1. Introduction

Nutraceuticals are characterized as ‘specially designed preparations’, formulated with the aim of fulfilling specific dietary requirements and/or offer preventive health care. Nutraceuticals are the formulation of nutrient/nutrients which helps in prevention and treatment of some diseases, in addition to a supplement diet. Nutraceutical is a term given by Dr. Stephen De Felice in 1989 and came from two words “nutrition” and “pharmaceutical”. These are foods or a part of foods that are beneficial in providing various health benefits including the treatment and/or prevention of the disease. Science of nutrition has increasingly achieved new horizons, starting from the anticipation of deficiencies in nutrients to prominence on human health and prevention and treatment of chronic ailments. Terms ‘nutraceuticals’, ‘food supplements’, ‘dietary supplements’ have evolved after the concept was originated by Dr. De Felice. There is no sharp demarcation between food supplements and nutraceuticals given by regulatory authorities. Literature of recent years emphasizes on redefining the concept of nutraceuticals, taking into consideration the efficacy, safety and toxicity of these products. Food products are nourishing substances that are eaten, drunk or otherwise taken to sustain life, provide energy and promote growth. Currently, isolation of nutrients from these food products are well recognized and used. The starting point to differentiate food/dietary supplements and nutraceuticals is the identification of an epidemiological target, followed by safety and efficacy studies that understand the mechanism of action. One approach to differentiate these two types of formulations is describing ‘food supplements’ as agents to compensate deficiencies in micro- or macronutrients; in addition, the use of a “nutraceutical” in the treatment of a pathological disease must be supported by strong scientific evidence [1]. With adequate clinical evidence, nutritional supplements should have a strong safety profile with few undesirable side effects and better bioavailability. There is a very fine line of demarcation between two type of formulations: the same ingredients may work as a nutraceutical or food supplement, but may be demarcated on the basis of claims. Nutraceuticals include single or combinations of pro- and pre-biotic foodstuff and food for special medical uses; and food supplements includes single or combinations of mineral, vitamins, protein supplements, functional foods and herbal products. By prolonging or eliminating the need for pharmaceuticals in subjects to fit for an alternative nonpharmacological treatment to a pathological condition, the incorporation of nutraceuticals into daily diet may aid in the prevention of pathological disorders. There are claims that foods including spices and herbs possess the tendency to decrease the risk of many diseases and can be highly beneficial in improving the quality of life [2]. There is a plethora of benefits that nutraceuticals have provided, including their promising results in the prevention and treatment of complicated diseases. However, there is a need of administration and prescription of nutraceuticals and they should be strictly regulated in order to prevent their uncontrollable use and side effects [3]. Several researchers have studied drug compound-based nutraceuticals to improve the efficacy as well as bioavailability. The safety and efficacy of various statins have been used in the prevention of cardiovascular diseases even in pregnant women. Nutraceuticals with an effective safety profile and well-established impact onpregnancy might be a suitable therapeutic option for preventing diabetes mellitus and hypertensive disorders, or as an adjuvant to therapy with standard medications. Calcium, omega-3 polyunsaturated fatty acids, vitamin D, folic acid, resveratrol, alpha-lipoic acid, zinc, inositol, and probiotic supplements are potentially proven candidates as novel nutraceuticals [4]. Researchers have evaluated the nutraceutical associated with the drug compound ezetimibe for patients atrisk of elevations of statin level, which further leads to cardiovascular diseases [5]. The use of a novel nutraceutical in blend with non-steroidal anti-inflammatory drugs (NSAIDs) has been proven a potential candidate for osteoarthritis, thus improving its efficacy and safety for commercial use [6].

The market remains robust and ever-growing for nutraceuticals such as antioxidants; omega-3 fatty acids; plants such asalgae, aloe vera, seaweed, and wheatgrass; teas and herbs such asginseng and Echinacea. A detailed findings including clinical data on nutraceuticals are shown in Table 1 [7,8]. A recent survey suggested that the nutraceutical market is expanding globally and the probability states that it may reach up to $340 billion by the year 2024. The compound annual growth rate (CAGR) of nutraceuticals is estimated to be 7.2% in the year 2016 to 2024. This increment in the growth of the nutraceuticals-based industry is associated with various factors such as a rise in demand for nutraceuticals, an awareness among people for the benefits of nutrition and an incremental rate observed in the healthcare graph [9,10]. Currently, Europe, USA and Japan account for ˃90% of the total global nutraceutical market and the global market is supposed to reach $336 billion by 2023 from $247 billion in 2019 at a CAGR of 8%. With this attainment of maturity of global markets, now the focus of nutraceutical players has been shifted towards developing economies, especially those across Asia Pacific, including India. The Indian market had only 2% market share of total global nutraceutical market in 2017. It is estimated to reach $11 billion by 2023, increasing at a CAGR of 21%. By 2023, India is also expected to hold at least 3.5% market share of the global market [11,12].

The COVID-19 virus is having a knock-on effect for every industry. The long-term repercussions are hard to predict as of yet. In a post-COVID-19 pandemic situation, the global economy is still struggling and its impact on the global trade and nutraceuticals market is rising with rapid deterioration in the supply of products irrespective of high demands. Nutraceutical industry is not able to bridge the gap between high demand and low supply as 75–80% of raw material used in nutraceuticals was sourced from China in North America, Europe and Asia Pacific. Due to China’s manufacturing shutdown, and the sudden recessive conditions in native regions, the nutraceutical production has reduced. The sharp surge in demand was observed for dietary supplements from consumers, as they provide a strong immune function and decrease possible health threats [25].

However, an officially shared and accepted definition of nutraceuticals is missing; these are also referred as ‘pharma food’—a powerful toolbox that is beyond the diet but before the drugs. Various formulations containing macronutrients (required in large amounts, e.g., omega-3 fatty acids, magnesium, potassium and calcium) [26], micronutrients (required in lesser amounts, e.g., minerals or vitamins) [27] and phytochemicals that are present in the food source [28] and are available at drug stores. Further, probiotics [29], minerals [30], polyunsaturated fatty acids [31], carotenoids [32], amino acids and proteins [33], vitamins [34], dietary fibers [35], spices and phytochemicals [36] have also become part of these formulations. Nutraceuticals exist as various types and may range from herbal products to isolated nutrient diets and may go up to existing genetically modified foods [37,38,39]. Plant foods such as vegetables, whole grains and vitamins are rich in dietary phytochemicals. Dietary supplements are consumed as such, or as isolated active ingredients. These phytochemicals are immensely diverse and these include carotenoids [40], phenolics [41], alkaloids [42], organosulfur [43] and nitrogen containing compounds [44]. However, these products may not be substantiated by scientific data on their safety, efficacy and effect on health and/or pathological conditions.

In the pharmaceutical industry, it is mandatory to do clinical tests on animals or in vitro for the verification of a compound’s effects. On the contrary, in nutrition, there was no such method in the past for the verification of effects of foods in preventing or treating diseases. In recent years, however, the food composition has been scientifically tested and verified as people are becoming more and more aware of health-related issues and how food can directly or indirectly be responsible for maintaining proper health and preventing diseases (Figure 1) [45,46].

Nutraceuticals provide their benefits in a wide range of therapeutic areas such as cough and cold [47], anti-arthritis [48], digestion [49], sleeping disorders [50] and treatment of cancers [51], depression [52], diabetes [53], cholesterol [54], blood pressure [55] and pain killers [56]. The research and development sectors for nutraceuticals are working at their peaks to discover how various nutraceuticals can prove to be of significance in the pharmaceutical industry. Scientific needs for nutraceuticals demand standardization of the constituents and cautious development of protocols and implement clinical studies which will form the foundation for consumer health and impact on nutraceutical companies [57,58].

In the last 10 years, a huge growth has been observed in the awareness of nutraceuticals and their use as powerful therapeutic supplements. Nutraceutical medicine has now been accepted as a part of Complementary and Alternative Medicine (CAM) and, thus, it has been incorporated as a new branch of CAM [59,60].

Due to dynamic action of nutraceuticals (nutritional and medicinal action), their popularity amongst general public and healthcare providers has increased over medicines. A current review comprehensively discusses the use of nutraceuticals in preventive and support therapy, followed by compiled literature on patents published on said topic.

2. Nutraceuticals in Various Diseases

Nutraceuticals help enhance health, wellbeing and modulating immunity, thus preventing and treating various diseases and health issues (Figure 2) [61]. There are a variety of diseases that can be treated with the help of nutraceuticals which are discussed below:

3. Formulations and Challenges Involved

A quality nutraceutical formulation with physical and chemical stability, adequate safety, technological feasibility and still cost effective entails many challenges. When compared with drug molecules that are well defined chemical entities, botanicals are complex ingredients containing multiple chemical constituents and usually several classes of compounds are present in a single product. Most of these botanicals are susceptible to heat, light, oxygen, alkaline pH and elevated humidity. These are usually having poor flow, bulk density and variable particle size distribution. Thus, successful development of nutraceutical formulation requires knowledge of the fundamental aspects of the physicochemical properties of the different types of ingredients, the use of adequate techniques of manufacturing, selection of the right excipients and the addition of suitable manufacturing overages based on critical stability studies [126,127]. Here, emphasis is given on:

• Challenges with various dosage forms;
• Approaches to deal with formulation challenges;
• Excipients selection.

4. Safety and Quality Control of Nutraceuticals

Nutraceuticals are taken as supplements by users, which are available as over-the-counter products. Therefore, their safety is of prime concern, else it may lead to lethal effects. The most commonly observed issues are contamination, adulteration (inadvertent or intentional) or misleading labels. To demonstrate adulteration, three different detection strategies may be adopted as (1) the presence of an undeclared substance, (2) that a component is deviated from its normal level (content) and (3) that a profile is unlikely to occur [155].

Adulteration may be inadvertent adulteration or intentional adulteration. Inadvertent adulteration may exist due to different conditions. For example, during the different stages of plant growth, the formulation and manufacturing of nutraceuticals, or during storage, contamination with fertilizers, heavy metals, fertilizers or microbial agents may take place. Adulteration may also take place with synthetic drugs, substitute species, dust, pollens, insects, rodents, parasites, microbes, fungi, mold, toxins and heavy metals. Any of this type of contamination may lead to infections or even serious illnesses such as gastritis and associated complications, liver injury and even life-threatening conditions. Therefore, raw-material and finished-product quality control is required and may be determined by specifications outlined in certain monographs, along with stability of active compound(s) and microbiological control [156].

Serious harmful effects may result from the intentional adulteration in supplements or herbal remedies. It usually occurs with synthetic compounds, mostly undeclared. It usually occurs with the intentions of altering pharmacological response and earns economic benefits. The sourcing of nutraceuticals from plants is often very limited, and extract preparation is time- and cost-consuming [157,158]. Therefore, these adulterations are not allowed from regulatory authorities.

Some examples of adulterations are quoted in below sections.

• (a)

  Ibutramine hydrochloride monohydrate is a drug molecule that works by inhibiting serotonergic and noradrenergic reuptake and shows effects as an anti-obesity drug, and is a common adulterant. In a study conducted with twenty-two samples of dietary supplements in China, eleven were found to be contaminated with phenolphthalein, N-mono-desmethylsibutramine, and sibutramine. In another similar study performed on fifteen samples in China, four of them contained sibutramine and N-di-desmethylsibutramine [159]. Further, it has also been reported that two pregnant women in Turkey lost their wombs due to consumption of adulterated Chinese herbal medicine “meizitanc” [160]. Sibutramine has also been reported as a solvent in slimming preparations. It has led to mania-like psychosis in two women in Hong Kong [161].

• (b)

  Fenfluramine is another dug that was used as an adulterant in Chinese traditional medicines and found in many slimming preparations. It caused primary pulmonary hypertension and valvular heart disease. This drug was withdrawn from market in 1997 [162].

• (c)

  In some weight control programs using an orexigens, diuretics, stimulants and laxative agents, it has been demonstrated that these products contain adulterants as ephedrine, norephedrine, caffeine and furosemide [163].

• (d)

  Morphological substitute usage is another common example of adulteration that may cause serious health issues. For example, Panax ginseng (Araliaceae), also known as “Asian or Korean ginseng”, is used as traditional medicine. It has been found to be adulterated with roots of Panax quinquefolius L. (American ginseng) and Eleutherococcus senticosusmaxim (Siberian ginseng), which may cause health problem [164,165]. Another similar example is Panax ginseng being used as adulterant in roots of Mandragora officinarum L. (Solanaceae) because they are morphologically similar, but have completely different pharmacological effects and phytochemistry [166]. Further, roots of Pfaffia panaculata (Mart.) Kuntze (Amaranthaceae), also known as “Brazilian ginseng or suma root”, morphologically resembles P. ginseng roots, but the phytochemical content is different and, hence, pharmacological action is also different [167].

• (e)

  Some other examples of physical similarity between species include the flower Anthemisnobilis L. and the chamomile, Matricaria chamomilla L. (Asteraceae), both of which are listed in the European Pharmacopoeia as therapeutic plants, as well as several other species in the family Asteraceae, such as Tanacetum parthenium (L.) Sch. Bip., Tanacetum cinerariifolium (Trevir.) Schultz Bip., Tripleurospermum callosum (Boiss. et Heldr.) E. Hossain, Bellis perennis L.and Leucanthemum vulgare L. Furthermore, the pharmacological activity differs depending on the phytoconstituents [168,169].

• (f)

  One of the serious intentional adulterations is use of peanut skin extract in different grape products. Grape seed-containing drugs are said to have very high bioactive polyphenols content and used in prevention of cardiovascular and neurodegenerative disorders. The peanut skin is used as it is widely available, is a high-volume byproduct and is very cheap compared to grape products. However, it is a potential allergen, which may cause serious concerns when used as adulterant, which has been reported in a study where tested products contained no detectable quantities of grape seed extract, but only peanut skin as adulterant [170].

• (g)

  One of the most important categories affected by adulteration is species containing essential oils (spices). As these spices are of high economic value and are export-oriented commodities, these are widely adulterated with natural and synthetic adulterants. One of the most commonly reported examples is adulteration of pure Lavandula angustifolia Mill. (Lamiaceae) oil with other species of same genus, which are almost six times cheaper. Essential oils from citrus are usually adulterated with sweet orange essential oil. Another quoted case is use of citronella oil (Cymbopogon winterianus), which is quite cheaper, as an adulterant in very high economic value essential oil from Melissa officinalis herb (balm oil). Melissa officinalis herb contains citronellal as the main constituent whereas citronella oil contains enantiomeric mixtures of citronellal [171,172].

• (h)

  Another intention of adulteration is to add to the industrial value to the product. For example, synthetic α-irone and β-irone is added to iris (Iris sp., Iridaceae) oil to enhance the commercial value of the product, linalyl acetate or linalool, as the olfactory quality of bergamot or lavender oil becomes improved [171,172]. Other similar cases are when vegetable oils are added to increase the weight of other products—for example, lemongrass oil is diluted with coconut oil and sandalwood oil with polyethylene glycol. Leaf cinnamon essential oil contains lesser quantity of cinnamaldehyde but has the same olfactory notes as those of cinnamon bark essential oil, and, therefore, it has been reported as adulterant. Cheaper petit-grain oil made from leaves is used as adulterant in neroli oil made from the flowers of Citrus aurantium L. spp. amara L. var. pumilia (Rutaceae) [171]. Another case study reports that samples of the dietary supplements containing the leaf extract of G. biloba, used for cerebrovascular diseases, tinnitus and Alzheimer’s type of dementia, were demonstrated to be adulterated with free flavonols and glycones (such as quercetin and kaempferol, respectively) as well as genistein, the isoflavone derivative [173]. In another case, abietic acid has been reported as an adulterant in a herbal preparation used for the treatment of psoriasis [174].

• (i)

  One potential hazardous adulteration that has harmful effects on human health is adulteration with allopathic drugs. The commonly used molecules in such types of adulterations are non-steroid anti-inflammatory drugs (NSAIDs), steroids, anti-diabetics and analgesics. For example, glibenclamide and metformin are reported in anti-diabeticherbal/botanical supplements [175,176,177]. In addition, it has been reported that herbal anti-diabetic remedies contain chlorpropamide, gliclazide, glimepiride, glipizide, pioglitazone, tolazamide and tolbutamide. Many analgesic compounds, including codeine, indomethacin, ketoprofen, morphine, oxyphenbutazone, paracetamol, phenylbutazone, diclofenac, dipyrone, ibuprofen, mefenamic acid, salicylamide and salicylic acid, are found in adulterated dietary supplements. It has been reported that herbal preparations contain anabolic steroids and hormones, such as rostendione, betamethasone valerate, betamethasone, clenbuterol, dexamethasone, flumethasone, hydrocortisone, prednisolone, prednisone, testosterone propionate, testosterone isocaproate, testosterone phenylpropionate and testosterone decanoate [178]. Another significant case that has been reported is adulteration with phosphodiesterase type-5 (PDE-5) inhibitor analogues, such as sildenafil citrate (Viagra^®, Pfizer, New York, NY, USA), vardenafil hydrochloride (Levitra^®, Bayer, Leverkusen, Germany), and tadalafil (Cialis^®, Elli Lilly, Indianapolis, IN, USA), have been found in dietary supplements containing well-known natural constituents such as Panax ginseng L., Astragalus membranaceus (Fisch.) Bunge, Schizandra chinensis (Turcz.) Baill., Ginkgo biloba L., and many others. One of the possible consequences of such adulteration with prescription-only drugs such as phosphodiesterase type-5 (PDE-5) inhibitor analogues, which are contraindicated in men taking nitrates, may lead to unsafe drop in blood pressure. Such reported adulterations are homosildenafil in a food beverage; acetildenafil and hydroxyhomosildenafil in some other herbal products; vardenafil, sildenafil, tadalafil, and vardenafil in an herbal product sold in Hong Kong; benzamidenafil in herbal products; and thiosildenafil, a thioketone analogue of sildenafil, in herbal aphrodisiac supplements; nitroso-prodenafil, a prodrug of aildenafil, is also a reported adulterant, which is as carcinogenic as nitroso derivatives. Researchers examined 91 herbal items for the presence of PDE-5 inhibitors and found that 74 of them actually contained the PDE-5 inhibitor analogs, despite the fact that none of the labels mentioned the presence of a synthetic inhibitor. Eighteen of twenty-three herbal dietary supplements on the Dutch market tested positive for sildenafil or a comparable PDE-5 inhibitor in a similar investigation. [179,180].

Misleading labels are also one of the sources that lead to harmful effects on human health. In one study conducted on five samples of soy-based dietary supplements, the isoflavone content was analyzed and compared with claimed label checked. It has been reported that three of five supplements failed to contain the claimed amount of the isoflavones, i.e., genistein and daidzein. It has also been mentioned that one of the preparations that claimed to contain 60 mg of isoflavone based on genistein per tablet and was found to contain 1.538 mg of genistein per tablet after HPLC analysis [181].

5. Formulation Challenges

Drug interactions may be described as the situation when the activity of one active constituent is affected due to presence of other constituents. It may be food–drug interaction or drug–drug interaction. The pharmacological response may alleviate, lessen or induce side effects [182,183].

• (a)

  Garlic (alicin) exhibits a hypotensive property and a hypocholesterolemic effect, acts as an anti-inflammatory agent and possess anti-bacterial as well as anti-fungal properties. When it is administered with anticoagulants (such as warfarin), it may lead to increased bleeding. With hypoglycemic drugs, such asinsulin or glipizide, it may cause hypoglycemia. With protease inhibitors (such as indinavir or saquinavir), garlic decreases their blood levels and effectiveness [184,185].

• (b)

  Ginger is commonly used to treat various types of stomach problems—such as, to expel gas, formotion sickness, diarrhea, nausea (anti-emetic) and loss of appetite. It is also used in pain relief from arthritis, menstrual pain, upper respiratory tract infections—coughs and bronchitis. Ginger taken with anticoagulants may lead to risk of bleeding. If ingested with hypoglycemic drugs, such as insulin or glipizide, it may cause hypoglycemia. When co-administered with calcium channel blockers, ginger might reduce further or cause an irregular heartbeat [186,187].

• (c)

  Green tea (polyphenols) improves mental alertness and thinking. It is also used to treat a plethora of other medical conditions, including Crohn’s disease, Parkinson’s disease, cardiovascular disease, diabetes, hypotension, chronic fatigue syndrome (CFS), tooth decay, kidney stones and skin conditions. Consuming green tea with stimulant medications could have dangerous consequences, such as elevated heart rate and blood pressure. Bortezomib (Velcade) may not be as effective against some cancers if used with green tea. Consuming green tea may reduce the effectiveness of warfarin [188,189].

• (d)

  The leaf extract of Gingko biloba is effective in the treatment of Alzheimer’s disease and other forms of dementia, Raynaud’s syndrome, peripheral vascular disease, vertigo and dizziness, premenstrual syndrome (PMS) and improving color vision in people with diabetes. Ginkgo, when administered with anticoagulants/with NSAIDs, it may increase the risk of bleeding. When administered with anticonvulsants, it may reduce the effectiveness in preventing seizures [190,191].

• (e)

  Licorice has been used for various digestive system complaints such as stomach ulcers, heartburn, colic and chronic gastritis. It is also used for sore throat, bronchitis and in treating infections caused by bacteria or viruses [192]. Licorice is also used in an herbal form called Shakuyaku-kanzo to increase fertility in women. It is also used to treat prostate cancer and the skin disorders such aseczema, in combination with other herbs. It may make antihypertensive drugs less effective, as it may increase salt and water retention. When taken with anti-arrhythmic drugs, it may decrease their efficacy as it may increase the risk of an abnormal heart rhythm. In some cases, it decreases the levels of potassium as it increases urine formation. In such cases, the risk of digoxin toxicity also increases, if patient is on digoxin [193,194,195].

• (f)

  Kava root (kava-lactones) medicine, native to South Pacific, is used to calm anxiety, stress and to treat insomnia. It is also used in the treatment of attention deficit hyperactivity disorder (ADHD), depression, migraines and other headaches, chronic fatigue syndrome (CFS), epilepsy, psychosis, common cold and other respiratory tract infections, muscle pain, tuberculosis and cancer prevention. Kava is applied to the skin for some skin disorders such asleprosy, to promote wound healing. It is also used in urinary tract infections (UTIs), pain and swelling of the uterus, menstrual discomfort and hot flushes in women with menopause. It is also used as pain reliever in toothaches. When co-administered with barbiturates and benzodiazepines, it may prolong or intensify their effects [196,197].

• (g)

  Chamomile (tea extract) is used as tea or dietary supplement for stomach cramps, to treat irritation from chest colds. It is also used for slow healing wounds, abscesses, gum inflammation, and skin conditions such as eczema, chickenpox and diaper-rash. The risk of bleeding increases when it is co-administered with anti-coagulants. Iron absorption also reduces in the presence of tea extract. The pollen is allergic in some cases. If one is allergic to ragweed pollen, chamomile use must be prohibited [198,199].

6. Patent Literature

Several published patents on nutraceutical applications in various areas, such as the agriculture and healthcare sector (such as promotion of health and disease prevention), and as nanocarriers for the improved delivery of nutraceuticalsas a support therapy for many diseases, have been summarized in Table 3. Many nutritional products are commercially available and used widely.

7. Conclusions and Future Prospects

To conclude, nutraceuticals area potentially growing sector and are engaged in both the fields, either medical treatment or nutrition so as to assure integrated medical assistance. These act as potential dietary supplements, prevention of diseases such as CVD, the support and treatment of various types of cancer, and other healthcare benefits. Therefore, nutraceutical industries now understand and perceive extensively about the potential success of nutrients that affect people in healthcare. At present, medical care is assessed to be the domain of drugs. On the contrary, nutrition is only appraised to be a product for healthy living. In the forthcoming years, it is anticipated that work will be performed, as they both interact and complement each other. The implementation of newer technologies such as the application of genetically modified technology in the food industry, nanotechnology-based nutraceuticals, etc., leads to better medical treatment and health care benefits, which further extended the increase in the nutraceuticals revenue market. The scientific research ratifies that the improved safety and potential effects of newly developed nutraceutical products will further stimulate the investments in newer technologies, such as nutrigenomics, converging techniques, varied imaging technologies and its applications in nutrition development and healthcare.

Author Contributions

Conceptualization, A.S.; methodology, V.P., M.N. and G.A.D.; resources, T.S.; writing—original draft preparation, V.P., A.S., D.D., K.H. and G.A.D.; writing—review and editing, A.S., I.S., G.A.D., M.N., T.S. and M.S.; supervision, K.H. and I.S. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Funding Statement

This research received no external funding.