Rosacea Topical Treatment and Care: From Traditional to New Drug Delivery Systems

Rosacea is a multifactorial chronic inflammatory dermatosis characterized by flushing, nontransient erythema, papules and pustules, telangiectasia, and phymatous alterations accompanied by itching, burning, or stinging, the pathophysiology of which is not yet fully understood. Conventional topical treatments usually show limited efficacy due to the physical barrier property of the skin that hinders skin penetration of the active ingredients, thereby hampering proper drug skin delivery and the respective therapeutic or cosmetic effects. New advances regarding the physiopathological understanding of the disease and the underlying mechanisms suggest the potential of new active ingredients as promising therapeutic and cosmetic approaches to this dermatosis. Additionally, the development of new drug delivery systems for skin delivery, particularly the potential of nanoparticles for the topical treatment and care of rosacea, has been described. Emphasis has been placed on their reduced nanometric size, which contributes to a significant improvement in the attainment of targeted skin drug delivery. In addition to the exposition of the known pathophysiology, epidemiology, diagnosis, and preventive measures, this Review covers the topical approaches used in the control of rosacea, including skin care, cosmetics, and topical therapies, as well as the future perspectives on these strategies.

1.Introduction

Rosacea is a chronic inflammatory dermatosis that affects a small percentage of the world population. Rosacea is considered a chronic skin disorder owing to its prolonged course, periods of exacerbation and remission, and manifestations, including persistent erythema (redness) that resembles sunburn. (1,2) Although rosacea is not considered life-threatening, it still has profound negative psychological and social effects on the quality of life of patients and presents a high likelihood of depression, social phobia, and anxiety. Depending on the morphological features, they can be classified into four major subgroups: erythematotelangiectatic rosacea (ETR) (subtype 1), papulopustular rosacea (PPR) (subtype 2), phymatous rosacea (subtype 3), and ocular rosacea (subtype 4). (3).

ETR rosacea is a subtype that most people are familiar with, and it typically manifests as persistent redness in the central face region, often accompanied by telangiectasia. (4) In turn, PPR rosacea is characterized by a variable number of small domed papules and superficial pustules associated with erythema and edema distributed in a centrofacial pattern. (5) Ocular rosacea presents several nonspecific signs and symptoms, such as eyelid inflammation, photosensitivity, telangiectasias of the eyelid margins, redness of the conjunctiva, tearing, irritation, a sensation of foreign bodies, burning, and stinging; it is often underdiagnosed, and there is no laboratory test for its detection. (5-7) Late diagnosis can compromise vital vision structures, which can lead to visual impairment. (5) Ocular rosacea can be classified into three grades according to the signs and symptoms presented: grade one is characterized by mild itching, dryness, telangiectasia, and palpebral erythema; grade two corresponds to a burning sensation, eyelid with erythema and edema, and chalazion; and grade three corresponds to photosensitivity, blurred vision, corneal changes, severe eyelid changes, loss of eyelashes, and severe inflammation of the conjunctiva. (8) Phymatous rosacea manifests as thickening of the skin with irregular surface contours and nodules as a consequence of several factors, such as fibrosis, sebaceous hyperplasia, and lymphedema. (6) This condition primarily affects the nose (rhinophyma) but can also affect any facial region that has sebum secretion, such as the chin (gnatophyma), forehead (metophyma), eyelids (blepharophyma), and ears (otophyma). (6) In dermatologists’ everyday clinical practice, patients may morphologically manifest either one rosacea subtype or a combination of rosacea subtypes and complain of increased sensitivity of facial skin followed by burning, stinging, pain, or pruritus. (2,9)

Considering the plethora of overlapping morphological presentations, several unanswered questions related to rosacea physiopathology remain. (10) Generally, it is known that inflammatory and vascular effects characteristic of rosacea result from an exacerbated innate immune response and aberrant neurovascular signaling triggered by numerous environmental stimuli and endogenous factors based on a certain genetic background. (7) On the other hand, as in acne, skin microbiome alterations may be related to the likely pathogenesis of rosacea by instigating or propagating the exacerbated immune response. (11)

The management of rosacea remains a challenge to dermatologists. Treatment options for rosacea may include skin care, systemic or topical therapies, laser- and light-based therapies, invasive methods (e.g., microneedling), and several combinations of these options. (12) The only Food and Drug Administration (FDA)-approved oral drug is 40 mg modified-release doxycycline once daily for the treatment of inflammatory lesions of PPR. (13) However, off-label use of numerous drugs is common in the treatment of rosacea. (10) Oral azithromycin has been used as a therapeutic alternative in patients who present with PPR rosacea and who cannot be prescribed tetracycline. (10) Minocycline and clarithromycin are two antibiotics that are also commonly prescribed for this condition. (14) Additionally, drugs from other therapeutic classes have been used to control PPR symptoms (e.g., erythema and flushing with papules and pustules), such as oral contraceptives, amitriptyline, clonidine, pimozide, aspirin, β-blockers, ondansetron, and COX-2 inhibitors. (15) Highly severe cases of PPR require the prescription of oral isotretinoin. (13) Other drugs, such as ketoconazole and prednisolone, have also been prescribed for this condition. (10) However, oral therapy is related to systemic side effects, and bacterial resistance is one of the main concerns associated with the oral administration of antibiotics. (16)

Topical therapy is often an alternative to oral therapy, since it allows local action related to fewer side effects and simultaneously provides greater ease and convenience of application. (17) FDA-approved topical therapies consists of metronidazole (MTZ) 0.25%, 0.75%, and 1% cream, gel, and lotion; azelaic acid (AZA) 15% gel; sodium sulfacetamide 10%; sulfur 5%; and sodium sulfate 10%. In addition, these other formulations are also used as off-label therapies: topical brimonidine 0.33% gel, 1% oxymetazoline cream, 1% ivermectin cream, calcineurin inhibitors such as 0.1% tacrolimus and 1% pimecrolimus cream, topical retinoids, and 5% permethrin. (17) These topical formulations have low therapeutic efficacy, which is related to the low permeation of the formulation on the skin. (18) To overcome this limitation, nanoparticles have been widely studied since, due to their reduced size and character, they manage to have higher skin permeation rates and, consequently, greater therapeutic efficacy because a greater amount of drug is available in the site of action. (18) These new drug delivery systems have enormous potential in formulations for topical applications since, as the skin is an impenetrable physical barrier to most substances, developing products that can overcome this barrier is an extremely important step for dermatoses. (18) In the specific case of rosacea, studies carried out using these new drug delivery systems have revealed the promising role they will have in the therapeutic arsenal for the management of chronic inflammatory dermatoses, as these formulations present greater permeation in the skin because their reduced size allows penetration occurs through intracellular and extracellular transport and they have greater cutaneous retention, which in turn reduces the frequency of application of the formulation. (18)

Moreover, skin care plays a vital role in the management of rosacea. (19) Patients should cleanse the skin morning and evening using gentle cleansing products with a neutral or slightly alkaline pH, preferably syndets, to avoid damaging the skin barrier, preparing the skin for the application of an extremely important moisturizer on this sensitive skin. (19,20) Considering that the sun is a triggering factor, the application of sunscreen with a sun protection factor (SPF) of 30 or greater containing ultraviolet (UV) B and UVA protection is crucial to avoid possible exacerbation and worsening of the disease. (21) In addition to these cosmetics, corrective cosmetics to camouflage redness can also be used to minimize the negative psychological effects that the characteristic facial appearance of rosacea has on these patients. (22)

Currently, the effects of probiotics on rosacea management have been studied, since they are associated with an alteration in the skin microbiome. (23) In addition, studies are currently being carried out to assess the possible benefits of siRNA- and TNF-α-based therapies in the treatment of rosacea. Concerning the diagnosis of rosacea, new techniques have been studied to obtain an early stage diagnosis of rosacea and assess the involvement of the deeper layers of the skin. (24)

It should be noted that patient lifestyle management plays a vital role in rosacea treatment. (25) Therefore, patients should be aware of the factors that can exacerbate and/or trigger characteristic signs and symptoms of rosacea to avoid them. (26) For instance, in the current context of the COVID-19 pandemic, instruction regarding the choice of personal protective masks and daily cosmetic skin care is essential, since individual protection measures have a high potential not only to intensify preexisting dermatological conditions but also to initiate new pathological processes.(27)

Overall, the treatment of rosacea must be personalized based on its subtypes, dermatosis severity, quality of life implications, comorbidities, trigger factors, and treatment compliance. (28) The present paper intends to address recent literature describing the following aspects of rosacea: pathophysiology, epidemiology, diagnostic methods, available topical care and therapies, and innovative treatments.

Download the full article as PDF here: Rosacea Topical Treatment and Care: From Traditional to New Drug Delivery Systems

or read it here

Excipients mentioned in the paper: Labrafil M1944CS , Cremophor EL, Tween 80 , Kolliphor RH 40, Carbopol 974P, chitosan, Labrasol, Transcutol P, Labrafac lipophile, soybean oil

Ana Cláudia Paiva-Santos, Tatiana Gonçalves, Diana Peixoto, Patrícia C. Pires, K. Velsankar, Niraj Kumar Jha, Vivek P. Chavda, Imran Shair Mohammad, Letícia Caramori Cefali, Priscila Gava Mazzola, Filipa Mascarenhas-Melo, and Francisco Veiga. Rosacea Topical Treatment and Care: From Traditional to New Drug Delivery Systems. Molecular Pharmaceutics Article ASAP
https://doi.org/10.1021/acs.molpharmaceut.3c00324