Epidemiology of Rosacea:

Rosacea prevalence in the population as a whole range from 0.09% to 22.41%¹⁴. It is most prevalent in those with fair skin. However, the prevalence of its diagnosis has been rising among Asians, Latin Americans, African-Americans, and Africans. Individuals with rosacea often have a higher concentration of Demodex mites than those without the disorder¹⁵.

Figure 2: Illustrates the distribution of rosacea according to age and sex¹⁶.

Psychological Impact of Rosacea:

People who suffer with rosacea may experience adverse effect on their emotional and mental health

Figure 3: Illustratesthe psychological impact of rosacea on people¹⁷.

Diagnosis:

Since there is no conclusive laboratory test to diagnose rosacea, the condition must be diagnosed through clinical observation and patient history, but it is also required to do a thorough analysis along with the clinical symptoms.

Table 2: Various diagnosis for rosacea^18,19,20

Sr No	Tests	Description
1	Visual Inspection	The doctor will examine the skin areas that you are concerned about closely along with the other areas of your skin. They also carefully inspect your eyes and may recommend an eye doctor for a checkup.
2	Dermoscopy	Is a method that involves attentively inspecting the skin with a specialised magnifying tool. This facilitates the identification of Demodex tails and Demodex follicular openings linked to rosacea.
3	Reflectance confocal microscopy	Doctors use a special microscope called reflectance confocal microscope to examine the affected areas for thinning skin and oedema, cell changes, and microscopic bugs (Demodex mites) to better understand this condition.
4	Computer-aided diagnostic system	This technology provides a visual representation of how blood vessels are distributed on the face as well as a real-time assessment of the severity of the redness (erythema).
5	Other	Ultrasonic spectroscopy Optical coherence tomography infrared imaging

CONVENTIONAL TOPICAL THERAPIES AVAILABLE FOR ROSACEA:

Cream:

Ivermectin 1% cream has been used in order to treat papulopustular rosacea. Ivermectin 1% cream or vehicle was administered once daily for 12 weeks in two identically structured, randomized, double-blind, controlled studies by Linda Stein et al.to individuals with mild to severe PPR in order to measure the drug's effectiveness and safety. In both investigations, more participants in the IVM 1% group hadclear oralmost clear skin (38.4% and 40.1%, respectively, compared to 11.6% and 18.8% for the vehicle.) These benefits began in week four and lasted until week twelve. In contrast to the placebo, a greater percentage of patients receiving ivermectin exhibited no dryness or irritation. Thus, treating papulopustular rosacea with ivermectin 1% cream was successful²¹.

A multicentre, investigator-blind, parallel-group trial was carried out by M.V. Dahl et al. and it was discovered that when used once a day, both the 0.75% and 1.0% Metronidazole creams provide effective and well-tolerated options for therapy for people with mild to severe rosacea²².

The FDA approved the new topical medication Oxymetazoline HCL in January 2017 to treat rosacea, providing a novel therapeutic option for the condition. It is marketed as oxymetazoline hydrochloride 1% cream. Alpha-1 adrenergic receptor agonist oxymetazoline is utilized to treat rosacea patients who have moderate to chronic face erythema. By tightening blood vessels in the afflicted area, Oxymetazoline HCL reduces redness by reducing blood flow and erythema²³. The results of the study by Tanghettiet al.which observed patients having facial erythema using oxymetazoline cream for 29 days, showed that the use of topical oxymetazoline is a safe and effectivechoice when used once daily for those with moderate to severe facial erythema²⁴.

Gel:

Fowler Jr. et al.'s study established the efficacy of 0.5% brimonidine tartrate gel, an α2-adrenergic receptor agonist, in mitigating moderate to severe rosacea-related redness. In a randomized, double-blind, vehicle-controlled trial, participants applied either brimonidine tartrate gel or a blank gel daily for four weeks, followed by a four-week observation period. Results demonstrated significant redness reduction on days 1, 15, and 29, visible within 30 minutes of application, with highly significant p-values (<0.001). Despite a slightly higher incidence of adverse events with the active gel, mostly minor and temporary dermatological issues indicated good tolerance. The study concludes that once-daily use of 0.5% brimonidine tartrate gel is both risk-free and notably effective in rapidly reducing mild to severe rosacea-related redness.²⁵.

The FDA has approved Azelaic acid as a 15% gel for managing mild-to-moderate rosacea. It functions by inhibiting NADPH oxidase activity on neutrophilic cell membranes, hence reducing reactive oxygen species (ROS) activity, and reducing redness (erythema) and inflammatory lesions²⁶.

NOVEL TOPICAL THERAPIES FOR ROSACEA:

The common drawbacks associated with these conventional topical therapies are worsening of erythema, tenuous and transient, skin sensitivity, redness at the site of application, skin rash, skin irritation, burning, increased inflammation and dermatitis. To overcome these adverse effects and to increase the effectiveness of active ingredients novel dosage forms has been developed^27,28.

Foam:

Azelaic Acid foam at a concentration of 15% was compared to a vehicle in a phase 3 randomised, double-blind, vehicle-controlled trial by Zoe Diana Draeloset al. toevaluate its effectiveness and safety in treating individuals with mild to severe PPR. For a duration of 12 weeks, the AzA foam and vehicle were administered morning and night, twice daily. At the end of the treatment, it appears that AzA foam group had a greater IGA success rate (32.0%) than the vehicle group (23.5%), indicating that the newly developed azelaic acid foam can be deemed as an effective and reliable treatment choice for patients with moderate to severe papulopustular rosacea²⁹.

FMX103, a 1.5% Minocycline foam, is a novel topical formulation of Minocycline approved as the first Minocycline product for the management of rosacea. To investigate the safety and pharmacokinetics of FMX103 in people with moderate-to-severe rosacea, Terry et al. carried out an open-label study. In this study twenty participants who met the study's inclusion and exclusion criteria applied approximately two grams of FMX103 1.5% to their entire face once a day for 14 days. Pharmacokinetic (PK) datarevelled that FMX103 1.5%, when used topically once a day did not significantly increase systemic exposure to Minocycline, according to a phase I study. As a result, this study states that application of FMX103 1.5% is a potential topical therapy for rosacea patients³⁰.

Solid-Lipid Microparticles:

KS Dwaipayan et al. formulated Metronidazole-loaded Solid Lipid Microparticles (SLM) in gel form to enhance skin localization. According to the ex-vivo investigation, the gel formulation with 1.25 percent carbomer showed improved drug release capabilities, retaining the maximum MNZ after 24 hours at 2.35±0.05 mg. In comparison to the control formula and other formulas, the outcomes obtained also demonstrated a significant difference (p < 0.05). As a result, this research established a novel strategy of drug delivery for treating rosacea³¹.

Microemulsion:

Microemulsions are potential novel drug delivery systems because they offer advantages such as long shelf life, efficient drug solubilization, and easy preparation and administration.³² Due to the low water solubility and challenges in penetrating the uppermost layer of the skin, known as stratum corneum (SC), microemulsion has been formulated as a highly promising nanocarrier for improving the solubility and skin permeability. Wan Hsuan Hung et al.created an Azelaic acid-loaded oil in watermicroemulsion using a spontaneous emulsion technique. In-vitro permeation studies have shown that microemulsions have the capacity to improve the permeability of azelaic acid due to its submicron-sized droplet decrease the formulation's contact angle with the skin. In-vivo anti-inflammatory test showed that the drug-containing formulation decreased inflammation. Based on the results, the oil in water microemulsion could be a promising drug delivery vehicle for Azelaic acid topical administration³³.

Nano emulsion:

In order to improve drug delivery of Minocycline and increase retention time in the targeted area, Ayesha Siddiqui et al. formulated Minocycline Nano emulgel utilizing aqueous titration method. From ex vivo study total drug amount that permeated after 6 hours from Minocycline nano emulsion and nano emulgel were 75% and 58%, respectively which indicates that the nano emulgel has sustained release pattern and will provide an improved result after an extended duration of skin application. Therefore minocycline-loaded nano emulgel is likely to improve therapeutic outcomes in the treatment of acne rosacea³⁴.

Nano lipid carrier (NLC):

Azelaic acid is difficult to topically administer since it is poorly soluble in water. Nanostructured lipid carriers loaded with Azelaic acid-loaded were developed by Sweety Kumari et al. using solvent diffusion-solvent evaporation method to enhance skin retention as well as reducing adverse effects. Skin retention experiments revealed that the NLCs gel retained azelaic acid at a remarkable 63.964%, while the drug solution and pure drug-loaded gel had much lower retention rates of 4.781% and 15.123%, respectively. The results states that NLC increase the penetration of azelaic acid across the epidermis and could enhance the effectiveness of rosacea management³⁵.

U.A. Shinde et al. formulated Metronidazole-loaded nanostructured lipid carrier to enhance skin deposition as well as retention. The carrier's lipophilic nature, size, and occlusion feature allowed more medicine to enter and be held in the skin while reducing systemic exposure. In terms of minimum inhibitory concentration and zone of inhibition, the formulation also surpassed the commercial formulation significantly. The outcomes of the research show that nanoparticle lipid carriers of anti-rosacea drugs have the ability to manage rosacea effectively³⁶.

Gel forming Spray:

Timolol, is a nonselective β-blocker. Since inflammation is widely acknowledged to be a major contributing element to the development of rosacea, timolol may be able to provide a novel therapeutic approach for the condition. In a split-face study by Jerry Tsai et al. topical timolol gel-forming solution 0.5% was administered twice daily to 8 people with rosacea characterised by flushing and persistent erythema. The participant's faces were treated on one side for 16 weeks, while the other side was untreated for 8 weeks before receiving treatment for 8 weeks. Apart from one incidence of temporary reduced eyelid sensitivity, there were no side effects observed. Importantly, none of the participants showed worsening of their flushing symptoms while receiving treatment, and they all reported improvement from their flushing symptoms after using topical Timolol. These results show that timolol is a safe and efficient treatment for rosacea³⁷.

FUTURE PERSPECTIVES:

Although there are varioustherapies available for the management of rosacea,in comparison to other inflammatory disorders rosacea has limited novel therapies. Scientist are doing research on the finding new therapies for the management of rosace. The findings of these researches could be aneffective approach in treating rosacea.

Targeting Sphingolipid Signalling for innovative therapeutic strategies for rosacea.

Dr. Yoshikazu Uchida and Peter Elias discovered that heat and UV stress on skin cells causes physiological processes that cause the production of a particular substance. The antimicrobial peptide cathelicidin (CAMP), which helps in physical repair but might worsen rosacea symptoms, is one of these compounds. They studied components in the pathway of CAMP production to maintain its advantages and discovered a chemical known as SP1 that is responsible for the higher CAMP formation. A chemical known as C1P was also found by researchers. It leads to the synthesis of protective chemicals that prevent the skin from excessive production CAMP. They observed that inhibiting or altering the metabolic pathway using a medicinal product at this distinct stage might decrease inflammation while increasing skin's natural antimicrobial defence, possibly leading to the creation of novel rosacea treatment³⁸.

Role of mast cells in rosacea:

A study by Dr. Anna DiNardo revealed the function of mast cells in the activation of particular cathelicidin subtypes, innate immune response enzymes that are frequently overproduced in rosacea patients. Dr. DiNardo's team observed that treating mice to the neuropeptide PACAP encouraged mast cells to release enzymes, which resulted in the production of cathelicidin. This chain reaction did not happen in mast cell-deficient animals. Dr. DiNardo's group will examine if cromolyn sodium, a mast cell stabiliser, can reduce rosacea symptoms in their next trial. Additionally, they will determine if tryptase and chromotryptase levels, which are usually high in rosacea clients, return to normal with the use of the mast cell stabilizer³⁹.

Probiotics:

As stated by the FDA, probiotics are living microorganisms that are meant to improve health when consumed or administered topically. Certain microbes like Demodex mites and H. pylori have been associated with rosacea. Topical probiotics may help strengthen the skin barrier directly where applied. A case study by M. C. Fortuna showed combining oral probiotics and doxycycline effectively treated scalp rosacea without side effects. More research on topical probiotics is warranted, as they may provide a safe, effective rosacea treatment option⁴⁰.

The Crucial Role of Beta-Arrestin in Cutaneous Flushing:

Insights from Niacin-Induced Flushing Mechanisms:

In a study, Dr. Robert Walters and and Robert J. Lefkowitz identified the molecular mechanism underlying the flushing brought on by niacin, a vitamin B3 that is usually linked to rosacea. Niacin, which is present in many foods including spinach, avocados, beef liver, yeast, and yeast products, is frequently a cause of flushing in rosacea patients. They discovered that when the GPR109A niacin receptor on cell surfaces is activated, G-proteins as well as beta-arrestin proteins are activated. These receptors are cellular components that respond to specific chemicals and alter the physiological state of nervous tissue. Beta-arrestins were also linked to increased blood flow since it was discovered that they were required for the cPLA2 enzyme's activation, which results in chemicals that directly influence the blood vessels in the skin. Flushing caused by niacin has a chemical mechanism, by studying this mechanism a novel therapy can be developed which may prevent this flushing⁴¹.

CONCLUSION:

Rosacea is a common and relapsing skin condition. It is challenging to treat rosacea due to its unknown etiology. In last 15 years the number of researches on rosacea has been increased. Novel drug delivery system is a combination of new technique, new formulations and new methods for delivering the active pharmaceutical ingredients. The recently developed formulations surpass traditional ones by providing significant benefits. Novel therapies including nano emulsion, microemulsion, solid-lipid microparticles etc has not only enhanced the efficacy of topical agents but also decreased the adverse effects, revolutionizing the options for the treatment of rosacea. Also, scientific investigations will shortly be anticipated corresponding to rising advancement.

CONFLICT OF INTEREST:

The authors have no conflicts of interest in this matter.

ABBREVIATIONS:

IVM: Ivermectin; AzA: Azelaic acid; SLM: solid lipid microparticles; MNZ: Metronidazole; NLC: Nano lipid carrier

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Received on 12.10.2023 Modified on 04.01.2024

Research J. Pharm. and Tech 2024; 17(7):3452-3458.

DOI: 10.52711/0974-360X.2024.00540

Sr no.	Types	Symptoms
1	Erythemato-telangiectatic Rosacea	· Prominent redness, continual redness · Tingling or burning sensations · emergence of visible blood vessels
2	Papulopustular Rosacea	· Recurring papules · Pustules · Raised red patches
3	Phymatous Rosacea	· Enlargement of nose · Skin may swell and thicken
4	Ocular Rosacea	· Painful bumps on eyelids · Formation of chalazia and hordeola

2

Dermoscopy

3

Reflectance confocal microscopy