Compounded Topical Pain Creams Review of Select Ingredients for Safety, Effectiveness, and Use (2020) / Chapter Skim
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5 Science of Compounded Topical Pain Creams
5 Science of Compounded Topical Pain Creams
Pages 87-120
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From page 87... ...
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.
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From page 88... ...
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)
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From page 89... ...
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)
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From page 90... ...
. DERMAL ABSORPTION Dermal absorption is a critical consideration in the science of compounded topical pain creams.
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Additionally, the active drug must penetrate the outer protective barrier of the skin (stratum corneum) and reach the viable lower layers of the epidermis and dermis to effectively treat pain.
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. Of note, many compounded pain creams are marketed as transdermal (Swidan and Mohamed, 2016)
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. 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)
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NOTE: (Left) Top view of the stratum corneum showing tightly packed skin cells (corneocytes in light brown)
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. 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)
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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.
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From page 97... ...
. 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)
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From page 98... ...
, 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)
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. Physiochemical Properties of the Active Pharmaceutical Ingredient Complex Considerations The physiochemical properties of a drug's active ingredients play a substantial role in the drug's absorption.
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From page 100... ...
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)
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From page 101... ...
213.66 1.3 207 9.62 and 3.67 Bupivacaine 288.43 2.59 107 8.2 Cannabidiol 314.46 -- 66 5.79 Carbamazepine 236.27 2.45 191 7 Clonidine 230.09 1.59 130 8.12 Cyclobenzaprine* 275.39 5.2 218 8.47 Dexamethasone 392.46 1.93 262 12.42 Doxepin 273.38 –0.548 184 8.96 Gabapentin 171.24 –1.1 166 3.68 and 10.70 Ketamine 237.73 3.12 92.5 7.5 Lidocaine hydrochloride 270.80 <0 77 7.9 Meloxicam 351.40 3.43 254 4.08 Memantine 179.31 3.28 258 10.27 Naproxen 230.26 2.79 153 4.15 Nifedipine 346.30 2.50 173 4.3 Orphenadrine 269.39 3.77 156 8.91 Pentoxifylline 278.31 0.38 105 -- Topiramate 339.36 –0.5 125 8.6 Tramadol 263.38 1.34 181 9.4 NOTES: To add an additional layer of complexity of physiochemical properties that af fect dermal absorption, certain drugs have chemical functional groups on the drug mol ecule with different pKa values, such as baclofen (pKa of 9.62 for the amino group and 3.67 for the carboxyl group)
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From page 102... ...
If meloxicam or nifedipine were formulated in combination with the above drugs, they would exist in an almost completely ionized state at pH 9, which could hamper their penetration significantly. In summary, optimizing a formulation to properly deliver multiple active ingredients with differing physiochemical properties in a reproducible manner is a difficult balance of both art and science.
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From page 103... ...
Percent of Applied Drug Dose Absorbed Across the Cadaver Skin Active Pharmaceutical Ingredient Lipoderm Lipoderm ActiveMax 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 formula tions for compounded topical creams. SOURCE: Bassani and Banov, 2016.
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From page 104... ...
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.
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Excipients ("Inactive" Ingredients) A wide range of bases, vehicles, and solvents are used to formulate topical pain creams.
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. 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.
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polyethylene glycol 3350 Suspending Acacia; agar; alamic acid; alginic acid; alpha-lactalbumin; aluminum and/or monostearate; attapulgite, activated; attapulgite, colloidal viscosity- activated; bentonite; bentonite, purified; bentonite magma; increasing carbomer 910; carbomer 934; carbomer 934p; carbomer 940; agent (89) 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; medium-chain 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, dental-type; 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.
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From page 108... ...
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 10 Additional reference lists are available in international pharmacopeia, such as the Euro pean Pharmacopeia (see https://www.edqm.eu/en/databases [accessed March 2, 2020]
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From page 109... ...
• 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.
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From page 110... ...
110 COMPOUNDED TOPICAL PAIN CREAMS TABLE 5-6 Listed Components in Lipoderm ActiveMax from Patent US2013/0085171 Listed on FDA Approved Listed on the Inactive Homœopathic Ingredient Pharmacopœia Database Listed on USP List of of the United Excipient (Y/N) Excipients States Water n/a Y n/a Cetearyl alcohol Y N N Piukenetia volubilis seed oil N N N Isopropyl myristate Y Y N Propylheptyl caprylate N N N Sodium stearoyl glutamate N N N PEG-8/SMDI copolymer N N N PEG-100 stearate N N N (includes other forms of PEGs)
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Food and Drug Administra tion; PEG = polyethylene glycol; SMDI = saturated methylenediphenyldiisocyanate; USP = United States Pharmacopeia. SOURCES: FDA, 2019; HPUS, 2020; Ray and Hodge, 2013; USP-NF, 2019.
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Dimethyl sulfoxide (DMSO) is a penetration enhancer used in compounded topical pain creams that has repeatedly occasioned concern among the committee.
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. There is concern that the addition of DMSO to other ingre ients in d topical pain creams may affect toxicity and safety of the preparation.
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Physicochemical or analytical testing complexity FDA stated that it will consider these criteria individually and col lectively when evaluating whether a drug product or a category of drug products is demonstrably difficult to compound. SOURCE: Drug Products That Present Demonstrable Difficulties for Com pounding Under the Federal Food, Drug, and Cosmetic Act; Establish ment of a Public Docket.
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From page 115... ...
To address this complexity and to minimize potential variability in performance, there is a need for optimal consistency in formulations of compounded topical pain creams -- with standardized methods for disclosing formulation procedures -- to ensure acceptable and consistent performance of the compounded preparation. There is insufficient evidence to evaluate the extent of topical absorption or potential transdermal penetration of active and inactive ingredients (used alone or in combination)
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2016. Compounded topical analgesics for chronic pain.
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2009. Enhancement of transdermal drug delivery via synergistic action of chemicals.
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Paper com missioned by the Committee on the Assessment of the Available Scientific Data Regarding the Safety and Effectiveness of Ingredients Used in Compounded Topical Pain Creams (see Appendix C)
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2012. Skin barrier and transdermal drug delivery.
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2015. Resistance to water diffusion in the stratum corneum is depth-dependent.
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