TOPICAL DELIVERY - Novel Approaches to Topical Antibiotics Promise Innovation in the Treatment of Acne & Rosacea

INTRODUCTION

As antibiotic resistance becomes frighteningly routine, dermatologists worried about their heavy reliance on these drugs are on a quest to find new ways to treat common skin conditions like acne and rosacea, which affect up to 66 million Americans (50 million and 16 million, respectively).¹

The medical community is expressing enthusiasm for some promising new therapeutic products in clinical trials. These products – using a novel formulation of minocycline –have the potential to be the first real advances in antibiotic acne treatment in nearly 40 years.

Innovation is critically important. Dermatologists represent 1% or less of the US physician population, yet they order nearly 5% of antibiotic prescriptions.² Between 2003 and 2013, they prescribed antibiotics up to 9 million times annually – representing at least 20% of all their prescriptions. Up to two-thirds of these antibiotic prescriptions were for the treatment of acne vulgaris.^3-6

The most effective antibiotics – and the most commonly prescribed – are in the tetracycline class. Unfortunately, the most effective formulations of tetracycline-class antibiotics like doxycycline and minocycline are only available as orals, which cause greater concerns about antibiotic resistance. These oral formulations flood the bloodstream with drugs in order to reach the microbes in the skin being targeted for treatment. This increases the likelihood that bacteria will become resistant to the medicine and significantly increases the risk of antibiotic resistance in dermatology patients.

THE ANTIBIOTIC RESISTANCE PROBLEM IS REAL

Studies show dermatologists have few satisfactory alternatives to oral antibiotics.⁷ For example, minocycline, which is a commonly prescribed oral antibiotic and seems to have the least potential for resistance of the tetracycline class, is not commercially available in topical form.^8,9 Meanwhile, many of the antibiotics that are available as topical products, such as clindamycin and erythromycin, have surprisingly high resistance rates, and therefore are marginal in efficacy.⁷ As Table 1 shows, the antibiotic resistance problem is enormous.

This is why dermatologists have been forced to embrace a standard of care using combination therapies that alternate the use of oral antibiotics and topical products like benzoyl peroxide or retinoids. These combinations offer the best-available treatment and are currently recommended by the American Academy of Dermatology.¹²

But these combination therapies have their own shortcomings. For example, the antimicrobial benzoyl peroxide is associated with adverse effects, such as stinging, burning, itchiness, dry skin, irritation, and bleaching of dark clothing. This poses two problems. First, side effects often deter adherence. Second, patients frequently do not follow physician instructions about usingbenzoyl peroxide along with the topical antibiotic and use the antibiotic alone.¹³

NEEDED: ALTERNATIVE WAYS TO DELIVER ANTIBIOTICS

Dermatologists and their patients need a better way to deliver antibiotics effectively without contributing to the resistance problem.¹⁴ An ideal solution might be a new topical antibiotic formulation that could theoretically deliver effective therapy in a more targeted way with a lower dosage of antibiotic, thereby reducing the risk of antibiotic resistance associated with oral formulations.

That better solution may be on the horizon. Two companies have developed topical formulations of one of the most effective tetracycline-family antibiotics: minocycline. BioPharmX, Inc. of California and Foamix Pharmaceuticals of Israel attack the problem differently but both have products in the clinical research stage.

Minocycline, a second-generation tetracycline, is appealing because it demonstrates the lowest resistance rates of all the tetracycline class of antibiotics.^6,7,15 It is particularly effective in managing several different inflammatory skin diseases, and its oral formulation is one of the most prescribed antibiotics for acne. While oral minocycline was long perceived to be more effective in the treatment of acne than other antibiotics, its use has decreased somewhat over concerns about its safety, including the risk of systemic side effects, such as headache, dizziness, nausea, hyperpigmentation of skin and teeth, autoimmune hepatitis, systemic lupus erythematosus, and ANCA vasculitis.¹⁶

A topical formulation of minocycline should remove these risks by significantly reducing or even eliminating the systemic exposure through precise delivery to the layer of skin where treatment is needed and the reliance on dosages that are just a fraction of the standard oral dosage.

Several companies have unsuccessfully attempted to develop commercial topical or transdermal delivery systems for minocycline for the US market. For years, researchers have been unable to stabilize minocycline in a delivery system that can penetrate the stratum corneum, the outer layer of the epidermis.

TWO APPROACHES TO A TOPICAL MINOCYCLINE

BioPharmX has solubilized minocycline with HyantX^TM, an anhydrous hydrophilic topical gel system that research shows delivers minocycline into the pilosebaceous unit. Foamix delivers a suspension of minocycline using a foam formulation that research shows allows antibiotic penetration. Both formulations are in clinical trials to assess their use in treatment of certain dermatological skin conditions, including acne and rosacea.

Both products hold out the promise of delivering effective levels of minocycline. However, the differences between the two companies’ delivery systems may affect each product’s utility in dermatological care.

The BioPharmX gel delivery system promises to be a cosmetically elegant solution. The gel fully solubilizes minocycline and leaves no trace of the antibiotic on the skin. It also leaves no oily residue on the skin that may discourage patient compliance. The BioPharmX BPX-01 topical minocycline gel formulation for acne also evaporates, which increases the surface concentration gradient to enhance delivery of the API into the skin and can soothe and cool the skin. Clinical research on BPX-01, a 2% minocycline concentration, found the medication was well tolerated with a good safety profile and was virtually undetectable in blood plasma.¹⁷ As a result, no systemic side effects are anticipated. Subjects in the clinical trial also demonstrated rapid improvement and better outcomes than vehicle control in the treatment of moderate-to-severe non-nodular inflammatory acne vulgaris.¹⁸ This treatment may provide an effective new option with a favorable safety profile and potential for high patient compliance.

It is worth highlighting that the HyantX delivery system contains a number of excipients, including ethanol, which is a versatile solvent, miscible with bothskin.^19,20 This helps deliver minocycline into the epidermis and pilosebaceous unit. Ethanol is naturally bactericidal, non-bleaching of skin and clothing, and is designed to be non-irritating in the BioPharmX formulation. In sufficient concentration, ethanol has a therapeutic effect in the treatment of P. acnes (BPX-01 vehicle contains ethanol levels above MIC/MBC).

The Foamix foam suspends minocycline and leaves residue on the skin that may irritate the skin and stain clothes and bedding.²¹ While researchers detected minocycline in the pilosebaceous unit, including the hair follicle and the sebaceous gland, it is not clear whether the lipid-based foams will clog pores, something that may be worrisome for acne patients and their clinicians.

It is interesting to note that, based on clinical trials, the two companies use different concentrations of minocycline in their products. BioPharmX uses 2% solubilized minocycline in BPX-01 gel, while Foamix uses double the concentration – or 4% minocycline. The higher Foamix concentration may be needed for a few reasons. In its formulation, the minocycline is not dissolved, it is suspended in the foam. This may make it more difficult for the minocycline to penetrate into the pilosebaceous unit, against the flow of sebum. Accordingly, the foam vehicle remains on the skin to help penetration, but with more drug, which may irritate the skin and clog pores.

CLINICAL RESULTS ARE PROMISING

Both BioPharmX and Foamix have reported clinical research data suggesting their products work.

A novel Fluorescence Lifetime Imaging Microscopy (FLIM) analysis of the BioPharmX BPX-01 topical gel penetration into the skin demonstrated detectable fluorescence of minocycline following a single daily application after a 24-hour incubation period. Minocycline was detected at 2.5 mg/cm² and was found in the epidermis, infundibulum, hair follicle, and sebaceous glands.²² This analysis is noteworthy because it represents the first time FLIM was used to determine minocycline penetration in the skin, and it is the most accurate and precise measurement method of such penetration undertaken to date with a single daily dose.

In a randomized and vehicle controlled clinical trial, the BioPharmX formulation showed rapid improvement in clinical onset. There was a 25% reduction in lesions at week 2 of a Phase 2b clinical trial, a 43.3% reduction at week 4, and a 58.5% reduction at week 12. Compared to oral formulations of minocycline, such as Solodyn^®, BioPharmX was able to achieve results comparable to 12-week efficacy of oral minocycline in only 4 weeks.¹⁷ The treatment was found to be generally safe and well tolerated in the clinical study setting thus far. No serious treatment-related adverse effects were reported. Neither were photosensitivity or post-inflammation hyperpigmentation, nor adverse events of staining and/or skin discoloration. A participant survey conducted as part of the trial also found that BPX-01 was considered by patients as a positive experience, with most subjects saying they would consider using the product again.²³

An analysis of the Foamix FMX101 minocycline foam product showed that most of the antibiotic remained unabsorbed as residue on the skin surface. Nonetheless, appreciable amounts of minocycline did accumulate in the skin following 24 hours of drug treatment. The total mean amount of minocycline in the skin was 108.90 μg (≡61.52 μg/cm²) for the 4% formulation. The stratum corneum, including its deeper layers, contained 105.41±24.98 μg (≡ 59.55 μg/cm²) for the 4% formulation.²¹

As with the BioPharmX product, the Foamix solution resulted in significant improvement to patients. The company’s two trials reported reductions in the number of inflammatory lesions of 43.93% and 42.94% after 12 weeks.24 However, Foamix failed one of its endpoints in its Phase 3 studies, likely due to insufficient patient numbers, and extended the trial to add a third study.

HOW MUCH UPTAKE IS ENOUGH?

It has been shown that the minimum inhibitory concentration (MIC) for a typical strain of P. acnes is approximately 30 ng/mL for minocycline. As a result, the dosage applied on the skin in both BPX-01 2% and FMX101 4% are above the concentration required to address surface proliferation of these bacteria.

Further, because the HyantX delivery system contains ethanol, which is bactericidal, it could potentially help address the concerns of development of bacterial resistance against minocycline, similarly as benzoyl peroxide does for clindamycin in combined topical formulations.

Additionally, minocycline in BPX-01 is fully solubilized, as opposed to being in suspension in FMX101. This may have an impact on bioavailability of minocycline for each formulation.

CONCLUSION

Both the BioPharmX and Foamix products offer promise to a dermatologic community that is eager to have effective new therapies that may reduce the risk of systemic antibiotic resistance. Despite ongoing efforts to identify alternatives to antibiotics for the treatment of conditions like acne and rosacea, the substitutes have not been ideal. Research continues to find alternatives.

One thing is certain – the dermatologic community is anxiously awaiting a topical antibiotic such as minocycline. Finding a way to deliver an effective topical formulation of minocycline – which has the lowest resistance rate among the tetracycline class of antibiotics – would address dermatologists’ needs for delivering effective care while limiting systemic exposure to antibiotics in patients.

We look forward to the results of both companies’ ongoing research in hopes that their products are found to be effective and safe enough for commercialization.

REFERENCES 

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2. John Jesitus. Dermatologists contribute to overuse of antibiotics. Dermatology Times. 2013 Oct. 1:http://dermatologytimes.modernmedicine.com/dermatology-times/content/tags/acne/dermatologists-contribute-overuse-antibiotics.
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9. Ross JI, Snelling AM, Carnegie E, et al. Antibiotic-resistant acne: lessons from Europe. Br J Dermatol. 2003;148(3): 467–478.
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16. Chan K. BPX Phase 2B Results presented as part of State of Acne Symposium. June 2017. One patient of BPX-01 2% measured 42 ng/ml but demonstrated no adverse effects. The measurement was below the limit of quantification for the study.
17. Alexis A, Del Rosso JQ, et al. Rapid Improvement with BPX-01 Minocycline Topical Gel in the Treatment of Moderate-to-Severe Inflammatory Acne Vulgaris: a Randomized, Double-Blind, Vehicle-Controlled Study. Presentation at Fall Clinical Dermatology Conference 2017.
18. Dirk W Lachenmeier. Safety evaluation of topical applications of ethanol on the skin and inside the oral cavity. Journal of Occupational Medicine and Toxicology. 2008;3:26.
19. Skin Barrier – Principles of Percutaneous Absorption, 1996, Schaefer et al, 247.
20. Hazot Y, Malinov T, et al. Topical OleaginousMinocycline Foam: Efficacious Delivery into Skin Layers. J Anal Pharm Res 4(5): 00117. DOI:10.15406/japlr.2017.04.00117.
21. Jeong S, Hermsmeier M, et al. Visualization of Cutaneous Distribution of Minocycline from a Topical Gel in Human Facial Skin with Two-Photon Excitation Fluorescence Lifetime Imaging Microscopy (FLIM) and Phasor Analysis. A presentation to the Fall Clinical Derm Conference, 2017.
22. Alexis A, Del Rosso J, Desai SR, Downie J, Draelos ZD, Feser C, Forconi R, Fowler J, Gold M, Kaufman-Janette J, Lain E, Lee M, Ling M, Shamban A, Werschler W, and Daniels A. Results from a Randomized, Double-Blind, Vehicle-Control Study to Assess the Safety and Efficacy of BPX-01 Minocycline Topical Gel in the Treatment of Moderate-to-Severe Inflammatory Acne Vulgaris. Presentation at Alabama Dermatology Society Dermatology Summer Symposium, June 2017.
23. Foamix Reports Topline Results from Phase 3 Trials for FMX101 in Patients with Acne. Corporate press release. March 27, 2017.

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Dr. G. Scott Herron is a physician scientist with nearly three decades of dermatology experience and an active clinical practice in Palo Alto, CA. As a member of the Stanford University School of Medicine faculty, he conducted biomedical research, consulted with the biopharmaceutical industry, authored or co-authored more than 30 peer-reviewed papers, and secured several patents in the biomedical field. He serves as Medical Director for BioPharmX Corporation.