Botanical-Based Polyherbal Gels for Acne Treatment: A Critical Review of Formulation and Evaluation Parameters

Abstract

A prevalent skin ailment that affects many people worldwide is acne vulgaris. Although there are numerous therapy options available, many of them have unfavorable side effects or don't work for everyone. Recently, polyherbal gels have become more popular as an all-natural and successful acne vulgaris therapy. These gels are composed of a variety of herbal extracts that complement one another to address the root causes of acne. The current research on the effectiveness and safety of polyherbal gels for acne vulgaris is summarized in this review article. The article describes the several ways in which these gels work, such as their anti-inflammatory, antibacterial, and antioxidant qualities, which can successfully regulate the elements that lead to the development of acne.The plant extracts' phytochemical makeup was identified. The microbroth dilution technique was used to determine the minimum inhibitory concentration (MIC) of the extracts and gels. The formed gels' physicochemical characteristics, including their homogeneity, color, texture, odor, grittiness, spreadability, extrudability, viscosity, pH, and drug content, were assessed. Alkaloids, flavonoids, tannins, triterpenoids, and coumarins were present in every plant extract. The gel formulations exhibited differing levels of effectiveness against Pseudomonas, Candida albicans, Escherichia coli, Staphylococcus aureus, and Staphylococcus epidermidis. An inflammatory skin disorder caused by the immune system is acne vulgaris. It affects more than 80% of teens worldwide and is the eighth most common skin disorder. The disease's complex pathophysiology includes the interplay of several variables, including dysbiosis of microbiota, aberrant hyperkeratinization of pilosebaceous follicles, hyperactivation of sebaceous glands, and immune-mediated inflammation. A mix of various anti-acne medications is recommended due to the disorder's complexity. To sum up, this revised review offers a thorough overview of acne, including its pathophysiology, existing treatment approaches, and new treatments. Recognizing the complex nature of acne and keeping up with developments in its treatment will assist medical professionals in treating patients with this frequent dermatological problem in an efficient and customized manner

Keywords

Introduction

 

 

Acne Vulgaris:- Acne vulgaris is the medical name for common acne -- the presence of blackheads, whiteheads, and other types of pimples on the skin. The most common spots for breakouts are the face, chest, shoulders, and back. Although mild acne may improve with over-the-counter treatments, more severe forms should be treated by a dermatologist. [10]

Comedones:- A comedo, or basic acne lesion, is a hair follicle that has become clogged with oil and dead skin cells. Comedones (the plural of comedo) can develop into bumps called whiteheads and blackheads. Products that may trigger comedones are called "comedogenic." Makeup labeled "noncomedogenic" is less likely to clog pores and contribute to acne. [11]

Blackheads:- Blackheads are comedones that are open at the surface of the skin. They are filled with excess oil and dead skin cells. It's not dirt that causes the comedone to turn black. The black hue results from the irregular reflection of light coming from clogged hair follicles. Blackheads can frequently be treated with over-the-counter medications. [12]

Whiteheads:- Comedones that stay closed at the surface of the skin are called whiteheads. This happens when oil and skin cells prevent a clogged hair follicle from opening. Many of the same over-the-counter medicines that treat blackheads are also effective against whiteheads.[13]

Papules:- Papules are comedones that become inflamed, forming small red or pink bumps on the skin. This type of pimple may be sensitive to the touch. Picking or squeezing can make the inflammation worse and may lead to scarring. A large number of papules may indicate moderate to severe acne. [14]

Pustules:- Pustules are another kind of inflamed pimple. They resemble a whitehead with a red ring around the bump. The bump is typically filled with white or yellow pus. Avoid picking or squeezing pustules. Picking can cause scars or dark spots to develop on the skin.[15]

Nodules:- Nodules are large, inflamed bumps that feel firm to the touch. They develop deep within the skin and are often painful. Nodules should be treated by a dermatologist since they can scar. Over-the-counter treatments may not be powerful enough to clear them up, but prescription drugs can be effective. [16]

Cysts:- Cysts are large, pus-filled lesions that look similar to boils. Like nodules, cysts can be painful and should be treated by a dermatologist since they also can scar. People who develop nodules and cysts are usually considered to have a more severe form of acne.[17]

0. Pathophysiology of acne:

 Acne vulgaris is an inflammatory condition affecting the pilosebaceous gland [16]. At first the acne forms invis ible micro comedones, then become clinically visible whitehead or blackhead (comedones) that progress into inflammatory red papules or pustules which possibly covered with either atrophic or hypertrophic scars nodules. Moreover, Acne can create cysts, nodules, and subcutaneous fistulas that are difficulty treated. Commonly, acne is noticed on the face, neck, chest, and upper back, where sebaceous follicles present. Acne primarily develops due to enhancement sebum production, increased keratinocyte growth, and reduced shedding of these cells within the pilosebaceous unit. Combination of sebum and keratinocytes lead to forma tion of keratotic plug and blocks the pilosebaceous ducts, f inally producing microcomedones.[18] The primary patho logical processes in sebocytes are hyperseborrhea and dysseborrhea. Hyperseborrhea is an abnormal increase in sebum quantity, while dysseborrhea refers to changes in sebum composition. These changes promote C. acnes overgrowth and biofilm formation, trigger inflammation, disrupt the follicular barrier, and lead to comedone for mation . Androgens was found to enhance the formation and production of lipids as well as the differentiation of sebocytes.[19] When androgens bind to androgen receptors (AR) located in the cell nucleus, mTOR phosphorylation increases. Studies have shown that mTOR expression in both the cytoplasm and nucleus is higher in inflamma tory sebaceous glands within acne lesions compared to non-lesional skin. mTOR serves as the catalytic core of mTORC1, which stimulates lipogenesis by activating sterol regulatory element-binding protein-1 (SREBP-1). Moreover, Androgen negatively regulated endogenous Wnt/β-catenin signaling pathway. Consequently, target genes of Wnt/β-catenin, like c-MYC, are upregulated, promoting sebocyte differentiation. Differentiating sebo cytes show high levels of nuclear androgen receptors (AR) and peroxisome proliferator-activated receptors (PPARs). [20] Throughout this process, lipids gradually build up until sebocytes are fully differentiated, at which point they release their contents into the sebaceous duct through holocrine secretion. Additionally, insuline growth factor (IGF-1) signaling has the principal role in acne pathogenesis. A significant hyperandrogenism and acne formation were recorded in Laron patients, who are treated with high-dose IGF-1. Conversely, individuals not exposed to excessive IGF-1 treatment never develop acne. Furthermore, Insulin and IGF-1 enhance the PI3K/Akt pathway, which stimu lates forkhead box protein O1 (FoxO1) nuclear export. FoxO1 is a key factor in the pathogenesis of acne. It hid ers lipogenesis by both antagonizing the expression of SREBP-1c and restraining the transactivation of andro gen receptors (AR). Further, FoxO1 activates of adenosine 5′-monophosphate-activated protein kinase (AMPK) pathway , which is a negatively regula tor of mTORC1. Hence, insulin and IGF-1 increase lipid synthesis by mediating the attenuation of FoxO1 inhibition. Concerning immunological and bacterial aspects, in early lesion the infiltration of CD4 around the follicles was recorded. Inside the microcomedone, mac rophages, CD3, and CD4 cells are also detected as well as activation of vascular adhesion molecules such as E-selectin and integrin [21-22]. Moreover, IL-17, IL-23, and TNFα are significantly upgraded in acne lesions [23]. Although C. acnes is a normal flora in skin, C. acnes is primary included in the pathogenesis of acne. infundibular keratinocytes, sebocytes, and Langerhans cells in the intrafollicular ducts through activation of Toll-like receptor 2 (TLR2). [24]This cascade causing exces sive production of TNFα, IL-12, IL-8, IL-6, and IFNγ. In addition, Th1 cells are predominantly observed in acne follicles. Also, C. acnes was found to enhance the production of activator protein 1 (AP1) and nuclear factor (NF)-κB, resulting in activation of IL-1β, IL-8, and matrix metalloproteinases (MMPs) [33]. Consequently, MMPs stimulate the degradation and fragmentation of collagen, and TNFα, IL-1β, IL-8, and MMP trigger neu trophils, causing rupture of hair follicles and massive inflammation.[25]

0. Current drugs and drawbacks:

Topical treatments, including washes, gels, lotions, and creams, are the most common used therapies for acne vulgaris. These treatments often consist of antibiotics, antibacterial agents and retinoids. In contrast, systemic treatments are generally reserved for more severe or resistant cases and include oral isotretinoin, oral antibi otics, and hormonal therapies such as spironolactone and oral contraceptive. When selecting topical agents, factors such the age of the patient, the severity and location of the acne, the effectiveness and safety of the medication, cost, and patient preferences should be considered. Most patients f ind that a combination of treatments is most effective. [26-27]

Individuals with dry skin usually prefer lotions or creams, whereas those with oily skin tend to choose gels. Topical retinoids, including tretinoin, tazarotene, adapalene, and trifarotene, are the preferred choice for managing mild-to-moderate acne. These vitamin A derivatives work by inhibiting the proliferation of skin cells, which helps prevent clogged pores and the forma tion of microcomedones. They also possess anti-inflam matory properties and are effective against various acne lesions . Common side effects include skin dryness, f laking, redness, and irritation, and some patients may experience an initial exacerbation of acne referred to as"retinoid flare". [28-29]

Retinoids are typically applied once daily at night, and patients are advised to use sunscreen due to potential photosensitivity. Tazarotene is catego rized as a pregnancy category X medication and should not be used during pregnancy. Topical retinoids can be utilized either on their own or in conjunction with other treatments such as benzoyl peroxide or antibiotics.  Zinc is an essential micronutrient recognized for its therapeutic benefits in treating acne vulgaris. Research indicates that individuals with acne often have lower zinc levels compared to those without the condition.[30-31] Zinc enhances immune response by improving the function of macrophages and neutrophils, stimulating natural killer cells, and activating the complement system. It also helps regulate inflammation by inhibiting pro-inflammatory cytokines and reducing inflammatory mediators. [32]

Additionally, Zinc directly inhibits the growth of Propionibac terium acnes, the bacterium linked to acne and blocks the activity of 5α-reductase. This action prevents the conver sion of testosterone to dihydrotestosterone (DHT), which stimulates sebaceous gland activity and contributes to the formation of acne. Benzoyl peroxide (BPO) is highlighted as an effec tive non-antibiotic treatment due to its strong bacteri cidal properties and minimal risk of developing bacterial resistance.[33] It acts quickly to kill acne-causing bacteria, reduce inflammation, and has mild keratolytic effects. BPO can be utilized on its own or alongside retinoids or antibiotics, and it is considered safe for use during preg nancy.[34] Common side effects of BPO involve the dryness of skin, peeling, and irritation, although these usually decrease with continued use. To reduce these side effects and enhance patient compliance, it is advisable to begin with lower concentrations. Guidelines recommend using BPO in combination with a topical retinoid as a f irst-line treatment for inflammatory acne, and alongside topical clindamycin for mild-to-moderate cases. Overall, while BPO is an effective treatment, it is important to consider potential side effects to ensure patient comfort and adherence to the treatment plan . Topical antibiotics are effective in treating acne due to their anti-inflammatory properties and ability to be either bactericidal or bacteriostatic.[35]

They have lower sys temic toxicity compared to oral antibiotics but should not be used as monotherapy to avoid bacterial resistance. Combining them with topical retinoids or benzoyl perox ide improves treatment outcomes and reduces the risk of resistant strains of C. acnes. Azelaic acid is a naturally occurring substance known for its antibacterial, anti-inflammatory, and antioxidant effects, which makes it effective in treating acne vulgaris and post-inflammatory hyperpigmentation. It is offered in gel formulations of 15% and 20% and is deemed safe for use during pregnancy and breastfeeding.[36] Common side effects may include mild local reactions such as red ness, dryness, burning, stinging, itching, and possible hypopigmentation, especially in those with darker skin tones.

Notably, there have been no documented cases of bacterial resistance linked to azelaic acid. Superficial chemical peels, which may contain lactic acid, salicylic acid, or glycolic acid, are also used to treat acne. These peels can cause skin irritation and should be selected based on the patient’s specific acne severity and skin type. Clascoterone, a topical androgen receptor inhibitor approved by the FDA in 2020, is effective for both non inflammatory and inflammatory acne. While it is gen erally well-tolerated, potential side effects include skin irritation and concerns regarding hypothalamic–pitui tary–adrenal axis suppression due to its rapid metabolism.[37]

0. TYPES OF BACTERIA CAUSING ACNE

• Propionibacterium acnes:-

P. acnes, an opportunistic pathogen that plays an important role in the progression of inflammatory acne vulgaris, are ubiquitously present within the sebaceous follicles of the human skin. These acne-causing bacteria are usually gram positive, nonmotile, fat splitting microorganisms, having the ability to grow under different oxygen tensions. Being an exclusive occupant of the follicular canal, when clogging of hair follicle happens the bacterium aids in the rupturing of the follicular walls, using their secretory enzymes with degradative properties. These bacterium also target other skin cells, namely, keratinocytes and phagocytic cells like macrophages, stimulating the cells to produce proinflammatory cytokines, including interleukin (IL)-1β, IL-8, IL-12, and tumor necrosis factor-α, leading in the inflammatory acne disease. The genomic information clearly highlights that the products of the P. acnes have a major impact on the acne process, but not the invasiveness of the organism.[38]

• Staphylococcus Aureus:- 

S. aureus, the most prominent member of the skin microbiota, plays a role as a pathogen in many skin infections such as folliculitis and impetigo and their co-existence with other microbes in acne lesions has been reported. In order for the pathogen to invade the host cell, it produces extracellular matrix and serum binding proteins such as adhesins [surface protein (SasG)] and the fibronectin binding proteins FnBP-A and FnBP-B. These factors help in their internalization into the host cells by connecting them to the cellular integrins. Once it invades the human skin as a pathogen, it starts producing several extracellular enzymes such as proteases, lipases (geh1), hyaluronidases, and collagenase, that aid in tissue damage and thus helps the pathogen to spread into the deeper tissues.Further, in their pathogenic life cycle, they are known for their production of exfoliative toxins, such as enterotoxins A–E, toxic shock syndrome toxin-1, Panton–Valentine leucocidin, leukocidin E D, S. aureus exotoxin, and cytotoxins such as α-, β-, γ- hemolysins.[39]

• Staphylococcus epidermidis:-

S. epidermidis is a facultative anaerobe of cutaneous microbiota harbored in acne lesions. These microbes which are nonpathogenic resident flora of the human skin at some point of life turns into an infectious agent due to extrinsic factors like an immune system deficiency. The first and foremost virulence factor produced by this organism is fatty acid modifying enzyme which esterifies the fatty acids in the skin to cholesterol, as fatty acids are bactericidal for the organism to survive. The bacterium possesses several adhesion factors for its attachment to the skin surface, like surface anchored proteins, fibrinogen binding protein, autolysin protein, PIA, and poly-N-succinyl glucosamine, helping as a probable attachment factor.[40]

• Staphylococcus pyogenes:-

S. pyogenes, inhabiting skin surfaces, are β-hemolytic and catalase negative in nature and are found to be inhibited by the free fatty acids released by P. acnes, which breaks the host cell. The pathogenicity is due to the expression of an array of virulence factors by the microbes.[41]

• Streptococcus agalactiae:-

Like other microorganisms, S. agalactiae is also found on the surface of the human skin which causes prominent diseases such as septicemia, pneumonia, etc. Two major virulence factors, namely pore-forming toxins and the capsular polysaccharides, will be discussed here in the mechanism of pathogenesis. Pore-forming toxins such as β-hemolysin/cytolysin and CAMP factor are produced during their pathogenic lifecycle, which mediates their entry into the host cells like epithelial and endothelial cells.[42]

• Klebsiellapneumoniae:-

K. pneumoniae is a gram-negative bacterium found on the skin flora and that causes infections in acne patients undergoing long-term antibiotic therapy. Exhibiting various virulence factors such as capsular polysaccharides, adhesins, siderophores, etc., these virulence factors are responsible for producing papules and pustules in acne patients, called as gram-negative folliculitis.[43]

6.0. Some common methods for preparing polyherbal gel include [44-46]

1. Hot infusion method: In this method, the herbs are steeped in hot water or oil to extract their active compounds. The resulting infusion is then mixed with a base material such as glycerin or aloe vera gel to create the gel.

2. Cold infusion method: This method is similar to the hot infusion method, but the herbs are steeped in cold water or oil instead. This method is often used for more delicate herbs that may be damaged by heat.

3. Decoction method: This involves simmering the herbs in water to extract their active compounds. The resulting liquid is then strained and mixed with a base material to create the gel.

4. Emulsification method: In this method, the herbal extracts are mixed with a base material and an emulsifying agent to create a stable emulsion. This method is often used for polyherbal gels that contain oils or other ingredients that are not water-soluble.

5. Micronization method: In this method, the herbs are ground into a fine powder, and the powder is then mixed with a base material to create the gel. This method is often used for herbs that are difficult to extract using traditional methods.

6. Alcohol extraction method: In this method, the herbs are soaked in alcohol to extract their active compounds. The resulting extract is then concentrated and mixed with a base material to create the gel.

7.0. Antibiotic resistance and acne:

 Concerns regarding the effects of oral antibiotics on anti microbial resistance have led to a move towards alterna tive treatments for acne. The 2016 European guidelines recommend the use of topical antibiotics in fixed-dose combinations for different types of acne vulgaris, with the exception of comedonal acne. Meanwhile, systemic antibiotics such as doxycycline and lymecycline are rec ommended for all forms of acne except for comedonal. The 2021 NICE guidelines further endorse topical clindamycin as a primary treatment for mild to severe acne and in combination with oral treatments for more severe cases .[47] A significant study conducted in the UK from 2004 to 2019 found that 45% of 217,410 acne patients were pre scribed long-term oral antibiotics (28 days or more), with tetracyclines making up 80% of initial prescriptions.

Alarmingly, 66% of these patients exhibited antibiotic resistant Propionibacterium, with dermatologists seeing a higher prevalence of resistance compared to other phy sicians. Short-term antibiotic use has also been shown to disrupt skin microbiota, leading to a decrease in benefi cial species and an increase in potentially harmful ones . [48]

A randomized trial indicated that using a 2% erythro mycin gel for 12 weeks resulted in increased resistance among coagulase-negative staphylococci, persisting for up to 24 weeks post-treatment. Additionally, antibiotic use for acne is associated with a higher risk of upper respiratory tract infections, with a UK cohort study reveal ing that patients on antibiotics had a 2.15 times greater likelihood of developing such infections within the first year compared to those who did not use antibiotics. Overall, while antibiotics remain a key component in acne management, their long-term use raises significant concerns regarding resistance and broader health implications.[49-50]

Microorganisms (challenges) The role of Staphylococcus species in the development of acne In an experiment to explore how dysbiosis between C. acnes and S. epidermidis affects skin inflammation. Dif ferent bacterial ratios were cultured favoring either C. acnes, S. epidermidis, or a neutral 1:1 ratio, using human skin explants. Their findings revealed that an imbalance favoring either bacterium resulted in increased inflam mation compared to the neutral state. Specifically, S. epi dermidis was shown to significantly elevate IL-6 levels, a pro-inflammatory marker linked to innate immunity.[51]

In another study, researchers identified a strain of Staphylococcus capitis (S. capitis E12) that effectively inhibited the growth of C. acnes, demonstrating greater potency than traditional antibiotics. This strain produced phenol-soluble modulins, which acted as antimicrobial peptides specifically targeting C. acnes on pig skin and mice, while preserving other beneficial skin bacteria. Additionally, certain strains of skin commensal coag ulase-negative staphylococci (CoNS) are capable of pro ducing bacteriocins that specifically target and inhibit pathogenic bacteria like S. aureus, group A streptococci, and Escherichia coli on the skin. The role of Cutibacterium acnes in the development of acne.[52]

C. acnes is a Gram-positive, non-spore-forming, anaero bic bacillus that naturally resides on human skin, espe cially in hair follicles. While it is a normal part of the skin’s microbiota, it is also linked to acne, a chronic inflammatory skin disorder. Studies indicate that C. acnes plays a role in local inflammation by stimu lating the release of pro-inflammatory cytokines such as TNFα, IL-6, IL-8, and IL-12 via Toll-like receptor 2 (TLR2) pathways. It also activates the NLRP3 inflamma some in human monocytes, which leads to heightened production of IL-1β. This bacterium promotes Th17/Th1 immune responses, resulting in the secretion of IL-17A and interferon-γ, which further exacerbate inflammation.[5]

C. acnes influences keratinocyte differentiation and regulates sebum production, potentially worsening acne. It has been found to induce reactive adipogenesis in der mal fibroblasts, which may play a role in the development of acne lesions. T he bacterium is classified into six phylotypes, with certain"acnegenic"types linked to more severe acne. Notably, patients with severe inflammatory acne often show reduced phylotype diversity, particularly an increase in phylotype IA1.

However, some research indi cates that phylotype diversity may not significantly differ between mild and severe cases, and variations in phylo type prevalence can occur geographically. The idea of dysbiosis, or an imbalance in microbial populations, is significant in understanding acne sever ity. C. acnes competes in the follicular environment by producing substances like bacteriocins and propionic acid, which can influence its interactions with other skin microbes.[54]

While C. acnes is a natural component of the skin microbiome, its overgrowth or dysbiosis can trigger inflammatory responses that lead to acne. Treatments aimed at C. acnes, such as antibiotics or topical medi cations, may have side effects, including skin irritation, antibiotic resistance, and disruption of the normal skin microbiota. This disruption can result in secondary infec tions or worsen existing skin conditions. Therefore, a bal anced approach to acne management, which considers both the function of C. acnes and the overall skin micro biome, is crucial for effective treatment and minimizing adverse effects.

8.0. Bioactive compounds in plants as antiacne drugs:

Acne vulgaris is a common skin condition that affects a significant portion of the population, particularly ado lescents and young adults. The pathogenesis of acne involves multiple factors, including bacterial coloniza tion, inflammation, and hormonal changes. Traditional treatments often include antibiotics and retinoids, but these can have side effects and lead to antibiotic resist ance. As a result, there is growing interest in the use of bioactive compounds from plants as alternative or com plementary treatments for acne. Bioactive compounds from plants offer a promising alternative to conventional acne treatments. Their antibacterial, antioxi dant, anti-inflammatory, keratolytic, and sebum-reduc ing properties can effectively manage acne symptoms with fewer side effects.[55] However, further clinical studies are needed to fully establish their efficacy and safety pro f iles. In dermatology, organic acids derived from natural sources are commonly employed as keratolytics. Among the most promising phytochemicals for acne treatment are terpenes, terpenoids, flavonoids, alkaloids, phenolic compounds, saponins, tannins, and essential oils. Vari ous plant materials such as leaves, bark, roots, rhizomes, seeds, and fruits can be utilized to extract these beneficial compounds. Additionally, bioactive substances derived from seaweed may offer potential therapeutic applica tions for acne management. The subsequent section will explore the diverse phytochemicals that can be leveraged in the treatment of acne. [56]

Organic acids:

Organic acids are pivotal in the treatment of acne due to their keratolytic properties, which facilitate the exfo liation of dead skin cells and prevent clogged pores. Key compounds in this class include acetic acid , gly colic acid, citric acid, salicylic acid , and azelaic acid. Salicylic acid, in particular, is renowned for its ability to penetrate the skin and dis solve debris within pores, thereby reducing inflamma tion and bacterial growth. Azelaic acid also exhibits antimicrobial and anti-inflammatory effects, making it effective in treating both inflammatory and non-inflammatory acne lesions. These organic acids not only enhance skin texture but also contribute to a clearer complexion by addressing multiple factors involved in acne pathogenesis. [57]

• Terpenoids:

 Terpenoids are a diverse group of compounds known for their extensive therapeutic proper ties, particularly in dermatology. Notable terpe noids with anti-acne potential include carvacrol ,  α-pinene,  β-pinene,  limonene, and γ-terpinene. These compounds exhibit signifi cant antimicrobial activity against P. acnes, the bacterium primarily responsible for acne development. Addition ally, terpenoids such as linalool and α-terpineol possess anti-inflammatory properties that can mitigate the red ness and swelling associated with acne lesions. Other terpenoids like lupeol and ursolic acid further enhance skin health by promoting healing and reduc ing sebum production . The multifaceted actions of these terpenoids make them valuable candidates for inclusion in acne treatment formulations. [58]

• Alkaloids:

Alkaloids represent another class of bioactive compounds with notable efficacy against acne vulgaris. Among them, berberine stands out due to its potent antimicro bial properties, which can effectively inhibit the growth of acne-causing bacteria. Alkaloids have been shown to modulate various biological pathways that contribute to inflammation and sebum production, thereby addressing multiple aspects of acne pathology. Their incorporation into topical formulations may provide synergistic benefits when combined with other therapeutic agents, enhanc ing overall treatment outcomes [59].

• Saponins:

 Saponins are glycoside compounds recognized for their diverse biological activities, including anti-inflamma tory and antimicrobial effects. Prominent saponins such as madecassoside, mukurozisaponin E1, and glycyrrhizin  have demonstrated signifi cant potential in managing acne vulgaris. Madecassoside, derived from Centella asiatica, is particularly effective in reducing inflammation and promoting wound healing. T he ability of saponins to modulate immune responses further supports their role in alleviating acne symptoms while promoting skin health [60].

• Phenolic compounds:

Phenolic compounds are characterized by their antioxi dant properties and ability to combat oxidative stress, which is implicated in acne development. Key phenolic compounds such as ellagic acid, resveratrol, and curcumin exhibit strong anti-inflammatory effects that can help reduce the severity of acne lesions. Additionally, compounds like epigallocatechin-3-gal late (EGCG) from green tea have been shown to inhibit P. acnes growth while providing protective effects against UV-induced skin damage. The integration of these phe nolic compounds into skincare products may enhance their efficacy in treating acne while improving overall skin health [61].

• Flavonoids:

Flavonoids are a diverse group of polyphenolic com pounds known for their anti-inflammatory and anti oxidant properties. Flavonoids derived from plants such as Artocarpus hirsutus and Kaempferia pandurata have shown promise in managing acne due to their ability to modulate inflammatory pathways and inhibit bacterial growth. Notably, licochalcone A has demonstrated significant antibacterial activity against C. acnes, making it a valuable component in acne treatment formulations. The incorporation of flavonoids into topical applica tions can enhance therapeutic efficacy while minimizing adverse effects associated with conventional treatments [62].

• Tannins:

Tannins are polyphenolic compounds recognized for their astringent properties, which can help reduce excess oil production on the skin’s surface. Compounds like terchebulin and chebulagic acid have demonstrated antimicrobial activity against skin pathogens, contrib uting to their effectiveness in treating acne vulgaris. Tannins can also promote wound healing and reduce inflammation, making them beneficial for individuals with active lesions or post-acne scars [63].

CONCLUSION

For the development of innovative treatments, plants are regarded as a significant source of potentially advantageous ingredients because the vast majority of them are safe and have little to no side effects. (s). As comparison to cream and ointment, topical administration of gels at pathological locations offers substantial advantages in a faster release of a medicine directly to the site of action. This study indicated that all herbal ingredients have different chemical constituents and shows presence of antimicrobial activity.Acne remains as a challenging dermatological condition due to its multifactorial etiology and often required mul tifaceted treatment approaches. While both topical and systematic treatments for acne are widely available, each is associated with distinct limitation and potential risks. Dryness and irritation are side effects of topical retinoids that may discourage regular use. Because oral isotretinoin has teratogenic potential, it must be regularly monitored and safety protocols must be followed. The development of resistant bacterial strains and decreased efficacy are global concerns brought on by the overuse of antibiot ics. Many people seek alternative therapy since hormo nal medicines include hazards, such as the possibility of prenatal abnormalities and embolic events. So, our study of existing literature and recent studies sheds light on the promising potential of phytochemical and herbal formu lations in acne treatment such as; Tea tree oil, Curcuma longa, and Azadirachta indica. These herbal formulations can be incorporated into diverse topical application as creams, gels, or even as part of a skincare routine. Addi tionally, it has been demonstrated that several presented plants have anti-inflammatory, antiseptic, antibacterial activities and have the ability to reduce acne symptoms through different mechanisms that may be attributed to bioactive compounds; flavonoids and phenolics that are prevalent in the most studied plants. Further transla tional research and clinical studies supporting the use of herbal medicines and specially their formulation to treat acne should be assessed. These studies should include optimal dosage form, long-term safety, and mechanism of action particularly in the case of herbal combination remedies

REFERENCES

1. Kedia, S., Jain, S., & Jain, R. (2016). A review on herbal antidermatophytic formulations. International Journal of Pharmaceutical Sciences and Research, 7(6): 2340-2354.
2. Tiwari, V., Darmani, N. A., Ahmad, M., & Haque, S. (2017). Polyherbal formulation: concept of ayurveda. Journal of traditional and complementary medicine, 7(2): 234-244.
3. A Review of Epidemiology, Pathogenesis, and Treatment" by James Q. Del Rosso and Leon H. Kircik, published in The Journal of Drugs in Dermatology in, 2013; PMID: 23377320.
4. Microbial Strains in Acne Vulgaris: New Insights for Improved Therapy" by Christos C. Zouboulis, published in Dermatology in, 2009; PMID: 19752542.
5. Jain, A., Basal, E., & Inamdar, S. (2011). Clinical evaluation of polyherbal formulation in the management of acne vulgaris. International Journal of Ayurveda Research, 2(1): 22-26. doi: 10.4103/0974-7788.83176.
6. Singla S, Harjai K, Katare OP, Singh R. A polyherbal gel for the treatment of acne vulgaris: formulation and evaluation. Drug Dev Ind Pharm, 2012; 38(5): 574-581. doi:10.3109/03639045.2011.632109.
7. Kaur, S., & Gupta, A. (2018). Polyherbal formulation: a novel approach in the treatment of acne vulgaris. Journal of pharmaceutical sciences and research, 10(5): 1125-1129. International Journal of Research Publication and Reviews, April 2023; 4(4): 1123-1128.
8. Gram-Negative Folliculitis in Acne Vulgaris: A Review of Pathogenesis, Diagnosis, and Management" by Michael J. Alam and Jeffrey P. Callen, published in American Journal of Clinical Dermatology in, 2003. PMID: 12762826.
9. Choudhary S, Bisht S, Bist SS. Polyherbal formulation: Concept of ayurveda. Pharmacogn Rev, 2014; 8(16): 73-80. doi:10.4103/0973- 7847.134229.
10. Moghimipour E, Afsordeh O, Hajimonfarednejad M, Taghizadeh M, Shakeri MT. Design and development of novel herbal-based formulations for treatment of acne. Res Pharm Sci, 2015; 10(5): 417-424.
11. Zaidi KU, Ali SA, Ali AS, Alam MS, Ahmad S. Acne vulgaris: Herbal remedies vs conventional therapy. J Pharm Res, 2012; 5(2): 932-935.
12. Ahmad I, Ahmad F, Pasha A. Screening of some Indian medicinal plants for their antimicrobial properties. J Ethnopharmacol, 1998; 62(2): 183- 193. doi: 10.1016/S0378 8741(98)00055-9.
13. Naik, R. R., & Munshi, R. P. (2016). A randomized controlled study to evaluate the efficacy of polyherbal formulation in acne vulgaris. International Journal of Green Pharmacy, 10(4): 238-243.
14. Parekh, J., Chanda, S., & Ingle, P. (2011). Efficacy and safety of polyherbal formulation in acne vulgaris: a single-blind randomized controlled trial. Ayu, 32(3): 353-359.
15. Gupta M, Mahajan VK, Mehta KS, Chauhan PS (2004). Efficacy and safety of 3% polyherbal cream in mild to moderate acne vulgaris: A randomized, double-blind, placebo-controlled study. Indian Journal of Dermatology, Venereology and Leprology, 70(3): 163-165.
16. C. V. Patil et al., "Development and evaluation of herbal gel for acne," International Journal of Drug Development and Research, 2015; 7(3): 227-233.
17. S. A. Patel et al., "Development and Evaluation of Polyherbal Gel for Treatment of Acne Vulgaris," Journal of Pharmaceutical Sciences and Research, 2012; 4(12): 2402-2407. Viscosity.
18. The United States Pharmacopeial Convention (2021). United States Pharmacopeia (USP) General Chapter Microbial Examination of Nonsterile Products: Microbial Enumeration Tests. Ref no: USP 44-NF 39 microbial limit tes.
19. Martins Ekor, the Growing Use of Herbal Medicines: Issues Relating to Adverse Reactions and Challenges in Monitoring Safety, Researchgate, January 2014; 1-6.
20. Bipul Kumar, Rajiv Pthak, Burtin Mary, Diksha Zha, New insights into acne pathogenesis: Exploring the role of acne-associated microbial populations, Researchgate, February 2016; 67-72.
21. vinay verma, Rashmi Yadav, Journal of pharmacognosy and phytochemistry, 2018; 7(3): 34762-3480. 34. Ravi kumar, World journal pharmaceutical research, Pharmacognstical study of Amalaki, 11(1): 1656-1664.
22. Gouri Dixit, Ganesh Misal, Vijay Gulkari and Kanchan Upadhye. INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES AND RESEARCH, 2013; 4(3): 1186-1191.
23. G. Misal, G. Dixit, Vijay Gulkari, Formulation and evaluation of herbal gel, Indian Journal of Natural Products and Resources, December 2012; 3(4): 501-505.
24. International Journal of Recent Technology and Engineering (IJRTE), November 2019; 8(4): 2277-3878.
25. Conforti C, Giuffrida R, Fadda S, Fai A, Romita P, Zalaudek I, Dianzani C (2021) Topical dermocosmetics and acne vulgaris. Dermatol Ther 34(1):e14436. https:// doi. org/ 10. 1111/ dth. 14436
26. Vasam M, Korutla S, Bohara RA (2023) Acne vulgaris: a review of the pathophysiology, treatment, and recent nanotechnology based advances. BB Rep 36:101578. https:// doi. org/ 10. 1016/j. bbrep. 2023. 101578
27. Kotb EA, El?Shiekh RA, Hassan M, Abd?Elsalam WH, El?Tanbouly N, El?Senousy AS (2024) Potential anti?acne loaded nanogel formula tions of Origanum majorana L. and Chrysanthemum morifolium Ramat essential oils. Appl Biol Chem 67(1):9. https:// doi. org/ 10. 1186/ s13765? 024? 00859?w
28. Clayton R, Göbel K, Niessen C, Paus R, Van Steensel MA, Lim X (2019) Homeostasis of the sebaceous gland and mechanisms of acne patho genesis. Br J Dermatol 181(4):677–690. https:// doi. org/ 10. 1111/ bjd. 17981
29. Cong TX, Hao D, Wen X, Li XH, He G, Jiang X (2019) From pathogenesis of acne vulgaris to anti?acne agents. Arch Dermatol Res. 311: 337–349. https:// doi. org/ 10. 1007/ s00403? 019? 01908?x
30. Prasad SB (2016) Acne vulgaris: a review on pathophysiology and treat ment. Asian J Pharm Clin Res 9(4):54–59
31. Kurokawa I, Danby FW, Ju Q, Wang X, Xiang LF, Xia L, Chen W, Nagy I, Picardo M, Suh DH (2009) New developments in our understanding of acne pathogenesis and treatment. Exp Dermatol 18(10):821–832. https:// doi. org/ 10. 1111/j. 1600? 0625. 2009. 00890.x
32. Zaenglein AL, Thiboutot DM (2006) Expert committee recommenda tions for acne management. Pediatr 118(3):1188–1199. https:// doi. org/ 10. 1542/ peds. 2005? 2022
33. Gollnick H (2015) From new findings in acne pathogenesis to new approaches in treatment. JEADV 29:1–7. https:// doi. org/ 10. 1111/ jdv. 13186
34. Dréno B, Pécastaings S, Corvec S, Veraldi S, Khammari A, Roques C (2018) Cutibacterium acnes (Propionibacterium acnes) and acne vul garis: a brief look at the latest updates. JEADV 32:5–14. https:// doi. org/ 10. 1111/ jdv. 15043
35. Fox L, Csongradi C, Aucamp M, Du?Plessis J, Gerber M (2016) Treatment modalities for acne. Mol 21(8):1063. https:// doi. org/ 10. 3390/ molec ules2 10810 63
36. Savage LJ, Layton AM (2010) Treating acne vulgaris: systemic, local and combination therapy. Expert Rev Clin Pharmacol 3(4):563–580. https:// doi. org/ 10. 1586/ ecp. 10. 27
37. Tripathi SV, Gustafson CJ, Huang KE, Feldman SR (2013) Side effects of common acne treatments. Expert Opin Drug Saf 12(1):39–51. https:// doi. org/ 10. 1517/ 14740 338. 2013. 740456
38. Zaenglein AL, Pathy AL, Schlosser BJ, Alikhan A, Baldwin HE, Berson DS, Bowe WP, Graber EM, Harper JC, Kang S (2016) Guidelines of care for the management of acne vulgaris. JAAD 74(5):945–973. https:// doi. org/ 10. 1016/j. jaad. 2015. 12. 037
39. Sugisaki H, Yamanaka K, Kakeda M, Kitagawa H, Tanaka K, Watanabe K, Gabazza EC, Kurokawa I, Mizutani H (2009) Increased interferon?γ, inter leukin?12p40 and IL?8 production in propionibacterium acnes?treated peripheral blood mononuclear cells from patient with acne vulgaris: host response but not bacterial species is the determinant factor of the disease. J Dermatol Sci 55(1):47–52. https:// doi. org/ 10. 1016/j. jderm sci. 2009. 02. 015
40. Cunliffe W, Holland D, Clark S, Stables G (2000) Comedogenesis: some new aetiological, clinical and therapeutic strategies. Br J Dermatol 142(6):1084–1091. https:// doi. org/ 10. 1046/j. 1365? 2133. 2000. 03531.x
41. Kurokawa I, Nakase K (2020) Recent advances in understanding and managing acne. Research. https:// doi. org/ 10. 12688/ f1000 resea rch. 25588.1
42. Ak M (2019) A comprehensive review of acne vulgaris. J Clin Pharm 1(1):17–45
43. Melnik BC (2015) Linking diet to acne metabolomics, inflammation, and comedogenesis: an update. Clin Cosmet Investig Dermatol. https:// doi. org/ 10. 2147/ CCID. S69135
44. Monfrecola G, Lembo S, Caiazzo G, De Vita V, Di Caprio R, Balato A, Fabbrocini G (2016) Mechanistic target of rapamycin (mTOR) expression is increased in acne patients’ skin. Exp Dermatol 25(2):153–155. https:// doi. org/ 10. 1111/ exd. 12885
45. Kretzschmar K, Cottle DL, Schweiger PJ, Watt FM (2015) The androgen receptor antagonizes Wnt/β?catenin signaling in epidermal stem cells. JID 135(11):2753–2763. https:// doi. org/ 10. 1038/ jid. 2015. 242
46. Schneider MR, Paus R (2010) Sebocytes, multifaceted epithelial cells: lipid production and holocrine secretion. Int J Biochem Cell Biol 42(2):181–185. https:// doi. org/ 10. 1016/j. biocel. 2009. 11. 017
47. Guevara?Aguirre J, Balasubramanian P, Guevara?Aguirre M, Wei M, Madia F, Cheng C?W, Hwang D, Martin?Montalvo A, Saavedra J, Ingles S (2011) Growth hormone receptor deficiency is associated with a major reduction in pro?aging signaling, cancer, and diabetes in humans. Sci Transl Med 3(70):70ra13?70ra13. https:// doi. org/ 10. 1126/ scitr anslm ed. 30018 45
48. Bohrer LR, Liu P, Zhong J, Pan Y, Angstman J, Brand LJ, Dehm SM, Huang H (2013) FOXO1 binds to the TAU5 motif and inhibits constitutively active androgen receptor splice variants. Prostate 73(10):1017–1027. https:// doi. org/ 10. 1002/ pros. 22649
49. Ma Q, Fu W, Li P, Nicosia SV, Jenster G, Zhang X, Bai W (2009) FoxO1 mediates PTEN suppression of androgen receptor N?and C?terminal interactions and coactivator recruitment. J Mol Endocrinol 23(2):213 225. https:// doi. org/ 10. 1210/ me. 2008? 0147
50. Chen CC, Jeon SM, Bhaskar PT, Nogueira V, Sundararajan D, Tonic I, Park Y, Hay N (2010) FoxOs inhibit mTORC1 and activate Akt by inducing the expression of Sestrin3 and Rictor. Dev Cell 18(4):592–604. https:// doi. org/ 10. 1016/j. devcel. 2010. 03. 008
51. Yoon JY, Kwon HH, Min SU, Thiboutot DM, Suh DH (2013) Epigallocat echin?3?gallate improves acne in humans by modulating intracellular molecular targets and inhibiting P. acnes. JID 133(2):429–440. https:// doi. org/ 10. 1038/ jid. 2012. 292
52. Kurokawa I, Layton AM, Ogawa R (2021) Updated treatment for acne: targeted therapy based on pathogenesis. Dermatol Ther 11(4):1129 1139. https:// doi. org/ 10. 1007/ s13555? 021? 00552?6
53. Jeremy AH, Holland DB, Roberts SG, Thomson KF, Cunliffe WJ (2003) Inflammatory events are involved in acne lesion initiation. JID 121(1):20–27. https:// doi. org/ 10. 1046/j. 1523? 1747. 2003. 12321.x
54. Kelhälä H?L, Palatsi R, Fyhrquist N, Lehtimäki S, Väyrynen JP, Kallioinen M, Kubin ME, Greco D, Tasanen K, Alenius H (2014) IL?17/Th17 pathway is activated in acne lesions. PloS One 9(8):e105238. https:// doi. org/ 10. 1371/ journ al. pone. 01052 38
55. Mouser PE, Seaton ED, Chu AC, Baker BS (2003) Propionibacterium acnes?reactive T helper?1 cells in the skin of patients with acne vulgaris. JID. 121(5):1226–1228. https:// doi. org/ 10. 1046/j. 1523? 1747. 2003. 12550_6.x
56. Kang S, Cho S, Chung JH, Hammerberg C, Fisher GJ, Voorhees JJ (2005) Inflammation and extracellular matrix degradation mediated by activated transcription factors nuclear factor?κB and activator protein?1 in inflammatory acne lesions in vivo. AJP 166(6):1691–1699. https:// doi. org/ 10. 1016/ S0002? 9440(10) 62479?0
57. Carlavan I, Bertino B, Rivier M, Martel P, Bourdes V, Motte M, Déret S, Reiniche P, Menigot C, Khammari A (2018) Atrophic scar forma tion in patients with acne involves long?acting immune responses with plasma cells and alteration of sebaceous glands. Br J Dermatol 179(4):906–917. https:// doi. org/ 10. 1111/ bjd. 16680
58. Islami AW, Effendi E (2021) Correlation between lipid profile, sebum excretion levels and severity of acne vulgaris in non?obese patients. Education 6(24):23. https:// doi. org/ 10. 5220/ 00081 52801 500154
59. Ottaviani M, Camera E, Picardo M (2010) Lipid mediators in acne. Med Inflamm 2010(1):858176. https:// doi. org/ 10. 1155/ 2010/ 858176
60. Picardo M, Eichenfield LF, Tan J (2017) Acne and rosacea. Dermatol Ther 7:43–52. https:// doi. org/ 10. 1007/ s13555? 016? 0168?8
61. Del Rosso JQ, Kircik L (2024) The primary role of sebum in the patho physiology of acne vulgaris and its therapeutic relevance in acne management. J Dermatol Treat 35(1):2296855. https:// doi. org/ 10. 1080/ 09546 634. 2023. 22968 55
62. Simard M, Tremblay A, Morin S, Martin C, Julien P, Fradette J, Flamand N, Pouliot R (2022) α?Linolenic acid and linoleic acid modulate the lipidome and the skin barrier of a tissue?engineered skin model. Acta Biomater 140:261–274. https:// doi. org/ 10. 1016/j. actbio. 2021. 11. 02
63. Hassoun LA, Chahal DS, Sivamani RK, Larsen LN (2016) The use of hor monal agents in the treatment of acne. 35(2): 68–73. https:// doi. org/ 10. 12788/j. sder. 2016. 027.