Innovative therapies to treat skin conditions like moderate-to-severe acne and rosacea have been lacking in the past decade. Considering that acne is the most common condition presented to dermatologists, this is a rampant problem and many physicians continue to rely heavily on antibiotics.
A survey to assess physician preferences for 15 drug systems found they “prefer topical delivery, either as a transdermal patch or topical gel/cream, and expressed willingness to switch their current mode of therapy to one available in these forms.”1
Why? Well-formulated topicals may be safer and more efficient because they may be able to: deliver medicine in a highly targeted way, requiring lower dosages; and reduce or eliminate adverse effects associated with oral formulations, including the risk of antibiotic resistance.
The tetracycline class of antibiotics is uniquely suited to the treatment of acne and rosacea, as they are able to kill P. acnes and are powerful anti-inflammatory drugs. The development of a stable topical formulation of the tetracyclines has been challenging.2,3 Other types of antibiotics, like clindamycin and erythromycin, have lost their effectiveness over the years due to the development of antibiotic resistance.4 That is why the standard of care continues to involve oral formulations of tetracycline-class antibiotics.5
This forces dermatologists to make a difficult choice: they can continue prescribing oral formulations that are effective, but associated with systemic side effects, or they can prescribe less effective topical antibiotics that are not in the tetracycline class, recognizing that their higher rates of antibiotic resistance make these drugs less than ideal.6,7,8
IMPROVING ANTIBIOTIC RESISTANCE
While dermatologists represent one percent or less of the United States physician population, they are responsible for nearly five percent of antibiotic prescriptions.9 At least 20 percent of the prescriptions dermatologists write are for antibiotics. From 2003 to 2013, United States dermatologists prescribed antibiotics 8 to 9 million times annually, with up to two-thirds of these antibiotic prescriptions being given for treatment of acne vulgaris.10,11,12,13
Dermatology relies on oral antibiotics for two reasons: first, the most effective antibiotics for the treatment of dermatological conditions are currently only available in oral formulations; 11 second, many of the antibiotics that are available in topical formulations, such as clindamycin and erythromycin, have high resistance rates, making them marginally efficacious.11
Antibiotic resistance should be top-of-mind for all physicians. In Spain, the P. acnes resistance rate to erythromycin or clindamycin is 91 percent.14 In India, P.acnes resistance rates are at 90 percent for clindamycin, 98 percent for erythromycin, and 100 percent for azithromycin.15 A United States study found resistance rates to erythromycin and clindamycin of 100 percent, to tetracycline of 97 percent, and to doxycycline of 83 percent.16 P. acnes resistance clinically manifests as poor response to antibiotics. More importantly, collateral damage is of concern. That is, which other organisms in and on the body are being destroyed and what resistant strains are being promoted by use, and perhaps abuse, of antibiotics should be considered.
To help address resistance issues, dermatologists attempt to treat skin without antibiotics using hormonal therapy, isotretinoin, topical retinoids, and benzoyl peroxide, as well as laser and light treatments. When oral antibiotics are necessary, combination therapy is always called for, adding topical products, such as benzoyl peroxide and retinoids, to reduce the incidence of resistance and to allow the discontinuation of antibiotics as soon as possible. Combination therapy is recommended by the American Academy of Dermatology and is an integral part of the new guidelines for care.17
FINDING METHODS TO TOPICALLY DELIVER ANTIBIOTICS
Many dermatologists believe that the development of an effective topical formulation of tetracycline-class antibiotics would be a particularly useful addition to their acne war chest. It would avoid many of the adverse effects associated with oral formulations and, because it is targeted directly, might be able to use lower dosages and perhaps reduce resistance risk.
However, delivering an antibiotic through the skin is challenging. The active pharmaceutical ingredient (API) must be able to penetrate the stratum corneum. While passing through the stratum corneum and into the viable layers of the epidermis, it must not irritate or trigger inflamation.
Complicating the development of a topical formulation, tetracycline-class antibiotics come in salt form, which helps to stabilize the active pharmaceutical ingredient (API) raw materials. This salt form works fine in oral formulations like pills and capsules that are easy to manufacture and keep stable because the end products are dry. However, topical formulations are semi-solids or liquid, and usually have water content that quickly degrades the API in tetracycline-class antibiotics. To stabilize the tetracycline salt in a topical formulation, developers have tried mixing the APIs in an oil-based formulation that ensures minimal exposure to moisture or water. Unfortunately, this oil-based approach creates an antibiotic suspension in which the APIs are neither fully solubilized nor bioavailable. Transepidermal delivery is poor and requires a higher dose of API because, without solubility, there is no concentration gradient to drive active ingredients into the skin efficiently and the amount that penetrates may not fully be bioavailable.
Two companies are taking different approaches to topical delivery of minocycline, an antibiotic that has been critical in the treatment of moderate-to-severe acne and rosacea since the 1970s. Minocycline has significant advantages for dermatologists. First, it has both antibacterial and anti-inflammatory properties – a combination that is useful in the treatment of acne and rosacea. Second, it has lower P. acnes resistance rates than other members of the tetracycline class of antibiotics.18
ALTERNATIVE APPROACHES TO TOPICAL FORMULATIONS
BioPharmX Inc. of California has developed a hydrophilic (non oil-based) gel delivery system that fully solubilizes minocycline and leaves no trace of the antibiotic on the skin. Clinical research on BPX-01, a two percent minocycline concentration, found the medication was well-tolerated with a good safety profile and was largely undetectable in the blood stream. Hence, no systemic side effects are anticipated. It also resulted in rapid improvement and better outcomes than vehicle control in the treatment of moderate-to-severe non-nodular inflammatory acne vulgaris.19
This treatment may provide an effective, new option with a favorable safety profile and potential for high patient compliance. Given the variety of adverse effects associated with common acne and rosacea treatments, patients appreciate a therapy that better meets their needs and reduces side effects.20,21 Better efficacy and tolerability profiles improve compliance, which, in turn, leads to improved patient outcomes.
The BPX-01 vehicle contains a number of excipients, including the versatile solvent ethanol, which is miscible with both water and oils and penetrates the skin.22,23 This helps deliver minocycline into the epidermis and pilosebaceous unit. Ethanol is naturally bactericidal, non-bleaching, and is designed to be non-irritating in the BioPharmX formulation. In sufficient concentration, ethanol may have a therapeutic effect in the treatment of P. acnes. BPX-01 vehicle contains ethanol levels above minimum inhibitory concentration (MIC)/minimum bactericidal concentration (MBC) that may be effective in the fight against antibiotic resistance.
Foamix Pharmaceuticals of Israel has developed FMX101, which suspends minocycline in an oil-based foam formulation that has been described as leaving a residue on the skin after application.24 An in vitro porcine skin model found the Foamix product delivered amounts of minocycline into the skin, so as to effectively treat conditions such as acne and rosacea. Researchers also detected minocycline in the pilosebaceous unit, including the hair follicle and the sebaceous gland.
Both of these delivery systems offer the promise of being able to provide similer benefits as oral minocycline, but in a more targeted manner, without systemic exposure or risk of collateral antibiotic resistance.
LIMITED THERAPEUTIC OPTIONS
With the exception of the call-to-arms to be better antibiotic stewards, the medical standard of care for acne has changed little in the last decades and the menu of available treatments has remained much the same.
Many of the therapies have limitations. Benzoyl peroxide is a concentration-dependent irritant that causes stinging, burning, and pruritis in many patients. It also bleaches fabric, much to the dismay of patients and dermatologists. Dermatologists have a concern that it is often the cause of allergic contact dermatitis. Although it rarely does, it has noteworthy limitations. These side effects often reduce compliance with regular benzoyl peroxide use.25 Topical retinoids are also common irritants, especially in the first two weeks of therapy. This, again, may lead to poor compliance.26,27 Other topical therapies such as azelaic acid, dapsone, and salicylic acid tend to be less effective than benzoyl peroxide and retinoids.
Oral medications other than antibiotics, such as isotretinoin and hormonal therapy, can have side
effect profiles that limit use or cannot be used in male patients, although highly effective.27
WHY NEW SOLUTIONS ARE NEEDED
Acne vulgaris is one of the nation’s most common skin diseases and it affects up to 50 million people a year.28,29 While most teenagers suffer from the disease, 37 percent of all acne patients are over the age of 24.30,31,32
Meanwhile, the problem of adult acne appears to be growing. Clinical studies show that 40 to 55 percent of the adult population, ages 20 through 40, is diagnosed with low-grade, persistent acne.33 The Journal of the American Academy of Dermatology reports that 54 percent of women older than age 25 have some facial acne.
The impact can be significant. Up to 20 percent of teenagers experience physical scarring.34 That rate increases in patients of color.26,35 Acne may cause dyschromia, including persistent erythema, and hyperpigmentation.25, 36,37
But perhaps a bigger concern is that acne – even in mild cases – can affect self-esteem.23 Up to 46 percent of people with acne vulgaris have significant psychiatric comorbidities.38 They may experience depression, anxiety, frustration, anger, and isolation. And, many patients do not partake in social, academic, or athletic events because of their acne.39 The psychological scars that are not visible can include damaged self-image, anxiety, depression, and a lowered self-esteem.30, 31, 40,41,42,43
A NEED FOR A SUPERIOR SOLUTION
As a result of the shortcomings in currently available treatments, the field of dermatology is on a quest to find better acne therapies.44 The objective is a treatment option that offers good efficacy, good tolerability, reduced risk of systemic side effects and antibiotic resistance, and an absence of factors or issues that reduce compliance.
Ideally, it would simplify the therapeutic choices available to dermatologists, who, today, must select from a variety of combination therapies that are considered the standard of care for acne. This ideal solution would deliver the following:
No skin irritation
No systemic absorption
Rapid onset of action
Minimal systemic antibiotic resistance
The ability to be applied under makeup
Lack of bleaching or staining
Clearly, a single product that combines all these advantages would be ideal. The new investigational topical antibiotic drugs currently in clinical trials appear to promise compelling advantages over existing treatments.
Dr. Baldwin, a board-certified dermatologist with nearly 25 of years of experience, is medical director of the Acne Treatment and Research Center in Morristown, N.J. Previously, she was associate professor and vice chair of the dermatology department at the State University of New York. She was a founding board member and president of the American Acne and Rosacea Society. She serves on the Medical Advisory Board of BioPharmX Corporation.
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2 Zaenglein, Andrea L., AL Pathy, BJ Schlosser, et al. “Guidelines of care for the management of acne vulgaris.” Journal of the American Academy of Dermatology. 74, no. 5 (2016): 945-
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3 Van der linden, MMD, AR van Ratingen, DC van Rappard, SA Nieuwenburg, and PI Spuls. “DOMINO, doxycycline 40 mg vs. minocycline 100 mg in the treatment of rosacea: a randomized, single-blinded, noninferiority trial, comparing efficacy and safety.” British Journal of Dermatology. 176, no. 6 (2017): 1465-1474.
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