Topical minocycline formulations: Evaluation and comparison of dermal uptake efficacy

Abstract

Acne vulgaris is a clinically distinct skin condition with evidence suggesting that inflammation plays a critical role in the pathogenesis of this disorder. Treatment of severe inflammatory acne often involves the use of oral antibiotics, sometimes in combination with topical products. Oral antibiotics often result in systemic side effects and the risks of antibiotic resistance, but no commercial topical minocycline is currently available. We have developed a unique, stable, hydrophilic topical gel formulation with fully solubilized minocycline (MNC-H). Minocycline delivered in our hydrophilic gel remained more stable in situ, resulting in less degradation product (4-epiminocycline) than a lipophilic formulation (MNC-L). The hydrophilic nature of our formulation enabled 2-3 fold increase in delivery into the skin ex vivo compared to a lipophilic counterpart, mostly seen in the epidermis and pilosebaceous units. The lipophilic formulation also appeared to be more occlusive, resulting in higher sebum production in minipigs, which may exacerbate acne vulgaris. As our results indicate, a 1, 2% minocycline hydrophilic gel may deliver sufficient drug (>15 μg/g) to potentially demonstrate clinical efficacy. These findings suggest that topical hydrophilic minocycline gel may provide a novel tool for topical acne therapy.

Keywords: Acne; Anti-inflammatory; Anti-microbial; BPX-01, 2% topical hydrophilic minocycline gel; Dermal; Hydrophilicity; MNC-H, topical hydrophilic minocycline gel formulations; MNC-L, topical lipophilic minocycline formulations; Skin; Tetracycline class; Transepidermal.

Graphical abstract

Fig. 1

Comparison of topical minocycline formulations MNC-H (1%, 4%) and MNC-L (1%, 4%) at 2 and 4 h post-application. Uptake is of (a) combined parent minocycline and 4-epiminocycline or (b) parent minocycline only in ex vivo human facial skin. Graph presents the mean ± standard error (SE). (^*P ≤ 0.05 between hydrophilic minocycline and the lipophilic minocycline formulations, 4% MNC-H versus 4% MNC-L at 2 and 4 h, and †P ≤ 0.05 between 1% MNC-H versus 1% MNC-L at 2 and 4 h).

Fig. 2

Minocycline epimerization resulting from topical application of MNC-H or MNC-L formulation in ex vivo human facial skin. 4-epiminocycline amount in formulation prior to dosing (0 h) and extracted from skin samples that were processed 2 or 4 h post-application with (a) 1% or (b) 4% formulations. Graphs present the mean ± standard error (SE) (^*P ≤ 0.05 between hydrophilic minocycline and the lipophilic minocycline formulations; 1% MNC-H versus 1% MNC-L at 2 h and 4% MNC-H versus 4% MNC-L at 4 h).

Fig. 3

Detection of minocycline (red fluorescence) in ex vivo human facial skin after application of hydrophilic MNC-H or lipophilic MNC-L formulations. Tissue was treated with an excess amount of 1% MNC-H, 1% MNC-L, 4% MNC-H, or 4% MNC-L and its appropriate vehicle control (hydrophilic MNC-H vehicle or lipophilic MNC-L vehicle) for 24 h. Relevant skin structures such as the stratum corneum, epidermis and sebaceous gland (SG) can be observed. Scale bar represents 100 μm. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 4

Minocycline uptake and visualization in rat skin treated with 4% MNC-H or vehicle over 14 days. (a) Uptake of minocycline in rats with daily application of 2.5 mg/cm² and 5 mg/cm² of 4% MNC-H or hydrophilic vehicle. Graph presents mean ± SE. (b) Visualization of minocycline (red) in the rat skin, specifically the sebaceous gland (SG) and stratum corneum (SC). Serial H&E images are also shown. Scale bar indicates 100 μm. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 5

Minocycline uptake in minipig skin after 14 days of various MNC-H formulations. MNC-H minocycline concentrations (0.5%, 1%, 2%, 4%) and application volumes (2.5, 7.5 and 12.5 mg/cm²) were applied daily to the skin. Triplicates of each sample were analyzed by LC-MS/MS. Graph presents mean ± SE.

Fig. 6

Sebum production observed from the skin of minipigs treated with 4% MNC-L, 1% MNC-H or non-treated (sham). Sebutape^© was used to collect sebum and weighed prior to and post Sebutape^© application on the skin. Graph presents mean ± SE (^*P ≤ 0.05 between sham and minocycline treated groups at baseline, day 7, 15 and 29, †P ≤ 0.05 between the 1% MNC-H and 4% MNC-L group on day 7, 15 and 29).