Topical Minocycline
New to the class is MCN topical foam, 4% which was approved in October, 2019 to treat inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients 9 years of age and older.52 Previously, the MCN molecular structure made stability a challenge so that a topical formulation was elusive, until a lipid-rich, hydrophobic formulation was developed.53 In the 12- week, phase III clinical trials, once-daily MCN topical foam, 4% demonstrated a significant improvement in both inflammatory and non-inflammatory lesions as well as the investigators global assessment. MCN topical foam, 4% was generally well tolerated, and related AEs were reported in less than 1% of subjects treated.54,55
Due to the relative infancy of this product, longer term data in regard to resistance are needed. Topical antibiotics such as erythromycin and clindamycin were also previously effective long-term acne treatments, but are not recommended any longer as monotherapy because of bacterial resistance.20 According to the current American Academy of Dermatology acne guidelines, the long term use of a topical antibiotic without benzoyl peroxide (BP) could be a concern for developing resistance, and for this same reason the use of BP is also recommended for patients on systemic antibiotic therapy as well.20 However, recently data has been presented that C. acnes displays a low propensity for resistance to MCN topical foam, 4%. Spontaneous resistance frequencies were determined to be low at <1 10−8.56 Also, systemic exposure is 730–765X lower than that on the skin, theoretically reducing the risk of systemic resistance.57
Advances in Minocycline Dosing and Formulation
Initially, and for many years subsequently, MCN dosing recommendations in dermatology mimicked those for systemic infectious disease where high doses of immediate release MCN (MCN IR) were prescribed to produce the fast Tmax and high Cmax necessary for serious infections. However, fast dissolution and high serum concentrations are not needed in acne vulgaris, and can correlate with adverse events.50,58 With profound serum concentration spikes, its characteristic lipophilicity can in turn enable the molecule to cross the blood-brain barrier, affecting the vestibular apparatus. Predictably, unnecessarily high MCN IR doses in acne lead to excessive drug exposure and predictable side effects, with doses 2–3 times the optimal range.
In 2006, a landmark MCN extended release (MCN ER) phase II dose ranging study demonstrated an optimal dose at 1 mg/kg in acne vulgaris where higher doses were no more efficacious but risked vestibular side effects.50,58 The extended release formulation and optimal weight-based dosing regimen afforded slower drug release and less systemic drug exposure, with steady accumulation in the lipid-filled follicle over time. Ultimately, MCN ER with weight based dosing at 1 mg/kg study was a critical advancement, because high efficacy was complemented by a side effect profile more similar to placebo.50,58 The extended release formulation, Solodyn , was the first MCN to be FDA approved for acne vulgaris.59 All preceding tetracyclines had been “grandfathered” into use for adjunctive therapy in the absence of formal phase III testing in acne.
Advances In Delivery Systems
The introduction of Solodyn® substantially changed the use of MCN in acne vulgaris. It enabled the drug to maintain high efficacy with a significantly reduced dose, leading to markedly decreased vestibular side effects and other dose-related AEs. Building on the progress of the extended-release formulation, additional delivery systems have continued to evolve.
In 2012, a MCN ER formulation named Ximino® was released with an eye to improving the patient experience. The drug was formulated in small, 45 mg pellets placed within a gelatin capsule (Capsular Minotab Technology). Capsules are thought by some to be easier to swallow than tablets. Conversely, the small pellets within the capsule shell can be taken individually by those who find larger units difficult to swallow.
The most recent advancement in extended-release formulations was seen with the 2017 introduction of MinoLira™, a biphasic MCN (25% MCN IR/75% MCN ER) indicated to treat inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients 12 years of age and older.60 Although the extended release formulation of MCN combined with weightbased dosing was a landmark improvement, MCR ER did not utilize a delivery system for absorption. Leyden and Del Rosso reported that MCN absorption is variable from subject to subject and designated some patients as “high GI absorbers” and others as “low GI absorbers.” Accordingly, high absorbers may experience adverse events, and low absorbers may experience a lack of efficacy.28 Without delivery systems, pharmaceutical tablets are conventionally matrix-based, essentially the active pharmaceutical ingredient within a “cake” of binders held together until the gastrointestinal tract indiscriminately breaks it down for absorption.
The delivery system in Biphasic MCN ER is termed the Multiple Unit Pellet System (MUPS), and is designed to promote more uniform drug release, with predictable gastric emptying, and less risk of dose dumping (an immediate release of all the active pharmaceutical ingredient in an uncontrolled manner).61,62 MUPS distributes the dosage over multiple units with coated and uncoated pellets in a complex matrix reservoir, for controlled delivery.61 The potential advantage of the MUPS delivery system was indeed noted during the regulatory bioequivalence study designed to demonstrate close similarity of Biphasic MCN ER to MCN ER. Thirty-six patients participated in the
New to the class is MCN topical foam, 4% which was approved in October, 2019 to treat inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients 9 years of age and older.52 Previously, the MCN molecular structure made stability a challenge so that a topical formulation was elusive, until a lipid-rich, hydrophobic formulation was developed.53 In the 12- week, phase III clinical trials, once-daily MCN topical foam, 4% demonstrated a significant improvement in both inflammatory and non-inflammatory lesions as well as the investigators global assessment. MCN topical foam, 4% was generally well tolerated, and related AEs were reported in less than 1% of subjects treated.54,55
Due to the relative infancy of this product, longer term data in regard to resistance are needed. Topical antibiotics such as erythromycin and clindamycin were also previously effective long-term acne treatments, but are not recommended any longer as monotherapy because of bacterial resistance.20 According to the current American Academy of Dermatology acne guidelines, the long term use of a topical antibiotic without benzoyl peroxide (BP) could be a concern for developing resistance, and for this same reason the use of BP is also recommended for patients on systemic antibiotic therapy as well.20 However, recently data has been presented that C. acnes displays a low propensity for resistance to MCN topical foam, 4%. Spontaneous resistance frequencies were determined to be low at <1 10−8.56 Also, systemic exposure is 730–765X lower than that on the skin, theoretically reducing the risk of systemic resistance.57
Advances in Minocycline Dosing and Formulation
Initially, and for many years subsequently, MCN dosing recommendations in dermatology mimicked those for systemic infectious disease where high doses of immediate release MCN (MCN IR) were prescribed to produce the fast Tmax and high Cmax necessary for serious infections. However, fast dissolution and high serum concentrations are not needed in acne vulgaris, and can correlate with adverse events.50,58 With profound serum concentration spikes, its characteristic lipophilicity can in turn enable the molecule to cross the blood-brain barrier, affecting the vestibular apparatus. Predictably, unnecessarily high MCN IR doses in acne lead to excessive drug exposure and predictable side effects, with doses 2–3 times the optimal range.
In 2006, a landmark MCN extended release (MCN ER) phase II dose ranging study demonstrated an optimal dose at 1 mg/kg in acne vulgaris where higher doses were no more efficacious but risked vestibular side effects.50,58 The extended release formulation and optimal weight-based dosing regimen afforded slower drug release and less systemic drug exposure, with steady accumulation in the lipid-filled follicle over time. Ultimately, MCN ER with weight based dosing at 1 mg/kg study was a critical advancement, because high efficacy was complemented by a side effect profile more similar to placebo.50,58 The extended release formulation, Solodyn , was the first MCN to be FDA approved for acne vulgaris.59 All preceding tetracyclines had been “grandfathered” into use for adjunctive therapy in the absence of formal phase III testing in acne.
Advances In Delivery Systems
The introduction of Solodyn® substantially changed the use of MCN in acne vulgaris. It enabled the drug to maintain high efficacy with a significantly reduced dose, leading to markedly decreased vestibular side effects and other dose-related AEs. Building on the progress of the extended-release formulation, additional delivery systems have continued to evolve.
In 2012, a MCN ER formulation named Ximino® was released with an eye to improving the patient experience. The drug was formulated in small, 45 mg pellets placed within a gelatin capsule (Capsular Minotab Technology). Capsules are thought by some to be easier to swallow than tablets. Conversely, the small pellets within the capsule shell can be taken individually by those who find larger units difficult to swallow.
The most recent advancement in extended-release formulations was seen with the 2017 introduction of MinoLira™, a biphasic MCN (25% MCN IR/75% MCN ER) indicated to treat inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients 12 years of age and older.60 Although the extended release formulation of MCN combined with weightbased dosing was a landmark improvement, MCR ER did not utilize a delivery system for absorption. Leyden and Del Rosso reported that MCN absorption is variable from subject to subject and designated some patients as “high GI absorbers” and others as “low GI absorbers.” Accordingly, high absorbers may experience adverse events, and low absorbers may experience a lack of efficacy.28 Without delivery systems, pharmaceutical tablets are conventionally matrix-based, essentially the active pharmaceutical ingredient within a “cake” of binders held together until the gastrointestinal tract indiscriminately breaks it down for absorption.
The delivery system in Biphasic MCN ER is termed the Multiple Unit Pellet System (MUPS), and is designed to promote more uniform drug release, with predictable gastric emptying, and less risk of dose dumping (an immediate release of all the active pharmaceutical ingredient in an uncontrolled manner).61,62 MUPS distributes the dosage over multiple units with coated and uncoated pellets in a complex matrix reservoir, for controlled delivery.61 The potential advantage of the MUPS delivery system was indeed noted during the regulatory bioequivalence study designed to demonstrate close similarity of Biphasic MCN ER to MCN ER. Thirty-six patients participated in the
