the listed excipients in Table 5-5, Lipoderm is listed twice and Emulsifix is listed once. Unfortunately, neither Emulsifix nor Lipoderm provide a publicly available list of excipients to inform the decision-making process of the pharmacists, prescribing clinician, or patient. This is also the case with several other proprietary bases used in compounded preparations.
One exception is Lipoderm ActiveMax, a patented base that is similar to Lipoderm and Emulsifix in that it contains preformulated excipients for topical application. The composition of Lipoderm ActiveMax is available on a publicly available patent (Ray and Hodge, 2013) and is detailed below in Table 5-6. In reviewing the composition of this base, half of the listed excipients are not included either in the USP-National Formulary 19 compendium or in the FDA inactive ingredient database. In addition, given the long list of excipients included, it is difficult to evaluate the potential
|Excipient||Listed on FDA-Approved Inactive Ingredient Database (Y/N)||Listed on USP List of Excipients||Listed on the Homœopathic Pharmacopœia of the United States|
|Piukenetia volubilis seed oil||N||N||N|
|Sodium stearoyl glutamate||N||N||N|
(includes other forms of PEGs)
(in other forms)
|Populus tremuloides bark extract||N||N||Y|
|Lonicera japonica (honeysuckle) flower extract||N||N||N|
|Lonicera caprifolium (honeysuckle) flower extract||N||N||N|
|Leuconostoc radish root ferment filtrate||N||N||N|
|Pentaclethra macroioba seed oil||N||N||N|
|Butyrospermum parkii (shea butter)||N||N||N|
|Carthamus tinctorius (safflower) seed oil||N||Y||N|
|Cocos nucifera (coconut) oil||Y||Y||N|
|Excipient||Listed on FDA-Approved Inactive Ingredient Database (Y/N)||Listed on USP List of Excipients||Listed on the Homœopathic Pharmacopœia of the United States|
(includes other forms of palmitate)
(in other forms)
|Caprylic capric triglyceride||N||Y (medium chain)||N|
|Disodium edetate (EDTA)||Y||Y||N|
NOTE: EDTA = ethylenediaminetetraacetic acid; FDA = U.S. Food and Drug Administration; PEG = polyethylene glycol; SMDI = saturated methylenediphenyldiisocyanate; USP = United States Pharmacopeia.
interactions of these excipients with each other or with APIs included in the pain cream; the patent provides minimal information to this regard.11 Furthermore, it is doubtful that each of those 30 or more ingredients actually contribute a unique advantage to the formulation, because formulations should be designed to be as simple as possible (Chang et al., 2013). This casts a cloud of doubt on the necessity of all the listed excipients in optimizing the safety and the effectiveness of the preparation.
11 The available patent information generally describes how these excipients enhance penetration. For example, paragraph 0060 states “In particular, the absorption profiles indicate a rapid penetration to a peak flux for gabapentin and baclofen occurring approximately 1 hour after dose application, and between approximately 4 to approximately 10 hours after dose application for ketamine” (Ray and Hodge, 2013).
Classes of Excipients: Penetration Enhancers
Penetration enhancers are a class of excipients of additional importance. This type of excipient enhances penetration of a drug into the inner tissues and ultimately into the blood stream (Prausnitz and Langer, 2008).12 Many chemicals can enhance penetration through the outer skin barrier by disrupting the highly ordered structure of lipid bilayers. However, this increased transdermal penetration is also associated with increased potential for irritation (Prausnitz and Langer, 2008). Many preformulated bases sold by such companies as the Professional Compounding Centers of America and Medisca are marketed as transdermal bases and touted for their ability to penetrate deeper below the skin (Medisca, 2020; PCCA, 2013). In addition, even products intended to act near the skin surface, such as sunscreen agents, are actually absorbed into the systemic circulation (Matta et al., 2019). Clearly, safety is an issue if large doses of a topically applied drug are absorbed systemically, especially if it is assumed that the drug is limited to local action or a drug has a narrow therapeutic window.
The 11 commonly accepted categories of permeation enhancers, classified by chemical structure, are water; hydrocarbons; alcohols; acids; amines; amides; esters; surfactants; terpenes, terpenoids, and essential oils; sulfoxides; and lipids (Karande and Mitragotri, 2009). Between and within these classes are numerous chemicals with different properties that affect their effectiveness as enhancers. A recent analysis of skin permeation studied more than 40 different enhancers in hairless mouse skin or human epidermal membrane. The analysis found that molecules within the same class and those with similar structures can have drastically different enhancer potencies. For example, 2-nonanol exhibited an enhancer potency parameter over four times greater than 2-octanol (Li and Chantasart, 2019). Obviously, factors such as potency and concentration need to be considered by individuals who compound when they choose to add permeation enhancers to their compounded preparations.
Dimethyl sulfoxide (DMSO) is a penetration enhancer used in compounded topical pain creams that has repeatedly occasioned concern among the committee. DMSO appears to be used in compounded topical pain creams as both a penetration enhancer and as an active ingredient (Kopsky and Keppel Hesselink, 2011; Russo and Santarelli, 2016). While the evidence is far from conclusive, some studies suggest that DMSO may help treat osteoarthritis pain and complex regional pain syndrome (Brien et al., 2008; NHS, 2020). In fact, DMSO is the primary inactive ingredient in PENNSAID, an FDA-approved topical solution for osteoarthritis pain
(Nuvo Research, 2016). However, the primary concern surrounding DMSO is its effect as a potent penetration enhancer.
The material safety data sheet for DMSO states “DMSO readily penetrates skin and may significantly enhance the absorption of numerous chemicals. Increased absorption of these other chemicals could lead to their increased toxicity” (Fisher Scientific, 2007). The instructions for use for PENNSAID caution patients to apply the medication to clean skin and to avoid the application of other drugs or cosmetics to the area (Nuvo Research, 2016). There is concern that the addition of DMSO to other ingredients in topical pain creams may affect toxicity and safety of the preparation. Furthermore, patients using compounded DMSO preparations may not be provided with adequate instructions and warnings to ensure safe use.
Given the potential complexity of compounding, the Federal Food, Drug, and Cosmetic Act (FDCA) requires that to qualify for exemptions from new drug approval and other, drugs compounded at 503A or 503B facilities must not “present demonstrable difficulties for compounding” and directed FDA to provide guidance on this matter.13 Accordingly, in 2016, FDA developed a “Difficult to Compound” list that will preclude the use of listed drugs in compounded preparations. Many examples of drug preparations and categories have been nominated to the Difficult to Compound List. However, no final determinations on which drugs will be included have been made to date.14 See Box 5-4 for FDA’s criteria for a drug that is difficult to compound.
13 Federal Food, Drug, and Cosmetic Act. 21 U.S. Code Chapter 9.
14 See Section 503A Bulks List Final Rule Questions and Answers; Guidance for Industry; Small Entity Compliance Guide; Availability. 84 FR 24027 (May 24, 2019) (FDA announces development of criteria to evaluate drugs as demonstrably difficult to compound under 503A and 503B).
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