Clindamycin Phosphate–Tretinoin Combination Gel Revisited: Status Report on a Specific Formulation Used for Acne Treatment

Topical management of acne vulgaris (AV) incorporates a variety of agents with diverse modes of action (MOAs), including retinoids and antibiotics.^1-3 The first topical retinoid developed for acne therapy was tretinoin, available in the United States since 1971.^2,4 Topical retinoids, including tretinoin, exhibit multiple pharmacologic effects that are believed to correlate with efficacy for acne treatment,^1,2,4,5 such as the reduction of inflammatory and comedonal lesions and contribution to dermal matrix remodeling.^1,2,4-9 The predominant topical antibiotic used for acne treatment, often in combination with benzoyl peroxide (BP) and/or a topical retinoid, is clindamycin. Clindamycin is a lincosamide antibiotic that is closely related to erythromycin, a member of the macrolide antibiotic category.^1,3,10 Available data support that over time topical clindamycin has sustained greater efficacy in reducing AV lesions than topical erythromycin; the latter also has been shown to exhibit a greater prevalence of Propionibacterium acnes resistance than clindamycin.^1,3,10-12

Combination gel formulations of clindamycin phosphate 1.2%–tretinoin 0.025% (CP-Tret) are approved by the US Food and Drug Administration and available in the United States for once-daily treatment of AV in patients 12 years of age and older.^13-15 Large-scale randomized controlled trials (RCTs) have demonstrated both efficacy and safety for these formulations.^16,17 This article reviews important considerations related to both individual active ingredients (clindamycin phosphate [CP] and tretinoin [Tret]), formulation characteristics, and data from pivotal RCTs with a CP-Tret gel that has more recently been reintroduced into the US marketplace for acne therapy (Veltin, Aqua Pharmaceuticals).

What is the rationale behind combining CP and Tret in a single combination formulation?

Clindamycin is a lincosamide antibiotic that has been used for the treatment of AV for approximately 5 decades.^1,3,10,17 The main MOA of clindamycin in the treatment of AV is believed to be reduction of P acnes; however, anti-inflammatory effects maypotentially play some role in AV lesion reduction.^{3,10,12,17-19} Multiple RCTs completed over approximately 3 decades and inclusive of more than 2000 participants treated topically with clindamycin as monotherapy have shown that the efficacy of this agent in reducing AV lesions has remained consistent overall,^3,20-24 unlike topical erythromycin, which did not sustain its efficacy over a similar comparative time period.²⁰ Importantly, these data are based on RCTs designed to evaluate the efficacy and safety of individual agents, including topical clindamycin; however, topical antibiotic therapy is not recommended as monotherapy for AV treatment due to emergence of antibiotic-resistant bacterial strains.^{1,3,11,12,25-28} Although the prevalence of resistant strains of P acnes is lower in the United States and many other countries for clindamycin versus erythromycin, the magnitude of clindamycin-resistant P acnes strains increases and response to clindamycin therapy may decrease when this agent is used alone.^{12,25-27,29,30} Therefore, it is recommended that a BP formulation that exhibits the ability to adequately reduce P acnes counts be used concurrently with antibiotic therapy for AV to reduce the emergence and proliferation of antibiotic-resistant P acnes organisms; short-contact BP therapy using a high-concentration (9.8%) emollient foam formulation and sufficient contact time (ie, 2 minutes) prior to washing off also has been shown to markedly reduce truncal P acnes organism counts.^{1,3,10-12,25-33} The Table depicts the major characteristics of clindamycin related to its use for treatment of AV.

Tretinoin has been used extensively for the treatment of AV since its introduction in the United States in 1971.^1,2,4,5 The proposed MOAs of topical retinoids, including tretinoin, based on available data include a variety of pharmacologic effects such as inhibition of follicular hyperkeratosis (decreased microcomedone formation), modulation of keratinocyte differentiation, anti-inflammatory properties, and inhibition of dermal matrix degradation (Figure).^{1,2,4,5,14,34,35} Topical retinoids, including tretinoin, have been shown to reduce both inflammatory and comedonal acne lesions, likely due to multiple MOAs, and are devoid of antibiotic properties.^2,4-8,16 Available data support that topical combination therapy for AV with a retinoid and a topical antimicrobial agent augments the therapeutic benefit as compared to use of either agent alone.^{1-4,12,15,16,28,31,32}

The rationale for incorporating both clindamycin and tretinoin together into one topical formulation includes combining different MOAs that appear to correlate with suppression of AV lesion formation and to improve patient adherence through once-daily application of a single topical product.^16,31,32,36 Importantly, formulation researchers were able to combine CP-Tret into a specific aqueous gel formulation that maintained the stability of both active ingredients and proved to be effective and safe in preliminary studies completed in participants with AV.^16,23,37-39 This aqueous formulation incorporated a limited number of excipients with low to negligible potential for cutaneous irritation or allergenicity, including anhydrous citric acid (chelating agent, preservative, emulsifier, acidulent), butylated hydroxytoluene (antioxidant), carbomer homopolymer type C (thickening agent, dispersing agent, biocompatible gel matrix), edetate disodium (chelating agent), laureth 4 (emulsifier, dissolution agent), methylparaben (preservative), propylene glycol (low-concentration humectant), purified water (diluent), and tromethamine (buffer, permeability enhancer).¹⁴

Topical retinoid modes of action and potential impact on acne pathophysiology.1,2,4,5,9 TLR indicates toll-like receptor; AP-1, activator protein 1.