A Well-Known Plant and New Therapeutic Strategies: Turmeric and Its Components in Oral Inflammatory Diseases Treatment

Abstract

Turmeric has been known for centuries as a spice and an important element of traditional medicine. Nowadays, plant-derived compounds are still an object of extensive scientific investigations aiming at the development of novel drugs and dosage forms. Turmeric and its most important component, curcumin, reveal numerous interesting biological properties, including antioxidant, anti-inflammatory and antimicrobial activity. Numerous scientific studies focusing on various aspects of the activity of turmeric-derived compounds show that curcuminoids display an enormous potential as active pharmaceutical ingredients useful in a wide spectrum of medical conditions. Oral diseases comprising both mild inflammations and severe life-threatening conditions are classified as the most common ones, affecting an enormous part of the global population. In this review, the current research regarding turmeric and its constituents in oral diseases is summarized and discussed, with special attention paid to novel findings and future directions regarding scientific exploration of curcuminoids.

1. Introduction

The twenty-first century is the age of easily-accessible mass-produced synthetic drugs which dominate the pharmaceutical market all over the world. However, recently, an increased interest in non-conventional medicine and phytotherapy is observed. A number of non-conventional therapeutic approaches are considered as controversial and do not fall into the evidence-based medicine category. However, plant-based medicines and plant-derived compounds are subjects of numerous scientific studies, and phytotherapy has sound scientific foundations. The current knowledge on medicinal plants comprises not only the detailed information on their chemical composition but also on the processes and mechanisms underlying their pharmacological activities. It is estimated that 80% of the worldwide population uses herbal medicines, with even higher rates reported for developing countries [1]. It is also noteworthy that a lot of currently marketed active ingredients widely accepted for the treatment of numerous conditions, including cancer and cardiovascular diseases, either originate from plant sources or were synthesized based on phytochemicals [2]. Among the most important examples of plant-derived compounds that have played an enormous role in pharmacotherapy, morphine extracted from Papaver somniferum should be mentioned [3]. Some of the plants used for centuries for medical and non-medical purposes have recently become a subject of numerous studies showing their excellent therapeutic potential in many different areas. It is important to note that the biological activity of plants is often a complex interplay of numerous compounds showing synergistic effects, and the active ingredients isolated from them and applied separately do not reveal the same efficacy as the original herbal source. The described phenomenon makes the recognition of the mechanisms responsible for pharmacological activity of plant-derived medicines more challenging compared to the synthesized drugs. It is also important to note that a number of herbal drugs display multidirectional biological activities which may be particularly useful in the treatment of the conditions with complex etiology and pathogenesis, including cancer [4]. These natural products frequently act as chemopreventive agents, inhibiting tumor initiation step, and antiproliferative compounds, hampering tumor growth and metastasis. The mechanisms underlying these processes are even more complex and include immunomodulatory and anti-inflammatory effects [5]. One of the most extensively investigated plant materials revealing diverse beneficial health effects is turmeric, a well-known herb cultivated and applied in the India, Southeast Asia and Indonesia regions. The beneficial health effects of turmeric applied as a spice in Indian cuisine have been known for centuries. In traditional Indian and Chinese medicine, the plant was used as a remedy for various medical conditions, including hepatic problems, like jaundice, dermatological conditions, rheumatism, asthma, urinary tract infections and diabetic wounds [6]. Nowadays, turmeric constituents, including curcumin and other curcuminoids, have been confirmed as versatile active ingredients revealing numerous interesting properties and potentially useful in numerous conditions, as has been proven in many clinical studies [7]. Among the most important and early recognized advantages of turmeric and turmeric-derived compounds, their anti-inflammatory and anti-microbial activities should be mentioned. Turmeric was traditionally used in India as a hygienic agent in dentistry, and current studies indicate its usefulness in relieving the symptoms occurring in the inflammatory conditions localized in the mouth [8]. It is noteworthy that oral inflammatory condition is a general term, and it comprises several different diseases, including periodontal disease, gingivitis, mucositis, lichen planus and many others. The mentioned conditions may occur as a result of poor oral hygiene, chronic systemic diseases, infections in immunocompromised patients or as a side effect of anticancer treatment including chemo- and radiotherapy. All of the mentioned situations are associated with pain and significant discomfort, eventually leading to life quality impairment or the development of more severe conditions which may have serious implications particularly for the patients suffering from chronic diseases, including diabetes or neurodegenerative disorders [9]. The pathogenic microbiome associated with oral inflammatory diseases may also contribute to systemic complications, including cardiovascular problems, pulmonary diseases and rheumatoid arthritis [10], as oral cavity enables quick access to the gastrointestinal and respiratory systems. On the other hand, some inflammatory conditions localized in the mouth, like lichen planus or oral submucous fibrosis, are considered an initial stage of carcinogenesis, and they can potentially develop into cancer [11]. Considering the population health perspective, oral inflammatory conditions are important factor affecting an overall wellbeing and may lead to a significant impairment in terms of quality of life. According to World Health Organization (WHO) reports, oral health problems affect nearly 3.5 billion people, and the treatment is a global economic burden which is particularly difficult for the developing countries. It is also important to note that the expenses related to the treatment are usually not included in universal health coverage, which may contribute to the impaired access to the healthcare options even in high-income countries [12,13]. In this context, the most important strategies to improve global oral health emphasize cost-effective preventive actions with special attention paid to proper oral hygiene. According to the available literature reports, popularly accessible and effective natural products may play an important role in the prevention and treatment of oral inflammatory diseases [14]. In the case of turmeric and turmeric-derived compounds, anti-inflammatory and other activities have been known for centuries and proven in numerous scientific studies.

The aim of this review is to summarize the current knowledge on the application of turmeric and its active ingredients in various oral inflammatory conditions. Special attention has been paid to the most promising and the most extensively investigated scientific directions, as well as challenges related to the turmeric and turmeric-derived compounds.

2. Historical Background

Turmeric has been known since 4000 BCE, and the first mentions of this plant come from ancient Ayurvedic texts describing a historical alternative medicine system in the South Asian region. Since the ancient times, the yellow powder obtained from turmeric rhizome was widely applied as a culinary spice, a dye for ritual clothing and for medical purposes. There are more than 50 names of turmeric in Sanskrit [15], and its medical applications are mentioned in Charaka Samhita, one of the oldest Ayurvedic documents [16]. In Ayurvedic medicine, turmeric was applied orally as a digestive agent preventing obesity, relieving gas and fighting parasites. Moreover, it was used in many other conditions, like respiratory and liver disorders, rheumatism, irregular menstruation, gallstones or even common cold. On the other hand, turmeric was used topically in various skin conditions [17]. Beneficial properties of the plant are reflected by some of its Sanskrit names, e.g., varavarnini (which gives fair complexion) or rabhangavasa (which dissolves fat). In the Tamil culture of India and north Sri Lanka, turmeric was used as a remedy for wounds, skin parasites and blisters occurring as a result of Herpes simplex infection [18]. As a spice, it played an important role in long distance trade in the Indus Valley civilization during the Bronze Age [19,20]. By the 13th century, it probably reached China and Africa and then was brought to the European continent by traders and explorers. In 1280, Marco Polo during one of his travels to India described turmeric as similar to saffron, which probably gave origin to the term “Indian saffron” [20]. Nowadays, it is estimated that India is the largest turmeric producer, as well as the most important exporter and consumer. It must be also emphasized that Indian turmeric is considered as the most valuable one in terms of curcuminoids content [16].

3. Active Ingredients of Turmeric

Turmeric rhizome contains numerous bioactive compounds, including polyphenols known commonly as curcuminoids: curcumin [diferuloylmethane; 1,7-bis-(4-hydroxy-3-methoxy prenyl)-1,6-heptadiene-3,5-dione)], demethoxycurcumin and bis-demethoxycurcumin (Figure 1).

Usually, the plant material contains 3 to 5% of the mentioned active ingredients with curcumin as the main component. Curcumin isolation from the turmeric rhizome was reported in 1815 by Vogel and Pelletier. In fact, at first a mixture of turmeric oil and oleoresin was obtained, and the pure curcumin was isolated in 1842 [22]. The structure of the compound was identified by Miłobędzka et al. in 1910 [23]. It is noteworthy that even though turmeric was recognized for its beneficial properties for centuries, its main constituent did not draw a lot of scientific attention immediately after its discovery. A few decades later, several different research groups revealed its antibacterial, anti-inflammatory and many other biological activities. Since then, the number of studies focusing on curcumin has increased significantly, and in 2019, the number of manuscripts deposited in the Web of Science database was about 18,000 [24]. More than a half of them were published in 2014 or later which indicates growing scientific interest in this subject. However, even though curcumin is the most extensively investigated active ingredient of turmeric and is considered as the most potent one, the other curcuminoids also reveal pharmacological activities [21,25,26]. The rhizome also contains other compounds of potential biological importance, including mostly mono- and sesquiterpenoids of volatile oil responsible for the taste and scent of turmeric [27]. Among the most important terpenoid constituents of turmeric, zingiberene, turmerones and phellandrene should be mentioned. It is important to note that the exact chemical composition of the turmeric oil depends on the source of the plant [20]. Moreover, turmeric rhizome also contains fixed oils, carbohydrates, proteins, fiber, minerals, phytosterols, tocopherols and fatty acids. The composition of turmeric is presented in Figure 2.

3.1. Curcuminoids

3.1.1. Biological Activity of Curcuminoids

Curcumin reveals numerous pharmacological activities, most of them resulting from its anti-inflammatory [29] and antioxidant [30] properties. It was shown that the drug can effectively increase the activity of natural antioxidant mechanisms [31], as well as reduce the levels of oxidative stress by its own activity including reactive oxygen and nitrogen forms scavenging [32]. On the other hand, it can modulate the activity of enzymes, playing an important role in removing free radicals [33] or inhibiting activity of those inducing oxidative stress, like lipooxygenase (LOX) and cyclooxygenase (COX) related also to the mechanisms of inflammation [34]. The compound can inhibit the activity of inducible nitric oxide synthase, leading to the reduced production of nitric oxide (NO) which is an important pro-inflammatory mediator. The most important mechanisms of curcumin antioxidant activities are summarized in Figure 3.

Anti-inflammatory activity of curcumin is also closely related to the inhibition of pro-inflammatory cytokines, like interleukine-6 (IL-6) and tumor necrosis factor α (TNF-α), as well as reduction of the synthesis of microRNA-155 (miRNA-155) recognized as a factor activating inflammatory mechanisms in macrophages [35]. Curcumin modulates signaling pathways important in the development of inflammatory conditions, e.g. inhibits nuclear factor kappa-B (NF-kappaB) and activates peroxisome proliferator-activated receptor-gamma (PPAR-gamma) [29].

The antioxidant and anti-inflammatory properties of curcumin were recognized as useful in wound healing [36]. Because of the ability to affect cell signaling pathways, the compound was also investigated in targeted cancer therapy. It was shown that it has an impact on the processes important for carcinogenesis, like genomic modulations, cell invasion and cell death [37,38]. Curcumin has been analyzed as a remedy in popular civilization diseases, e.g. in prevention and treatment of type 2 diabetes. The drug can decrease the glucose levels and also exert beneficial effects on lipid metabolism which is promising in patients with metabolic syndrome including diabetes, hypertension and obesity occurring together [39]. Another important direction related to the studies focusing on turmeric-derived compounds is neurodegenerative disorders treatment and prevention. As a highly potent antioxidant compound, curcumin can play a protective role against lipid and protein oxidation potentially leading to the development of Alzheimer’s disease [40]. Apart from reducing the oxidative stress and nitric oxide-mediated damage, curcumin can also enhance the activity of antioxidative enzymes, like superoxide dismutase and glutathione peroxidase. It is noteworthy that curcumin, the main active component of turmeric, has the ability to cross the blood–brain barrier which is quite a unique property among active pharmaceutical ingredients. It is estimated that more than 98% of drugs cannot cross the barrier which is an immense obstacle in terms of efficient drug delivery to the brain [41,42]. In vitro and in vivo studies involving curcumin indicate that the compound can prevent the formation of β-amyloid in brain tissue and destabilize already formed plaques. On the other hand, it can bind with high affinity to amyloid and emit a strong fluorescence signal which can be applied in an early-stage diagnosis of Alzheimer’s disease. However, its stability and bioavailability may be insufficient for the diagnostic purposes. Therefore, chemical modifications of the original compounds are necessary to improve these parameters. In the scientific literature regarding this subject, dibenzylideneacetone [43] and difluoroboron [44] derivatives are mentioned. Moreover, the diagnostic probe can be radiolabeled with ¹¹C, ¹⁸F or ¹⁹F atoms which enables its application in PET and MRI brain imaging [45]. The antioxidant properties of curcumin are also recognized as useful in the treatment of rheumatoid arthritis [46] and inflammatory bowel diseases [47]. Curcumin also reveals antimicrobial activity which is related to its ability to absorb light in a blue spectrum and its photosensitizing properties [48,49]. This feature along with the antioxidant and anti-inflammatory potential of curcumin are recognized as potentially useful in wound healing applications [50,51].

3.1.2. Potential Problems Related to Curcumin Application

The available literature studies indicate an immense potential of curcuminoids in the therapy of various medical conditions, particularly the ones with underlying inflammatory pathomechanism. However, there are some difficulties related to the properties of curcumin and its derivatives that must be overcome to obtain the therapeutic effect.

Curcumin and its derivatives are hydrophobic and practically insoluble in water but dissolve in organic solvents, e.g. acetone and ethanol, alkaline solvents and strongly acidic media [52]. The compounds are relatively stable in the stomach. Curcumin undergoes keto-enol tautomerism with ketone form prevailing in the acidic and neutral environment and enol form in the alkaline media. However, the highest stability was observed in media with pH exceeding 11.7, while at the physiological value of 7.4 curcumin degraded rapidly [53]. Poor solubility in water is related to another drawback of curcumin as an active ingredient, i.e. poor absorption from gastrointestinal tract and low bioavailability after oral administration, also resulting from poor permeability through biological membranes [28]. It is estimated that the bioavailability of curcumin is only about 1% after oral administration of 500 mg/kg dose [54]. Taking into consideration poor water solubility and low ability to permeate through biological barriers, curcumin is classified as Biopharmaceutics Classification System (BCS) class IV [55]. Most of the ingested drug passes through the gastrointestinal tract and is eliminated with feces, while the absorbed amount undergoes rapid metabolism in the liver. Both poor absorption and quick metabolism are considered as obstacles in terms of the therapeutic efficacy. Therefore, numerous efforts and studies have been undertaken to modify the unfavorable properties of the compound.

One of the first approaches to overcome the challenges related to curcumin biopharmaceutical properties was its co-administration with piperine, an alkaloid derived from black pepper (Piper nigrum) and long pepper (Piper longum). It acts as an inhibitor of liver and intestinal enzymes responsible for the curcumin transformation to glucuronates. It was found that co-administration of both compounds resulted with significantly higher blood levels of curcumin when compared to curcumin administered alone [56]. It was also found that similar effects can be obtained with the use of silibinin and quercetin [57]. Other approaches are related to the systems applied as carriers for curcumin incorporation. Numerous studies describing nanoparticles [58], nano- and microemulsions [59,60], vesicular systems [61], cyclodextrins [62], micelles [63], dendrimers [64] and many others indicate that the unfavorable biopharmaceutical properties of the drug can be modulated using the proper drug delivery system. As a lipophilic compound with log P value of 3.29 [54], curcumin is also a good candidate to be incorporated in self-emulsifying drug delivery systems which are known for improving poor bioavailability of the drugs displaying low solubility in water [65,66]. In such formulations, the drug is dissolved in a mixture of oil and one or more surfactants, sometimes with additional co-surfactants and co-solvents. When the system gets to the stomach, upon the addition of gastric fluid, a fine emulsion is formed, and the drug is easily absorbed from the gastrointestinal tract. The described approach allows to improve the bioavailability of the drug and also to reduce the bioavailability differences related to interindividual variability and food effects, as it was observed for cyclosporine [67].

Another important and potentially challenging feature of curcumin is its susceptibility to chemical degradation caused by increased temperature, moisture and visible light. As a result, curcumin is transformed into ferulic acid and vanillin [68,69]. According to Liu et al. [69], in the case of simple curcumin dispersion irradiated with the use of fluorescent lamp (50 Hz, 30 W) for 5 min, the concentration was reduced to 60%. For curcumin incorporated in egg ovalbumin and subjected to the same treatment, however, the initial concentration dropped to 90%. The observed results indicate that the application of a carrier for curcumin incorporation can effectively improve its photostability. Similar conclusions have been made by Sandhu et al. [70] who compared photostability of free curcumin to curcumin-loaded solid lipid nanoparticles. Promising results were also observed for other carriers, including dendrimers [71], Eudragit^® microparticles [72] and PLGA nanoparticles [73].

All of the issues mentioned above can be potentially regarded as challenging when commercial product design is taken into consideration. Apart from low bioavailability related to poor solubility and rapid metabolism, as well as susceptibility to degradation, the clinical data proving the efficacy of turmeric-derived compounds still seem to be insufficient to include them in treatment guidelines for any particular condition. It is noteworthy that there are several curcumin-based commercial products, available either as dietary supplements or as topical products, including also formulations intended for mouth application (

Table 1. Marketed products with curcumin for the application in the oral cavity—examples.

Name, Dose (Manufacturer)	Active Ingredient (Dose)	Dosage Form	Application
Curenext® (Abbott India Ltd., Mumbai, India)	Curcuma longa extract (10 mg/g)	oral gel	gingivitis prevention
SNEC-G (Arbro Pharmaceuticals Pvt. Ltd., New Delhi, India)	curcumin (5 mg/g)	self-nanoemulsifying gel	mouth ulcers, gingivitis, periodontitis, bad breath
Colgate® Naturals (Colgate-Palmolive, Taguig, Philippines)	turmeric extract 1	toothpaste	gum health improvement, plaque and bacteria removal
Curcuzenica (Herbzenica Lifesciences Pvt. Ltd., Bhubaneswar, India)	soluble Curcuma longa extract (1% w/w)	oral gel	aphthous ulcers, gingivitis, glossitis, oral mucositis, oral submucous fibrosis, mucositis and ulceration related to cancer treatment

¹ No information on the concentration available.

). According to Hassanzadeh et al. [74], the most important factors limiting medical application of curcumin are related to its unfavorable pharmacokinetic features described above.

Curcumin is classified as safe and non-toxic, even when doses as high as 6 g/day are administered orally [75]. Taking into consideration medical conditions localized in the oral cavity and topical curcumin-based formulations, it may be assumed that the amount of the active ingredient administered to the patient in such cases is low, and so is the risk of any toxic effects. However, some areas related to general curcumin toxicity seem to be unclear and require more extensive investigations. For example, the scientific literature does not provide sufficient data on the potential risk related to prolonged exposure to curcumin [74]. Moreover, curcumin has been successfully applied in the studies focusing on cancer treatment, and its cytotoxic effects were confirmed in some conditions [76]. The observed toxicity towards cancer cells may suggest that curcumin can also be potentially toxic in some other conditions, so the exact mechanisms of these actions should be investigated in detail. Finally, curcumin is frequently incorporated in various types of nanocarriers in order to improve its unfavorable pharmacokinetic profile, and such novel formulations require additional safety studies [77].

3.2. Biological Activity of Other Turmeric Constituents

Even though the scientific interest focuses mainly on curcumin, there are reports indicating that other components of turmeric also reveal interesting properties. For example, it was found that the components of turmeric oil enhanced pharmacological activity of curcuminoids [78,79]. The active ingredients of oil act as absorption enhancers, increasing bioavailability of curcuminoids in humans [80]. On the other hand, the analyses focusing on curcuminoids-free turmeric extracts indicate that their pharmacological activity profiles were similar to curcuminoids, and in some cases, they revealed even stronger properties than curcumin. The described effect was observed by Lantz et al. [81] who investigated the anti-inflammatory activity of various turmeric extracts. It was observed that the combination of fractions containing the turmeric oils components revealed the highest ability to inhibit the activity of cyclooxygenase 2 (COX-2) in vitro. Quite surprisingly, the obtained results were better than those obtained for isolated curcuminoids. It was also shown that in terms of decreasing the production of prostaglandin E2, turmeric oil revealed similar ability to indomethacin, a well-known and widely applied non-steroidal anti-inflammatory drug. The main components of the oil, i.e. turmerones, also revealed some positive anti-proliferative and immunomodulatory results in in vitro tests, also enhancing the activity of curcuminoids [82]. Ar-tumerone reduced skin inflammation in a psoriatic mice model by suppressing cell proliferation and reducing inflammatory cytokine expression [83,84], and it also displayed some neuroprotective properties [85,86]. Moreover, turmerones were also tested positive for antifungal [87] activities, as well as antidiabetic potential related to the activation of peroxisome proliferator-activated receptors γ (PPAR-γ) [88]. Among the other terpenoid constituents, β-elemene, a sesquiterpene revealing anticancer properties, should be mentioned. The activity of the compound against various cancer cell lines was shown in numerous in vitro studies [89]. It was also observed that elemene enhanced the activity of widely applied antitumor drugs, like cisplatin, etoposide and tamoxifen [78]. It is noteworthy that the compound also has the ability to cross the blood–brain barrier [90] which can be advantageous in the treatment of brain tumors.

Turmeric is also a source of turmerin, a water-soluble protein revealing some interesting pharmacological properties. It was found that turmerin can decrease the activity of α-amylase and α-glucosidase, contributing in this way to the antidiabetic profile of turmeric. The compound also has the ability to scavenge reactive oxygen species and bind iron cations which also indicates its antioxidant potential [91].

Apart from the most important constituents of turmeric rhizome described above, the plant also contains numerous other compounds potentially useful in the pharmacotherapy of various medical conditions. Among the biologically active ingredients of turmeric, other sesquiterpenes like furanodiene, curdione, bisacurone, calebin A, germacrone and several monoterpenes, including carvone, geraniol and limonene, are mentioned in the scientific literature [78]. The chemical structures of most important constituents of turmeric other than curcumin are depicted in Figure 4. Taking into consideration the general activity profile of the mentioned compounds, the most important biological properties are similar to those displayed by curcuminoids. It is also noteworthy that the turmeric ingredients can act synergistically which indicates the potentially higher activity of plant extracts compared to pure compounds [79].

4. Topical Applications of Curcuminoids

Turmeric and its components have been subjected to numerous studies investigating their potential application in various medical conditions, particularly those involving some oxidative and inflammatory mechanisms. In most of the studies, turmeric constituents are considered for oral administration and are supposed to exert systemic effects. However, the antioxidant, anti-inflammatory and anticancer properties of curcuminoids combined with their antimicrobial potential can be also utilized in topical formulations designed to treat the conditions localized in skin and mucous membranes. According to the literature reports, curcumin can be useful in various skin infections, psoriasis, acne and skin cancer [92]. It is noteworthy that some of the difficulties encountered in oral curcumin administration can be overcome with the use of topical route. As curcumin is a lipophilic compound revealing log P = 3.29 and relatively low molecular mass [93], it may be expected that transdermal products can be advantageous in terms of drug bioavailability. However, in vitro skin permeation studies performed by Fang et al. [94] indicate that curcumin flux without any additional percutaneous absorption enhancers is low. On the other hand, in the case of topical formulations, other drawbacks of curcumin are mentioned, i.e., chemical instability leading to the decomposition upon the contact with UV and visible light and rapid elimination from the body [92]. Therefore, in the studies regarding topical administration of curcumin-based formulations, some approaches usually aim at minimizing the effects related to unfavorable properties of curcumin. Similarly to the formulations designed to be administered by other routes, nanostructured lipid carriers (NLC), liposomes, nanoparticles, nano –and microemulsions are taken into consideration [95]. The application of a proper drug delivery system allows for transporting the active ingredient through stratum corneum, the most important skin barrier, into the deeper skin layers.

One of the most extensively investigated directions in the studies regarding topical formulations with turmeric-derived compounds is related to wound healing. Curcumin reveals numerous activities useful in terms of tissue regeneration. It displays antimicrobial activity preventing the infection of damaged tissues, and its anti-inflammatory properties also support the regeneration. It was shown that curcumin increases fibroblast proliferation and helps in epithelium regeneration [96]. The study performed by Kulac et al. [51] with the use of animal model revealed that burn wounds healed significantly faster with the aid of curcumin compared to non-treated burns which was also confirmed by histopathological and biochemical tests. In the presence of curcumin, the epithelialization and granulation rate were much higher, which indicates the potential usefulness of curcumin in burn wounds therapy. Apart from antioxidant, anti-inflammatory and antimicrobial effects presented by curcumin, it also affected the process of collagen crosslinking, indicating the enhanced rate of wound healing [97]. Similar effects were observed in the case of wounds localized in the mucous membrane. Çakan et al. [98] investigated healing process in rabbits with perforated nasal septum in the presence of curcumin. It was found that the active ingredient significantly enhanced the process, increasing the amounts of collagen and granulation tissue. Similar effects were observed in various mucosal damages, including oral mucositis occurring as a side effect of anticancer therapy [99] and corneal wounds observed as a complication of diabetes [100]. As important drawbacks of curcumin, its low solubility in water and low bioavailability are mentioned. As a result, the designed formulations must contain high amounts of the drug which, in turn, increases the risk of toxic effects [36,101]. Therefore, to avoid the toxicity related to high curcumin concentrations, numerous studies focus on the incorporation of the drug in carriers enabling its penetration into the deeper tissues [36]. The most popular formulation approaches involve different nano-sized forms, like liposomes and other vesicles [102], micelle-based systems [101], nanoparticles [103], nanostructured lipid carriers [104] and other systems [105,106].

Curcumin-loaded topical formulation was also reported as an effective neuroprotective agent in glaucoma. In the study performed by Davis et al. [107], drug-loaded nanocarrier effectively protected immortalized R28 retinal precursor cells from induced hypoxia and toxicity and displayed protective properties towards neuronal cells located in the retina in an in vivo model of ocular hypertension. Topically applied nanoparticles with curcumin prevented corneal neovascularization which is an excessive blood vessel growth potentially leading to blindness [108]. Topical formulations with curcumin are also investigated as an alternative to the conventional topical anti-inflammatory products applied in ocular inflammations. It was shown that with curcumin-based products, efficacy similar to topical steroids can be achieved [109].

As curcumin reveals interesting antimicrobial properties, curcumin-loaded systems have also been investigated as novel therapeutic approaches in vaginal infections. Curcumin-loaded creams were effective against candidiasis in the tests performed with the use of an animal model [110]. The available literature studies also show that the compound could be useful in decreasing the inflammation symptoms in other infections, e.g., those inflicted by Herpes simplex virus, even though the antiviral activity of the compound was not confirmed [111].

5. Topical Curcumin-Based Formulations in Oral Diseases

As turmeric and its constituents reveal numerous pharmacological activities combined with low toxicity, they have been also extensively investigated as medicinal agents potentially useful in stomatology and in the treatment of conditions localized in mouth. It is noteworthy that according to USA Food and Drug Administration classification, curcumin falls into “generally recognized as safe” (GRAS) category [25]. Because of its centuries-long history as a spice and natural medicine supported with recent findings, it is well-recognized for its antioxidant, anti-inflammatory and chemoprevention potential combined with antimicrobial properties. One of the first studies focusing on the application of curcumin in the treatment of oral diseases was presented by Azuine and Bhide [112] and showed the chemopreventive effects of turmeric in oral carcinogenesis investigated in hamsters. Since then, numerous literature reports showing the potential of turmeric-derived compounds in various ailments related to oral diseases have been published. Among the investigated formulations, both systemically acting oral dosage forms and topical products, including pastes, gels, patches and mouthwashes, are presented. According to the literature reports, curcuminoids can be useful in the inflammatory conditions in oral mucosa and periodontal region, as well as mouth cancers.

5.1. Periodontal Disease

According to World Health Organization (WHO) data, periodontal disease affects about 10% of global population [12], and according to the Centers of Disease Control and Prevention (CDC), 47.2% of United States population aged 30 years and older experience some health problems related to periodontal disease [113]. The problem intensifies with age and occurs more frequently in men than women. Its higher prevalence is also correlated with poorer socioeconomic status, smoking and comorbidities including diabetes [114,115]. Periodontal disease affects gums which are swollen and bleed and can finally lose their supportive function towards teeth. This, in turn, is related to the increased risk of teeth falling out if the condition remains untreated. In most cases, the mechanisms underlying periodontal disease are related to the inflammatory processes caused by bacteria deposited in dental plaque. According to the classification proposed by the American Academy of Periodontology, periodontal disease comprises several different conditions, including gingival diseases, chronic periodontitis, aggressive periodontitis, periodontitis occurring as a manifestation of systemic diseases, necrotizing periodontal diseases, abscess of periodontium, periodontitis associated with endodontic lesions and other developmental or acquired deformities and conditions [116]. The general therapy of periodontal disease should focus on the mechanical removal of dental plaque and can also comprise antimicrobial therapy, involving both systemically and locally acting preparations. It was shown that the application of topical antiseptic formulations can be more effective, due to the possibility to obtain significantly higher drug concentration in periodontal pockets. Moreover, in the products administered locally, the substances displaying broad antimicrobial spectrum can be included with significantly lower risk of drug resistance-related problems compared to the drugs acting systemically. Finally, the topical administration minimizes the risk of systemic side effects [117]. In the treatment of periodontal disease-related symptoms, curcumin can be considered useful due to its antibacterial, antioxidant and anti-inflammatory properties. It is important to notice that the experimental studies showed that curcumin had the ability to suppress the growth of bacterial strains associated with the occurrence of periodontal disease, particularly Porphyromonas gingivalis [118,119]. The available literature studies presented in this paragraph usually focus on the application of curcumin as an adjuvant to standard procedures employed in periodontal problems.

For example, Gottumukala et al. [117] compared curcumin-loaded collagen sponges and Periocol CG chips containing chlorhexidine as adjuvant therapies to scaling and root planing which are the removal of the dental plaque above and below gums. For both compared systems, the clinical parameters, including plaque index (the thickness of dental plaque in supragingival region), gingival index showing the inflammation degree and clinical attachment level (CAL) were compared. In the study performed with volunteers suffering from chronic periodontal disease, it was shown that curcumin-loaded formulation administered locally resulted with reduced inflammation. As the most probable mechanism of this phenomenon, reduced expression of genes responsible for pro-inflammatory cytokines action was mentioned. The other possible pathway leading to anti-inflammatory results was the reduced activity of nuclear factor-κB (NF-κB). Similar results were observed for both compared formulations which suggested that curcumin can be effectively applied in the treatment of periodontal disease. However, after three months of study, the activity of curcumin-based formulation decreased compared to the chlorhexidine-based product. The observed effect could be related to the shorter biological half-life of curcumin or insufficient concentration.

Guru et al. [120] also performed a comparative study focusing on the efficacy an adjuvant therapy with either curcumin-loaded nanoparticles or chlorhexidine combined with scaling and root planing. The experiment was performed in chronic periodontitis patients who were divided into three groups receiving main treatment only, main treatment with additional topical curcumin formulation or main treatment with combined topical chlorhexidine therapy. As a response, three different bacterial strains in the dental plaque were monitored. Similarly to the previous study, it was found that in curcumin- and chlorhexidine-treated groups, the therapeutic outcomes were similar, and the levels of three periodontopathic bacteria were significantly reduced. Considering the fact that chlorhexidine is a widely known and applied antiseptic, the described effects are promising in terms of potential applicability of curcumin-based topical products in periodontal disease.

A similar study was performed by Kaur et al. [121]. Periodontal disease-affected patients were divided into two groups subjected to standard treatment with root scaling and planning with or without additional therapy with curcumin-loaded gel. The efficacy of the applied therapeutic approaches was evaluated by checking the levels of interleukin-1β (IL-1β) in the saliva samples and monitoring the clinical parameters. It was found that the adjuvant therapy provided some benefits for the limited time which was reflected by the clinical improvement. However, the results between the IL-1β in the two investigated groups were not statistically different.

In the study performed by Pérez-Pacheco [122] the same protocol was applied, and curcumin-loaded nanoparticles prepared with poly(lactic-co-glycolic acid) (PLGA) and poly(lactic acid) (PLA) were applied as an adjuvant therapy to standard periodontal disease treatment procedure. Probing pocket depth, bleeding and clinical attachment levels were investigated as key clinical parameters indicating potential improvements. Moreover, the levels of IL-1α, IL-6, TNFα and IL-10 in the gingival crevicular fluid were monitored after 3, 7 and 15 days after the formulation application. It was found that all clinical parameters improved in both compared groups to the same extent. The levels of biochemical markers were also not significantly different, except for IL-6 which had lower levels in curcumin-treated patients. However, the applied adjuvant therapy did not significantly reduce the inflammation which was reflected both in clinical symptoms and most of the investigated biochemical parameters. It is important to note that the applied curcumin concentration was 0.05 mg/mL which is relatively low value. Moreover, the authors indicate low viscosity of the investigated formulation which could possibly leak from periodontal pockets, decreasing the efficacy of the treatment. The same research group also performed a study involving an animal model for testing the efficacy of curcumin-loaded nanoparticles in periodontal repair [123]. In the laboratory animals, periodontitis was induced, and three types of treatment were tested. The first group was treated with the drug-loaded nanoparticles, the second group with placebo nanoparticles, while in the third group, sterile saline was administered. The degree of bone repair evaluated with the use of microcomputer tomography, as well as collagen content, were the highest in the drug-loaded nanoparticle-treated group. Another study describing application of curcumin-loaded nanoparticles was presented by Shirmohammadi et al. [124]. The investigated silica-based nanoparticles displayed mesoporous structure and rod-like shape. In the first 5 days, curcumin release was relatively quick, and then, the process followed the sustained release pattern. The obtained system was tested against Porphyromonas gingivalis, a microbe associated with periodontal disease occurrence. In vitro antimicrobial studies revealed that it was sensitive to curcumin incorporated in the investigated nanoparticles in the concentration range 6.25–50 μg/mL which is promising in terms of potential application in periodontal disease.

Another study involving nanoparticles was presented by Zambrano et al. [125] who investigated the efficacy of curcumin-loaded PLGA nanoparticles injected directly to the gingival tissues affected with inflammatory condition. The study was performed with the use of an animal model involving rats with artificially induced periodontitis. It was shown that local curcumin delivery resulted with the inhibition of inflammatory bone resorption. However, in order to evaluate the clinical efficacy of the analyzed formulation, further studies testing the local absorption of the active ingredient are required.

Direct formulation administration was also described by Nasra et al. [126], who developed and investigated the efficacy of curcumin-loaded in situ-forming gels designed to be administered to periodontal pockets. For the obtained formulations the physicochemical properties, i.e. gelation temperature, pH, viscosity, syringeability and stability, were evaluated. Moreover, the drug release was tested in an in vitro experiment, and clinical studies with volunteers suffering from periodontal disease were performed. It was found that the gelation temperature of the analyzed formulations ranged from 28 to 34 °C which is above room temperature and below body temperature. In this way, the product can be administered with a syringe as liquid which provides excellent condition for periodontal pockets penetration. The gelation process occurs upon the contact with physiological conditions, and due to the viscosity increase, the active ingredient can be released from the carrier in a prolonged manner, without the risk of leakage. Curcumin release mechanism followed zero order kinetics. In the clinical tests, the volunteers were divided into two groups, one of them receiving standard scaling and root planing treatment, and the other one treated additionally with topical in situ gel. It is noteworthy that the curcumin-loaded formulation was well accepted by the patients. The application of the additional curcumin-based preparation resulted with reduced bleeding and reduced periodontal probing depth. The differences in both parameters confirm the efficacy of the applied therapeutic approach and the reduction of inflammation.

Another adjunct therapy applied with root scaling and planing was described by Mohammad et al. [127] who investigated the efficacy of curcumin-loaded topical gel. The study was based on an animal model, and the effects observed in the group treated with standard therapy accompanied with curcumin were compared to those obtained for the group treated with tetracycline instead of curcumin and groups without any adjunct treatment, as well as positive and negative controls. In order to check the outcomes of the study, inflammatory markers, collagen fiber deposition and iron levels were checked. In both groups treated with adjunct therapies, inflammatory processes and bone resorption were significantly reduced when compared to the group without any additional treatment. The results for both curcumin and tetracycline were similar. Moreover, it was noted that curcumin revealed also additional osteogenesis and healing potential.

As curcumin is a subject of extensive investigations regarding its potential application in periodontal disease, and the number of available literature studies is high, some systematic reviews and metanalyses have been also published recently. Zhang et al. [128] in their systematic review regarding the efficacy of curcumin as an adjunct therapeutic agent applied in periodontal treatment indicated that the compound revealed anti-inflammatory efficacy reflected in the reduction of gingival index and sulcus bleeding index. Moreover, curcumin as a naturally-derived substance is considered as safe with low risk of associated side effects, which makes it worth considering in combined therapy. Another systematic review presented by Wendorff-Tobolla et al. [129] also evaluated the efficacy of curcumin as an adjunctive treatment applied locally with scaling and root planing. The analyzed parameters were attachment level and probing pocket depth, and the combined treatment with curcumin was compared to scaling and root planing alone and with chlorhexidine. The study revealed statistically significant differences between the treatment involving curcumin or turmeric and standard treatment; however, the observed differences were considered clinically insignificant. On the other hand, there were no statistically significant differences between both combined therapies. Considering the reported lack of clinical improvement, the authors do not recommend curcumin or turmeric products as adjunctive agents in periodontal disease treatment.

5.2. Oral Mucositis and Mouth Ulcers

The origin of oral inflammations is very complex due to multiple factors which have negative influence on the functioning of oral epithelium, flora condition or the immune system. The most frequently mentioned are inappropriate lifestyle and diet, poor oral hygiene, injuries, dental problems or neoplastic changes (ulcers). In the latter case, the risk of inflammation results not only from the existing disease but mainly from the applied therapy [130,131]. About 10–40% of patients undergoing chemotherapy, depending on whether it is basic or adjuvant, suffer from oral inflammation. In the case of patients receiving radiotherapy in head and neck cancer, when the radiation covers the oral cavity, the inflammation symptoms can be observed in almost 100% cases [132] and can last up to 3–6 weeks [133], leading to disturbances in salivary secretion, which significantly increase the risk of chronic inflammations [134].

Irrespective of the reason, administration of preparations containing turmeric ingredients may result in the reduction of the oral mucositis symptoms or its complete elimination [135]. In many cases, the efficiency is higher as compared to the commonly used preparations containing synthetic compounds, i.e., chlorhexidine. In order to confirm the therapeutic activity of curcumin toward oral mucositis induced by head and neck cancer treatment, Zhang et al. performed a meta-analysis of six randomized controlled trials [136]. The tested formulations included topical gels [137], mouthwashes [138], turmeric extract capsules [139] and nanomicelles [140]. General conclusions indicated that independent of the cancer type and treatment technique, curcumin had the potential to reduce the incidence of severe mucositis and accelerate total recovery. The authors noticed that the efficiency was mostly related to anti-inflammatory activity. However, they pointed out that the curcumin mechanism of action is not entirely explained so far. Elad et al. conducted a study on the tolerance of an oral rinse containing turmeric extract and curcumin. The test group consisted of pediatric oncology patients undergoing therapy with doxorubicin. The patients used a mouthwash with curcumin in addition to the standard rinse containing 0.2% chlorhexidine. Very good tolerance of the rinse by patients and no side effects of its use in the oral cavity have been observed. Some patients experienced a decrease in the symptoms of existing mucositis, while others developed it to a milder state. Additionally, the rinse was easy to use and easy to prepare at home [141]. Another study, presented by Patil et al. in a group of patients undergoing radio-chemotherapy, aimed at comparing the effectiveness of a standard rinse (0.2% chlorhexidine solution) with a 0.004% curcumin solution. The advantages of curcumin over chlorhexidine in the treatment and its better acceptance by patients have been shown. Moreover, in the control group, 40% of patients developed a fungal infection, while no infection was observed in the study group using the curcumin mouthwash [142]. Ramezani et al. [143] presented a randomized clinical trial involving patients with head and neck cancers also suffering from oral mucositis related to cancer treatment. The patients were divided into three groups receiving curcumin mouthwash, oral curcuminoids in the form of a capsule with nanomicelles or placebo mouthwash. The results indicate that both topical and oral formulations with curcumin significantly decreased oral mucositis symptoms when compared to placebo. It is noteworthy that, at the end of the study, about 33% of the patients treated with curcumin-loaded mouthwash and about 15% of the patients receiving oral capsules had no ulcers, while in the placebo group all patients still had inflammatory symptoms. Similar conclusions have been made by Fardad et al. [144] who compared the effectiveness of curcumin-loaded gel, mucosamin oral spray and chlorhexidine mouthrinse in the treatment of chemotherapy-induced oral mucositis. In a double-blind randomized study, they demonstrated that all three approaches were effective. However, the application of curcumin led to faster recovery.

Curcumin has also been considered as a potential therapeutic agent in recurrent aphthous stomatitis (RAS), a condition affecting about 20% of the population [145]. The disease has an unclear etiology and is characterized by the recurrent occurrence of single or multiple small painful ulcers surrounded by erythematous halo in oral mucosa. Bakhshi et al. [146] investigated the efficacy of 1% curcumin nanomicelle gel and 2% curcumin gel in the treatment of RAS in a double-blind clinical trial involving 48 patients. The aim of the study was to compare the conventional topical gel and nanoformulation with the same active ingredient. It was shown that in the case of nanomicelle-based treatment, pain and lesion size reduction was better when compared to the conventional gel. However, in the presented study, only two groups were analyzed, and no control group was applied. Therefore, the general efficacy of curcumin-based treatments cannot be evaluated in this study. On the other hand, there are also other studies and systematic reviews summarizing the current knowledge on this subject. Kia et al. [147] compared the efficacy of curcumin-loaded Orabase^® paste and the conventional therapy with triamcinolone acetonide. The study showed no statistically significant differences in pain severity and lesion diameter observed in both therapeutic approaches. The obtained results demonstrate that curcumin can be considered as an effective therapeutic agent in the patients with corticosteroids contraindications. Al-Maweri et al. [148] in their systematic review summarized eight clinical studies evaluating the efficacy of curcumin in RAS treatment and concluded that curcumin displays generally promising properties as a therapeutic agent decreasing pain and lesions diameter. It was shown that its efficacy was comparable to commonly accepted steroid-based therapy. In the studies involving placebo groups, superior effects were reported in the patients treated with curcumin.

Many studies indicate that compounds present in turmeric reveal potential against pathogenic microorganisms and thus contribute to the reduction of the inflammatory symptoms. However, it should be emphasized that using plant raw material may not provide the expected antibacterial effect, as it was described by Yang et al. The authors prepared a mouthwash from store-bought turmeric and used it against bacterial cultures taken form the oral cavity of volunteers. The results showed no apparent antibacterial and bacteriostatic activity. Moreover, some signs of bacterial growth promotion were even noticed [149]. Therefore, most of the current works describe formulations containing pure curcumin. The studies prepared by Hazzah et al. described the development of nanocarriers for improved delivery of curcumin in the treatment of bacterial or fungal infections in the oral cavity. The drug loaded into solid lipid nanoparticles showed greater stability and efficacy in neutralizing Staphylococcus sp. or Candida albicans [150]. The predicted positive therapeutic effect was also attributed to good mucoadhesive properties of the tested formulations ex vivo. Esposito et al. also pointed out the importance of mucoadhesion in relation to the topical efficacy of curcumin-containing formulations. The authors designed and developed zein/beta cyclodextrin mucoadhesive nanoparticles for buccal delivery of curcumin in the form of sprayable suspension. The ex vivo tests on porcine buccal mucosa showed superior resistance toward washing out and indicated great potential in local delivery of the drug [151]. Another studies presented by Andrade et al. concerned the curcumin-based photodynamic antibacterial therapy against oral mucositis in oncological patients. The drug was applied in the form of spray into the oral cavity and the tissue was further illuminated with blue light to achieve the phototoxic effect. This non-invasive technique revealed satisfactory antimicrobial, analgesic and anti-inflammatory effects, with good patient acceptance [152]. Fonseca-Santos et al. obtained an in situ gelling liquid crystal system based on PPG-5-Ceteth-20 for buccal administration of curcumin with the potential against oral candidiasis. The results indicate that due to extended residence time and increased solubility of the drug, the achieved efficiency was distinctly better than curcumin water solution [153].

In addition to the proven activity against oral mucositis, numerous studies have confirmed the effectiveness of turmeric ingredients in the prevention or treatment of oral cancers [154]. Most of the research concerns curcumin and its combinations with other drugs, and importantly, the formulations under development are not usually administered directly to the tumor. Maulina et al. confirmed the efficiency of food mixture containing curcumin in growth inhibition of oral squamous cell carcinoma induced by 7,12-dimethylbenz(a)anthracene [155]. Gefitinib and curcumin-loaded nanoparticles were investigated by Lai et al. in terms of cells apoptosis of human oral cancer. The particles were obtained by emulsification method followed by coating with γ-polyglutamic acid. The experiment with the use of an animal model (mice) indicated that 22 days therapy, based on nanoparticles suspension intraperitoneal injections, showed clear evidence of anti-cancer activity, better than after the use of drugs in a free form (Figure 5) [156].

5.3. Gingivitis

Gingivitis is a condition described as an inflammation of gingival soft tissues and can be an initial, reversible stage of periodontal disease. However, at this early stage, the teeth are still attached to gum tissues, and no separation is observed. The inflammation is a result of the presence of bacteria in dental biofilm [157]. An untreated condition may eventually lead to periodontal disease. The most important therapeutic intervention requires the removal of dental deposits, particularly calculus, which cannot be eliminated with brushing, and the dental plaque gathered at the top of it [158]. The proper oral hygiene and inhibition of bacterial growth are crucial factors in restoring healthy gums and preventing further progression of periodontal disease. For this purpose, mouthwashes containing chlorhexidine and triclosan can be applied. However, it has been reported that these antibacterial agents can cause allergic reactions and teeth discoloration [159]. Due to antimicrobial and anti-inflammatory properties of curcumin, it may be considered as an alternative to commonly applied agents. The available literature studies presented in this paragraph aimed at the efficacy comparison between curcumin-based formulations and other agents.

For example, Pulikkotil and Nath [160] analyzed the efficacy of three marketed gels containing standardized turmeric rhizome extract (10 mg/g), 1% chlorhexidine and 0.25% chlorhexidine combined with 1% metronidazole. The study involved 60 volunteers divided into three groups. All patients were subjected to mechanical teeth scaling and polishing. The gels were tested for the ability to inhibit the development of inflammation. As responses, the levels of IL-1β and chemokine (C-C motif) ligand 28 (CCL28) were tested. Moreover, clinical parameters including bleeding, gingival index and plaque index were checked. After 29 days of the study, it was shown that the formulations with curcumin and with combined metronidazole and chlorhexidine performed better compared to chlorhexidine alone. Moreover, the efficacy of turmeric-based product was slightly better compared to the metronidazole and chlorhexidine-based one. The obtained results indicate that curcumin could be potentially useful in the treatment of gingivitis.

A similar study comparing the effects of curcumin-loaded gels to the reference product containing 0.2% chlorhexidine gluconate was performed by Singh et al. [161]. In both groups receiving turmeric-derived product and the reference, bleeding, gingival index and plaque index were evaluated. It was shown that both treatments were effective, even though chlorhexidine gel performed better in terms of anti-plaque and anti-inflammatory properties.

Mali et al. [162] compared the effects of curcumin-loaded mouthwash with a chlorhexidine-based one on gingival inflammation. No statistically significant differences were shown between the groups using the turmeric-based product and the reference. Both mouthwashes were similar in terms of gingival and plaque indices. Moreover, both products revealed the same antimicrobial activity which shows that curcumin-based mouthwash can be effectively applied in gingivitis.

The promising results of in vivo studies involving human subjects are also supported by the results of in vitro tests. Based on the fact that lipopolysaccharide produced by Porphyromonas gingivalis, the main bacterial strain responsible for oral inflammation, induce the expression of cyclooxygenase-2, Hu et al. [163] investigated anti-inflammatory effects of curcumin using human gingival fibroblasts. The cells were pretreated with curcumin before being stimulated by P. gingivalis. It was found that curcumin had an inhibitory effect towards the cyclooxygenase genes expression, and the phenomenon was dose-dependent. It was also observed that curcumin pretreatment resulted in the downregulation of nuclear factor kappa B (NF-κB) which is also an important finding in terms of explaining the mechanisms underlying the anti-inflammatory activity of turmeric-derived compounds. Another study involving bacterial strain was presented by Grant et al. [164] who focused on Fusobacterium nucleatum, one of the microbial species responsible for the development of gingivitis and periodontal disease. The study demonstrated that curcumin can decrease the inflammatory response in oral epithelial cell line, which is a promising result.

5.4. Other Inflammatory Conditions

Turmeric-derived compounds have also been reported as effective in other inflammatory conditions localized in the mouth. One of them is oral lichen planus (OLP), an autoimmune chronic inflammatory disease affecting mostly buccal mucous membranes but also tongue and gums. The exact etiology of lichen planus remains unknown. The disease is associated with the occurrence of various lesions in the oral cavity, combined with pain, burning sensation and discomfort. OLP is considered a premalignant condition [165]. The available literature data suggest that topical curcumin formulations can be useful in the treatment of OLP-related lesions. However, the comparative studies performed with the use of curcumin-based formulations and topical corticosteroids do not provide sufficient evidence for the replacement of steroidal therapy with curcumin [166,167]. It is also noteworthy that oral curcumin administration did not result with any clinical improvement [168,169].

Another chronic premalignant condition localized in mouth is oral submucous fibrosis (OSF). The most important symptom of the disease is abnormal collagen deposition resulting in fibrosis, ulceration, xerostomia and significant discomfort accompanied with restricted tongue mobility, dysphagia and reduced mouth opening. Among the most important risk factors contributing to the occurrence of OSF, chewing betel nut is mentioned. However, alcohol consumption, tobacco use, immunological comorbidities and vitamin and iron deficiencies can also be significant etiology factors [170]. Most of the available literature reports regarding the topical use of curcumin in OSF reveal improvement in clinical manifestations of the disease [148]. The observed effects were either comparable or better than those recorded for standard topical steroids therapy [171,172].

The results of the most important studies focusing on the application of different curcumin-based formulations in the conditions localized in the mouth are summarized in

Table 2. Curcumin-based formulations investigated in different oral conditions.

Condition	Dosage Form	The Most Important Findings	Reference
Periodontal disease	collagen sponges	anti-inflammatory results similar to chlorhexidine-based treatment the efficacy decreased after 3 months	[117]
Periodontal disease	nanoparticles	antimicrobial effect comparable to chlorhexidine treatment	[120]
Periodontal disease	gel	clinical parameters improvement without decreasing the levels of interleukin-1β (IL-1β) in the saliva of interleukin-1β (IL-1β) in the saliva	[121]
Periodontal disease	PLGA and PLA nanoparticles	no significant improvement was observed in the group with additional curcumin treatment the lack of significant effects was most probably related to low drug concentration and formulation leak	[122]
Periodontal disease (periodontal repair)	nanoparticles	bone repair and collagen content were significantly improved in the group treated with curcumin nanoparticles	[123]
Periodontal disease	silica-based nanoparticles	quick curcumin release in the initial stage followed with sustained release good antimicrobial effect against Porphyromonas gingivalis	[124]
Periodontal disease	PLGA nanoparticles (injection)	inhibition of inflammatory bone resorption in rats with induced periodontitis	[125]
Periodontal disease	in situ-forming gel	good efficacy as an adjuvant therapy bleeding and periodontal probing depth reduction	[126]
Periodontal disease	topical gel	the results were comparable to the adjuvant tetracycline therapy additional osteogenesis and healing potential	[127]
Oral mucositis related to chemotherapy	mouthwash	good tolerance milder side effects related to chemotherapy	[141]
Oral mucositis related to chemo- and radiotherapy	oral rinse	better tolerance compared to chlorhexidine rinse no fungal infections in curcumin-treated group	[142]
Oral mucositis related to cancer treatment	mouthwash, oral curcuminoids	significantly reduced inflammatory symptoms in patients treated with topical and oral curcuminoids	[143]
Oral mucositis related to chemotherapy	gel	similar effectiveness when compared to mucosamin oral spray and chlorhexidine mouthrinse the application of curcumin led to faster recovery	[144]
Recurrent aphthous stomatitis	1% nanomicelle gel, 2% plain gel	similar efficacy of both formulations reflected by lesion size reduction	[146]
Recurrent aphthous stomatitis	curcumin-loaded Orabase® paste	the same efficacy as triamcinolone acetonide in terms of pain severity and lesion diameter	[147]
In vitro antibacterial study	mouthwash	no antibacterial and bacteriostatic activity observed for mouthwash prepared with turmeric bacterial growth	[149]
In vitro antimicrobial study	solid lipid nanoparticles	good stability and efficacy towards Staphylococcus sp. and Candida albicans	[150]
Oral mucositis related to cancer treatment	oral spray	satisfactory antimicrobial, analgesic and anti-inflammatory results good acceptance	[152]
Oral candidiasis	in situ gelling liquid crystal system	better residence time at the administration site and better curcumin solubility better efficacy than curcumin solution	[153]
Squamous cell carcinoma	gefitinib and curcumin-loaded nanoparticles (peritoneal injection)	confirmed anti-cancer activity better results when compared to both drugs applied alone	[155]
Gingivitis	gel with standardized turmeric rhizome extract	curcumin-based formulation performed better than chlorhexidine-based formulations	[160]
Gingivitis	gel	both curcumin- and chlorhexidine-based treatments were effective chlorhexidine performed better in terms of anti-plaque and anti-inflammatory properties	[161]
Gingivitis	mouthwash	no statistically significant difference between curcumin- and chlorhexidine-based treatments the same antimicrobial activity	[162]

.

6. Curcumin in Oral Cancer

The most common form of oral cancer making up 90% of oral malignancy cases is oral squamous cell carcinoma (OSCC) [173]. The disease occurs more frequently in men than women and is usually unnoticed at early stages which may contribute to its high mortality rates [174]. The clinical manifestations include an ulcer with fissuring, raised exophytic margins, lumps or lesions. As the most important risk factors that may eventually lead to OSCC development, alcohol and tobacco use, some viral agents and premalignant conditions are mentioned. It was found that curcumin, as a compound revealing the ability to affect the signaling pathways in the cell, can act as an apoptosis-inducing agent preventing the proliferation of cancer cells. Moreover, the compound can also be considered an adjunct therapeutic agent, supporting conventional anticancer therapy, preventing drug resistance and supporting radiotherapy. It was shown that curcumin can interact with reactive oxygen species and signaling molecules including nuclear factor kappa B (NF-kB) contributing to the induced cell death. Moreover, it can play an important role in cell cycle arrest [175]. Some novel studies suggest that curcumin can be also used as photosensitizer in photodynamic therapy of cancer [176]. The active ingredient is delivered to the cells usually in nanoencapsulated form to improve the uptake efficacy. Curcumin present in the cells upon the irradiation produces reactive oxygen species triggering a sequence of mechanisms leading eventually to cell death. Considering the fact that this effect is activated only as a result of irradiation, the phototoxic effect can be limited to tumor only, without affecting the healthy tissues. The literature reports show some promising results regarding cancer cell lines [176,177,178]. However, photodynamic therapy involving curcumin as photosensitizer is more frequently investigated as an antimicrobial approach, targeting bacterial [179] and fungal cells [180].

There are several available literature reports focusing on the application of curcumin as an active agent towards OSCC cells in vitro. Beyer et al. [181] investigated curcumin as a potential photosensitizer in photodynamic therapy of OSCC. It was shown that the compound was effective towards cancer cells even at low concentration. However, further studies investigating animal models are necessary. Moreover, some beneficial effects of curcumin without irradiation have also been reported. Curcumin affected the mechanisms responsible for cancer progression and metastasis, decreasing the invasiveness [182], and also stimulated the immune response towards tongue OSCC which was reported by Liao et al. [183]. It is noteworthy that the compound was effective both in in vitro experiments and in vivo studies performed with the use of animal models with oral cancer induced with 4-nitroquinoline-1-oxide. Figure 6 depicts the treatment scheme along with the results recorded for the curcumin-treated group of animals and the control group which was given DMSO instead.

Curcumin was also investigated as a potential adjuvant therapeutic for co-administration with standard anticancer therapy. Sivanantham et al. [184] investigated the effects of commonly applied anticancer drugs, i.e., docetaxel, doxorubicin, 5-fluorouracil and cisplatin, combined with curcumin against head and neck squamous cell carcinoma cell line (NT8e). It was shown that 5-fluorouracil and doxorubicin combined with curcumin strongly inhibited the proliferation and induced apoptosis of the tested cells. The results of the study are presented in Figure 7.

7. Conclusions and Future Directions

Turmeric-derived compounds are currently among the most extensively investigated plant compounds. Their numerous activities including antioxidant, anti-inflammatory and antimicrobial ones confirmed in numerous studies are also considered useful in the treatment of inflammatory conditions localized in the oral cavity. For example, most of the comparative studies summarized in this review indicate that topical curcumin can be at least as effective in relieving the symptoms of inflammation as chlorhexidine, commonly accepted as a “gold standard” in the therapy. Other advantages of curcumin as an alternative to the conventional treatment comprise its low cost and low toxicity associated with minimized risk of side effects which are observed in chlorhexidine treatment. On the other hand, the studies comparing the efficacy of curcumin and topical steroids indicate that the conventional therapy most probably could not be replaced with the same effects. However, it is noteworthy that the summarized in vivo studies differ significantly in terms of experimental setup, measured responses, applied dosage form, etc. Therefore, direct comparisons of the presented results should be done carefully. Another conclusion that can be drawn from the summarized studies is that harmonized protocols for in vivo studies would be useful. As it was already mentioned by the other authors [169], some of the in vivo studies available in the literature regarding curcumin and its activities are constructed in a questionable way, without blinding or without reference groups of subjects treated with placebo formulation.

It must also be emphasized that some of the studies indicating the potential of curcumin as an active pharmaceutical ingredient report effects observed in vitro. The studies involving cell lines should be considered as a good starting point in the search for new pharmacological activities. However, in order to confirm the potential unambiguously, properly designed and conducted in vivo studies are necessary. It should also be noted that in the case of plant-derived compounds and plant extracts, the exact form must be taken into consideration, and standardized extract should not be treated as equivalent to the corresponding amount of pure active ingredient. As it was already mentioned in this review, turmeric rhizome is a rich source of many potentially active ingredients which can act synergistically. Therefore, the investigated form should be carefully described to avoid confusion and misinterpretation of the results, especially when the comparisons between different studies are made.

In the review, several different formulations designed for different purposes were presented, including mouthwashes, gels, different kinds of curcumin-loaded nanoparticles, collagen sponges and in situ gelling systems. As it was already mentioned, most of the summarized studies used different methodologies, which makes the direct comparisons difficult. However, in the selection of the most promising dosage form, a few important formulation aspects should be taken into consideration. As curcumin, the main active component of turmeric, reveals low stability susceptibility to photodegradation, the type of formulation should enable solubilization and also play a protective role towards the active ingredient. Therefore, plain suspensions seem to display the least favorable properties, as the drug is not protected from visible light and occurs in a crystalline form, which makes it less effective. Another important factor that can affect the efficacy of the product is related to the conditions in the mouth. In order to exert the therapeutic action, the dosage form must stay at the application site for a sufficient amount of time, without being removed with saliva. Therefore, in the case of formulations applied to oral mucosa, the addition of mucoadhesive agents should be considered.

As it was already mentioned by other authors [74], the physicochemical properties of curcumin, including poor solubility in water and instability, are the most important formulation challenges potentially limiting its incorporation in commercial dosage forms. On the other hand, the existing evidence of curcumin efficacy still seems to be insufficient to draw unambiguous conclusions. In order to fully understand the mechanisms underlying the curcumin activity and to define the areas of its application, more in vivo studies performed in comparable conditions are required.

In summary, the most important conclusions drawn from the literature review describing the potential applications of turmeric-derived compounds in oral diseases are as follows:

• the existing in vivo evidence of curcumin efficacy in oral diseases seems to be promising but is still insufficient;
• more extensive in vivo investigations, performed with the use of harmonized protocols, are required;
• due to low toxicity, low cost and promising literature reports, curcumin is worth considering mostly as an adjuvant therapy in some oral conditions;
• unfavorable physicochemical features of curcumin (e.g., susceptibility to degradation, poor solubility in water) may limit its application;
• in the case of nanoformulations, frequently investigated as potential carriers for curcumin in order to minimize the impact of its unfavorable properties, safety profile should be carefully assessed.