The Elements Defining the Potential for the Development of Health-Promoting Substances from Secondary Herbal Materials

Abstract

Agricultural waste is rich in bioactive molecules. When evaluating the viability of circular models for the development of health-promoting substances and final products, it is important to highlight that the industrial processing of fruits and other valuable herbal materials generates a considerable number of by-products and significant amounts of waste that contain health-promoting components. These by-products can be utilized purposefully in pharmaceuticals and related areas for the development of health-promoting products. The linear utilization of agricultural waste results in the loss of a range of valuable bioactive compounds, including polyphenols (anthocyanins, flavonoids, phenolic acids, and related compounds), antioxidants from other groups, phytosterols, tocopherols, and fatty acids. As an illustrative example, the waste materials of species belonging to the Vaccinium L. genus represent a notable secondary resource that can be purposefully applied to the development of health-promoting preparations. The fruits of these wasted herbal materials have been found to contain beneficial polyphenols, which play a pivotal role in the prevention of various chronic conditions, including precancerous conditions, inflammatory diseases, and other ailments. In addition, the fruits of blackberries, elderberries, and purple corn—which are similarly rich in anthocyanins—also provide a promising avenue for further development. Phenolic compounds suitable for recycling are also found in the by-products of sugarcane harvesting. Tomato waste contains a significant amount of lycopene, which is a valuable carotenoid. Other physiological functions may be attributed to the aforementioned by-products of fruit processing which, if used properly, can contribute to the prevention of certain diseases and improving quality of life. This review assesses the gaps in the existing literature on the development of health-promoting substances from herbal secondary materials.

1. Introduction

The development of health-promoting materials is a complex and resource-intensive process, both in terms of scientific experience and economic investment. The integration of various related processes is a crucial aspect of such activities. It is noteworthy that efforts to integrate sustainability aspects more universally remain limited in the pharmaceutical sector [1].

A variety of solutions may be selected to enhance sustainability, among which the application of circular bioeconomy models represents a particularly crucial approach. Over the past decade, there has been a notable increase in the number of research studies concerned with the development of sustainable and/or greener production processes. These processes are designed to achieve two key objectives: the first is the growth of the bioeconomy, and the second is a reduction in negative consequences felt by both society and the environment [2].

At this time, one of the promising areas related to health-promoting substances in the context of circular bioeconomic models is the isolation of and subsequent research into by-products derived from waste of plant origin. Recycling such waste can yield not only a versatile array of biofuels but also a spectrum of ingredients and products with superior health benefits [3]. For example, the fruit cake and seeds that remain after fruit processing are still being underestimated as a source of health-promoting compounds. Although residual seeds are rich in phytochemical compounds, which have a variety of health-promoting properties, recycling of such seeds is often uncomprehensive and is not widespread [4]. The use of residual seeds from other valuable forms of herbal waste in the pharmaceutical and functional food industries can help not only to solve waste problems but also generate additional revenue for fruit-processing facilities. However, further research is required to achieve this goal, as many of the nutritional components of fruit seeds remain to be identified [5]. One of the reasons for the continued debate surrounding the concept of recycling is the absence of a comprehensive and rigorous examination of secondary materials. Without such an examination, the true urgency of solutions and corresponding results cannot be accurately projected. This is because only a definition and understanding of our scientific and technical progress in the development of health-promoting substances from secondary herbal materials can help us to accurately perceive how badly solutions are needed. Therefore, the aim of the review was to identify the scope of the related scientific knowledge in this area.

1.1. A Circular Economy Model for the Development of Health-Promoting Products

Previously proposed bioeconomic models support the hypothesis of an effective closed-loop approach in which waste from human activities is recycled through the steps of circular processes [6]. In circular models, new ways of capturing and maintaining value are being developed (usually through the reuse of materials) [7,8,9]. In this context, the circular bioeconomy has been defined by the production of renewable biological resources and the conversion of such resources into value-added goods [10]. Such widely accepted principles are purposeful and well-supported. For example, the framework of the European Commission sets out targeted strategies to reduce misuse, reuse, recycle, and reclaim [9,11,12].

The integration of the circular principles in the inert sectors of the bioeconomy (such as the development of health-promoting products) necessitates substantial modifications to the prevailing system, encompassing both production and consumption activities [2,9]. Major reforms must aim to reduce barriers and bottlenecks. Contemporary economic solutions must be appropriately expanded to facilitate the conservation of natural resources and to manage existing inequalities in the availability and consumption of more sustainable health-promoting measures. The integration of the principles of the bioeconomy into the design and development of health-promoting products will be broadly beneficial and serve to provide sustainable goods and services that utilize renewable biological resources and processes [13].

In their 2019 study, Vermundt et al. provided an overview of the principal circular business models. The “product-as-a-service” business model is defined as a model in which the company retains ownership of the product and customers use the product as a service. Revenues are derived from leasing agreements and distributed over a period, rather than generated at the point of sale for a specific product. The second category comprises business models that extend the lifetime of the product through reuse, production, maintenance, or repair. This model is most closely associated with the “reuse” strategy. Meanwhile, business models aimed at closing resource loops are characterized by resource recovery and circular supply. The resource recovery business model is concerned with the recovery of resources to create new forms of value, which is most often associated with recycling and recovery strategies. In this process, a market participant may alter the function of the original product or component. For illustration, when electrical appliances are recycled, their original function is lost; however, the metals are recycled and can be used to manufacture other products. The utilization of circular alternatives in replacement of conventional materials and products may present certain challenges to product development, given the potential necessity for adjustments [9]. Some of the problematic factors are undoubtedly relevant in the field of the production of health-promoting products. The researchers identified several key challenges, including administrative burdens, infrastructural and management-related shortcomings, a lack of competence and knowledge, and limited volumes of raw materials currently available. Additionally, lack of awareness, resistance from market participants in the linear economy, regulatory policies, and limited support for the development and registration of quality products should be noted. Infrastructure and practical design-related barriers are less likely to be significant issues in the production of products that are closely related to agricultural sources, such as by-products of plant origin. In the field of herbal health products, there remain a few unfavorable factors, all of which require further action in pursuit of effective management. In a study published in 2021, Donner et al. identified five categories into which to split these factors; they are related to the production of secondary materials suitable for use in the manufacture of health-promoting products [2]. First, scientists concentrated on the technical and logistical aspects of the process, given that innovative technologies frequently require the implementation of novel, sufficiently complex methodologies to obtain valuable biomolecules or high-quality materials. Concurrently, they also highlighted effective and adaptable logistics and substantial storage capacity, emphasizing the heterogeneous and variable quality of agricultural resources. Further investment is required in the research and development of this second category. The prices of new herbal products are lacking in competitiveness and thus require regulation. The third category of factors encompasses organizational and spatial factors, whereby the optimal conditions for success include the adequate geographical proximity of entities. The fourth category of factors is institutional and legal [2]. Unfortunately, in the case of health-promoting products, these factors have the potential to be the most disappointing, as they are not sufficiently discussed or focused on. The current and regulatory inequities in the management of agricultural waste, coupled with the difficulty in predicting changes in individual regions, can lead to significant risks. It is important to note that there are regulatory gaps in the development of second-source active herbal medicinal substances. To illustrate, this subject has not been adequately addressed in the context of European herbal medicines regulatory practice. The European Medicines Agency has published a guidance document on the chemistry of active substances (EMA/454576/2016), which establishes the principles that should be adhered to guarantee the appropriate regulatory supervision of post-treatment chemicals. The guidance states that the process of reprocessing must be clearly described and that criteria must be established to determine when reprocessing is an appropriate action. Furthermore, the guidance addresses the recovery of process solvents and intermediates, as well as chemically active substances. It notes that such practices are generally considered acceptable in accordance with ICH Q7. The related document EMA/HMPC/453258/2013, which addresses the use of recovered and recycled solvents in the manufacture of herbal preparations intended for use in herbal medicinal products and traditional herbal medicinal products, sets forth requirements pertaining to the reuse of excipient solvents. It is important to note that the principles set out in the above-mentioned documents may not be directly applicable to the extraction of herbal health-promoting substances from secondary herbal material by biorefining. Factors such as differences in the composition of both the starting matrix and the targeted components, as well as the excipient vs. active ingredient functionally determined QA/QC principles, may lead to significant discrepancies between the two approaches. The absence of a viable regulatory model for the regulation of secondary herbal source materials or final medicinal products derived from secondary herbal materials represents a significant challenge for researchers and the developers of phytopharmaceuticals. This situation has led to the implicit creation of a model whereby active pharmaceutical ingredients derived from secondary sources are avoided due to their inherent risks, and the development of herbal medicines is restricted to solvents only. Within the commercial health promotion market, even targeted modifications used to increase the sustainability of traditional herbal pharmaceutical products can prove to be significantly challenging, as they must navigate a multitude of obstacles before reaching the market. The development of this market is subject to several barriers, including the validity of regulatory decisions and restrictions on the promotion and wider inclusion of medicinal herbal remedies in basic healthcare [14]. The promotion of a green economy requires both the suitable reuse of by-products in our current context and the purposeful formation of a new regulatory environment. A further (fifth) category of factors relates to the attitude of society toward “green” products and processes [2]. It has been noted that companies implementing circular models encounter low acceptance and trust from customers. This problem has often been addressed by actively raising awareness and strengthening legitimacy [9]. It has always been necessary to provide evidence that products are safe for consumers and the environment. In the context of health products, the potential for adverse consequences may emerge when trying to change admissibility, which involves changing prejudices and policies within the domain of health promotion.

1.2. The Recycling of Food Waste and Green Chemistry in Circular Models

Food and agricultural waste is a highly potential resource that can be used in the production of health-promoting sources. The process of isolating bioactive substances from such waste that remains after the processing of food products may play a vital role in the circular bioeconomy of the future [15]. The European Union’s action plan for the circular economy identifies food waste as a priority for intervention [2,16]. In addition, researchers have indicated that 1.3 billion tons of global food waste is put into landfills on an annual basis [10,17]. In Europe, every year, 700 million tons of crops are wasted [2,18]. The fruit processing industry generates large quantities of by-products, including pomace, peels, and seeds [19]. It is further estimated that more than 30% of all food worldwide is wasted [20]. Such losses could cost the global economy more than USD 900 billion [10]. A substantial proportion of waste materials originate from herbal sources. Selected herbal materials, such as blueberry processing waste, already undergo processing and conversion into valuable final products [10].

It is evident that the economic viability of the bio-recycling process for such residual materials is contingent upon a few factors, including initial installation costs, the quality of the waste to be recycled, the quantity of waste, the efficiency of the waste supply chain, the market price of the products created, and the level of support provided by the government and other stakeholders [3,21]. The scale and needs of technologies based on resource recovery must also be assessed in a region-specific context [22].

Additionally, within pharmaceutical development and related fields, it is crucial to adopt and apply the principles of green chemistry alongside the secondary utilization of raw materials. Although the concept of green chemistry is a relatively novel field of study, it offers a promising avenue for achieving sustainability at the molecular level [1,23]. By avoiding the use of toxic solvents, reducing the number of production stages, and creating safer processes, it is possible to develop more biologically sustainable pharmaceutical products. Innovative eco-based procedures can be expanded to reduce time, solvents, and energy expended on them [24]. The application of green chemistry principles to the development of pharmaceutical products is an attractive proposition with support and feasibility. Moreover, the principles of reducing dependence on rare and costly primary raw materials may also serve to reduce the overall environmental footprint and eliminate inefficiencies in current circular models [9,25,26].

1.3. Types of Potential Secondary Raw Materials of Plant Origin

The fruit processing industry produces various by-products and waste, the disposal of which is a challenge on a global scale [3]. For example, one by-product suitable for processing is fruit seeds (

Table 1. Main secondary herbal starting materials can be used for health-promoting products.

Food residues

Fruit pomace and cakes

Parts of the fruit (seeds and otherwise)

Leaves and parts of the plant remaining after crop collection

Residues of extracts

).

With the proper management of secondary herbal materials, the substantial number of fruits and seeds that currently are removed from the home and agri-food sector could be used for the development of pharmaceutical products and cosmeceuticals [13,19]. At present, fruit seeds are largely underexploited in the food industry, meaning they are underestimated and often discarded. The composition of these parts of the plants incorporates a variety of phytochemicals that can be utilized in the development of health-promoting products. In addition to seeds, the rest of the fruit is still the subject of scientific inquiry and is not yet widely employed in the creation of health-promoting products [27]. Campalani et al. (2020) evaluated the waste generated by one of Italy’s foremost producers of canned fruit [28]. In addition to the production of the final products, the company also generates approximately 80 tons of organic fruit waste (including seeds, pomace, and other byproducts) from blackberries, raspberries, black currants, wild strawberries, pomegranates, and blueberries annually. The remaining waste is primarily composted [28]. Nevertheless, the isolation of bioactive compounds from secondary materials is feasible when appropriate methods are employed. Extraction is a commonly used method for the isolation of such phytochemicals [29]. The waste produced in the processing of citrus fruit consists of the peel, pulp, cake, and seeds that remain after the initial processing. A range of extractable phytochemicals have been identified in this waste, including pectin, essential oil, polyphenolics and flavonoids, carotenoids, oligosaccharides, organic acids, and vitamins [30,31]. It has been reported that approximately 10 million hectares of land are dedicated to citrus production, with the global citrus harvest reaching 98.7 million tons of fresh fruit [31,32]. The phytochemicals derived from citrus (genus Citrus L.) waste can be utilized as ingredients in nutraceuticals, phytopreparations, and prebiotics, and may also serve as a source of pectin and fiber. Additionally, citrus phytochemicals can be applied as emulsifiers, encapsulating excipients, components of nanoparticles, and ingredients in natural packaging materials [31,33,34]. Pectin and zein from citrus peel have been used to create nanoparticles enriched with resveratrol. Moreover, pectin oligosaccharides, which are obtained through the partial hydrolysis of pectin, also possess prebiotic properties [31,35,36]. Therefore, the peel of various citrus fruits can be reasonably reused; its most useful repurposing occurs in small-scale bio-refinement facilities for the extraction of pectin, essential oils, and other phytochemicals [3].

1.4. The Presence of Beneficial Antioxidants and Phenolics in Secondary Materials

Irrational exploitation of by-products results in the loss of valuable bioactive compounds. Flavonoids, anthocyanins, other polyphenols, antioxidants, tocopherols, important fatty acids, carotenoids, and phytosterols are currently the most studied. For example, fruit-processing-related waste from the Vaccinium species is one of the important renewable resources that can be widely applied to the development of health-promoting products. The fruits of the Vaccinium species contain polyphenols, which play a significant role in the prevention of various chronic diseases, including precancerous conditions, inflammatory conditions, and other diseases [3,37]. Pomaces of bilberries and blueberries are rich in anthocyanins, the bioactivity of which has already been proven by numerous studies. Therefore, such waste is a clear choice in the development of health-promoting products. Anthocyanins have well-known anti-inflammatory effects, but the literature also confirms that they can stimulate wound healing, protect the retina, manage intestinal health, and have antidiabetic, antioxidant, antibacterial, and other effects [38,39,40,41,42,43]. The color properties of anthocyanins (alongside other coloring phytochemicals) may also have pharmaceutical purposes. Anthocyanins can be successfully used to color products as they are a natural alternative to synthetic regulated Red 40 dye [44,45].

Hydroxycinnamic acid esters, especially chlorogenic acid, are also found in sufficient quantities in the herbal waste of the Vaccinium species [3]. As about 20–30% of the biomass of the fruit is transformed into pomace, which is rich in phenols and other active substances, secondary raw materials from species of this genus must be considered an exemplary source of phytochemical compounds suitable for industrial use [3,22,46,47].

Significant concentrations of anthocyanins have also been observed in other dark-colored fruits and vegetables that can be processed in considerable amounts, such as blackberries, elderberries, purple sweet potatoes, and black carrots [45,48,49,50]. Blackberry (Rubus glaucus Benth.) fruits are commonly processed into concentrates, jams, and juices [51,52]. About 20% of the fruit mass remains as blackberry pulp [52].

Violet-colored maize (Zea mays L.) is also a viable alternative for the extraction of anthocyanins due to the high concentration of the aforementioned phytochemicals (4–10 g/kg) and the low costs of its storage and processing. It has been highlighted that most of the anthocyanin present in purple maize is concentrated in parts that can be easily separated, while the rest of the fruit can be used for food and the production of bioenergy [45].

High-quality biodegradable remnants remain in the wine industry. Waste originating from grapes is rich in phenols, including flavonoids and anthocyanins with high antioxidant potential [53]. Modified bio-processing methods can extract 71.9 g of grape seed oil and 322.8 g of polyphenols from the processing of 1.0 kg of dry grape marc [3,53].

Apples are widely consumed worldwide. Some 20–30% of the total weight of apples consists of solid ingredients such as seeds, cake, and peel [13,54]. Such waste contains bioactive phenolic compounds such as phloridzin, chlorogenic acid, quercetin glycosides, phloretins, epicatechins, and procyanidin B2, all of which are promising compounds in the development of health-promoting products as they have antioxidative and other important properties [54,55,56,57].

Valuable phenolic compounds and valuable flavonoids also remain in the pulp of sugar cane (Saccharum officinarum L.). Sugarcane flavonoids contribute antioxidant and antiproliferative properties [58]. Tricin, one such sugarcane flavonoid, has shown chemo-preventive actions against gastrointestinal carcinogenesis in mice [59]. The remaining materials, such as tops, straw, filter cake, molasses, and bagasse can be purposefully used not only for the isolation of phenolic compounds but also for the extraction of various health-friendly lipids (such as octacosanol, phytosterols, long-chain aldehydes, and triterpenoids) [60].

Common waste products resulting from the canning industry are the peels and seeds of tomatoes. Tomato (Solanum lycopersicum L.) peels contain lycopene, an important carotenoid that is widely used in the cosmetic and pharmaceutical industries [61,62,63]. At present, lycopene is produced synthetically or extracted from tomato fruits grown for this purpose. The use of waste products such as peels and seeds for extraction of valuable carotenoids may change such production systems from the first to the third generation [64]. It has also been demonstrated that the utilization of cake, a common by-product of the processing industry, can facilitate the production of a range of valuable compounds in the development of functional health products [3,65,66].

1.5. Alternative Herbal Secondary Materials for the Development of Health-Promoting Substances

It is important to note that, in addition to the cultivation and harvesting of the plants, a variety of other byproducts remain, which can be utilized to create functional ingredients (Table 1). It is estimated that farmers around the world harvest more than one billion tons of different fruits each year, with millions of tons of different types of waste generated during harvesting and processing, including crushed fruit [3,67]. Researchers have stated that most of the waste generated during the production of citrus juice is composed of peels, which account for between 50% and 55% of the total weight of the fruit, and seeds, which represent between 20% and 40% of the weight of the fruit [31]. In practice, the cultivation of species of Vaccinium results in the production of a considerable quantity of post-harvest biomass, predominantly comprising leaves and twigs that remain following the harvesting process. It is important to note that the phytochemical composition of both food-grade herbs and the leaves of medicinal herbs—as well as other vegetative organs—may be similar or may be characterized by other valuable features. It can therefore be postulated that the utilization of the residual components of herbs following the harvesting process represents a potential foundation for the establishment of a novel co-destructive processive branch. At present, the fallen leaves of blueberries are typically incinerated or allowed to decompose naturally. However, blueberry leaves also contain phenolic antioxidants. For instance, Debnath-Canning et al. (2020) investigated these compounds and discovered that some of the compounds present in the leaves may have anti-inflammatory effects on the nervous system [3,68]. A variety of phenolic compounds have also been identified in the leaves of the apple tree, including quercetin glycosides that can be utilized in the production of products designed to promote health and improve well-being [69]. Furthermore, the processing of apples generates approximately 20 million tons of non-conventional waste annually, which may also include leaves, branches, and spoiled apples [54].

Apple (Malus domestica Borkh.) pomace comprises soluble and insoluble fiber, including pectin, indigestible oligosaccharides, cellulose, hemicellulose, and lignin [54,70,71,72]. Apple waste may contain up to 51% dietary fiber. Insoluble fiber constitutes 37% of the total, while soluble fiber accounts for 14% [54,73,74]. It can, therefore, be concluded that different fiber fractions can be used both together and separately to develop targeted probiotic or eubiotic functionalized formulations.

Cashew (Anacardium occidentale L.) apples, which remain after the processing of cashew nuts, are also considered a by-product of the agricultural process [75]. It is widely acknowledged that cashew apples with a bitter and astringent taste are not yet a very attractive commercial proposition. However, in the production of products for health promotion, flavor characteristics are not the most important factor. Raw materials with such characteristics can still be successfully used for the purification of individual bioactive compounds and in the production of extracts, provided their basic safety has been properly affirmed.

Another promising precursor for secondary use is waste from the processing of plum (Prunus domestica L.) fruits. Their potential utilization in the production of health-promoting ingredients is supported by the successful isolation of oil and polyphenols from plum seeds and pomace [76,77]. Plum seed shells constitute approximately 86% of the seed weight and, in addition to the seed kernels, can be employed for a variety of purposes including medicinal applications [78,79].

We should strive to devote greater attention to fruit seeds that have not previously been the subject of study or evaluation, and which are consequently frequently discarded. One example is the seeds of dates (Phoenix dactylifera L.), which are often discarded as waste. In fact, date seeds constitute as much as 11.32% of the total weight of dates [80].

1.6. Bioactivity and Application of Recovered Herbal Substances

The health benefits of fruit seed processing products and their components can be attributed to a variety of biological functions that can help augment a person’s health status or prevent disease, thereby improving their quality of life. As an example, researchers’ findings have shown that the essential oils of citrus peels may be used as antimicrobials or preservatives in the pharmaceutical sector [81]. Notably, a chemo-preventive effect was observed in the study of the effect of pomegranate (Punica granatum L.) seed oil on mice, the effect of apple (Malus domestica L.) seed oil on human lung carcinoma and cervical cancer cells, the effect of mango (Mangifera indica L.) seed oil on human breast cancer cell lines, and of citrus seed oils on mouse melanoma cells (which had an inhibitory effect) [19,82,83,84].

It has been demonstrated that anthocyanin-rich extracts can inhibit the growth of pathogenic microorganisms. An extract prepared from North American raw materials has been demonstrated to inhibit the growth of strains of E. coli, S. aureus, and L. monocytogenes [85]. Extracts featuring anthocyanins have shown strong antibacterial activity, which results in damage to the microbial membrane and acts on target enzymes [85,86]. These findings provide a valuable foundation for assessing the diverse applications of secondary raw materials in the context of antibiotic resistance.

Punica granatum L. seed oil, which contains a high content of punicic acid, enhanced the function of mouse B cells in vivo [87]. The antidiabetic activity of methanol extracts from grape (Vitis vinifera L.) seeds has been linked to the inhibition of α-amylase and α-glucosidase. The activity of extracts on α-glucosidase has been proven higher than that of α-amylase. The co-authors of the study, who published the results, posit that grape seeds may serve as an attractive functional ingredient in foods and may alleviate glycemia when consumed after meals [19,88]. Given that grape seed extracts possess anticholinergic properties in addition to their antidiabetic effects, the researchers hypothesize that grape seeds may be utilized in the context of neurodegenerative disorders [88].

In a study published in 2019, Athaydes et al. evaluated the protective effect of the ethyl acetate fraction of the extracts of avocado (Persea americana Mill.) seeds against artificially induced gastric ulcers in mice. The researchers proposed that avocado seed extract could act as an appropriate natural source for the prevention and treatment of gastric ulcers [89]. In evaluating the feasibility of extracting and consuming lipophilic bioactive compounds, it is crucial to acknowledge the impact of combined n-3 polyunsaturated fatty acids and herbal sterols on the expression of anti-inflammatory markers. A reduction in C-reactive protein (CRP), tumor necrosis factor A (TNF-A), interleukin-6 (IL-6), and leukotriene B4 (LTB4), and an increase in adiponectin (which plays a role in regulating glucose levels and the breakdown of fatty acids) has been demonstrated in hyperlipidemic individuals because of the use of these isolated compounds [90]. The systematic review and meta-analysis conducted herein confirmed the cholesterol-lowering properties of functional products containing phytosterols [91]. When assessing the effect of biorefined octacosanol on mice fattened with high-fat diets, an increase in lower body fat and liver lipid levels and higher insulin sensitivity were noted; such outcomes are associated with an increase in brown tissue activity and an improvement in liver lipid metabolism [92]. In a study conducted by Lee et al., the effects of octacosanol supplementation were examined in taekwondo athletes who had experienced rapid weight loss due to high-intensity training and calorie restriction. The findings of the study indicated an enhancement in the lipid profile, characterized by an elevation in high-density lipoprotein levels and a reduction in low-density lipoprotein and triglyceride concentrations [93]. Orally administered octacosanol (at doses of 100 mg/kg/day) has been shown to inhibit the expression of inflammatory cytokines in the mouse colitis pattern. Such a mechanism of action is associated with the protective effect of the compound on oxidative stress-related reactions in intestinal cells [94].

Naringin and hesperidin, the flavanones found in citrus peels, have been the subject of research demonstrating their phytotherapeutic and nutraceutical benefits. These compounds have been shown to possess antioxidant, anti-inflammatory, and carcinogenic properties [31,95]. Polymethoxylated flavones nobiletin and tangeretin from citrus peels were purposefully studied in the treatment of cardiovascular diseases, cancer, resistance to oxidation, and inflammation [96,97]. After studying the role of polymethoxyflavonoids obtained from Citrus sinensis L. peel extract in the treatment and management of gastric ulcers in male albino rats, researchers found that during the extraction of peel extract, the pH of the stomach increased significantly, and gastric acid secretion decreased [98]. In addition, scientists have highlighted the antimicrobial and health-promoting effects of citrus peels alongside their hepatoprotective, immunosuppressive, and cardioprotective properties [31,91,99,100,101]. The inclusion of Citrus sinensis peel extract in the diets of rats has a proven beneficial effect on their gastrointestinal health [98]. The inclusion of aged citrus peels (chenpi) in the diet of rats reduced their body weight and suppressed the increase in fat cells and the accumulation of lipids in adipocytes [102]. Therefore, the bioactive components of citrus waste can be used purposefully to protect from infections, allergies, and other chronic diseases.

Restrictions on the use of secondary herbal raw materials for health-promoting products are based both on the isolation of valuable phytochemicals and on the removal of substances hazardous to health [103]. To cite just one example, Prunus armeniaca L. (apricot) is widely used in the food industry. However, due to the cyanogenic glycoside amygdalin, including raw seeds of these fruits for human nutrition or health promotion is limited. It is important to remember that amygdalin itself is non-toxic, but the product of its decomposition (hydrogen cyanide) is poisonous. Therefore, due to the possible toxicity of apricot or other fruit amygdalin-containing seed kernels, fermentation, soaking, ultrasonic action, and microwaving should be implemented in order to detoxify before consumption [103]. Nevertheless, the elimination of identified hazardous components is inadequate without targeted biomedical studies conducted prior to utilization (studies on genotoxicity, hepatotoxicity, nephrotoxicity, neurotoxicity, or chronic toxicity to specific user groups). Given the current lack of understanding of the side effects of most herbal ingredients, as well as their potential teratogenic effects during pregnancy, we must consider their potential impact on this high-risk consumer group [104].

1.7. The Extraction and Treatment Strategies for the Recovery of Health-Promoting Substances

A variety of extraction procedures are employed for the recovery of bioactive components from a seed or pomace matrix [13]. The extraction of phytochemical compounds, such as anthocyanins, from secondary herbal materials may not always be economically viable. This is due to a few factors, including the potentially excessive costs of raw materials, the substantial amount of energy required for storage and processing, and the purportedly low income to be derived from the gross product [45]. Extraction methodologies refer to a group of techniques used to obtain a constituent from a plant or other source. The specific techniques and conditions used can vary considerably, resulting in differences in cost, time, and availability. If the conditions are properly selected, a high degree of selectivity combined with repeatability can be achieved. Conventional extraction techniques, such as classical maceration, can be used successfully to isolate thermolabile compounds. Percolation is typically more efficient than maceration, although it is less effective in terms of extraction yield and extraction time. However, it may still be a viable technique for achieving higher concentrations of the final extract. The application of water as a solvent in the preparation of decoctions makes this technique environmentally friendly; however, it is not suitable for heat- or photosensitive compounds. Reflux extraction is distinguished by a reduced solvent ratio and a more time-efficient extraction process; however, it does not apply to volatile and heat-sensitive compounds. Although highly efficient, Soxhlet extraction is a relatively time-consuming process that requires the use of significant quantities of solvents, specialized equipment, and extensive sample preparation. Supercritical fluid extraction allows for greater penetration into the sample matrix and more efficient mass transfer, as well as a shorter extraction time, higher selectivity, and minimal waste. However, it necessitates the use of sophisticated instrumentation. The application of microwave energy in the extraction process offers benefits in terms of increased speed, reduced cost, and the use of a smaller solvent volume compared to conventional techniques. However, this method does not apply to compounds that are sensitive to heat or microwaves. High-pressure extraction is distinguished by reduced energy consumption and high yields, resulting in an effective technique for the extraction of both polar and non-polar compounds. However, the associated equipment and maintenance costs are considerable. Ultrasonic extraction is similarly distinguished by minimal energy consumption and high yields; however, it has the potential to generate free radicals that may affect the stability of bioactive compounds [13].

When evaluating classical extraction techniques, one must note that not all phytochemical compounds can be successfully isolated through simple technological steps. Waste typically contains various partially extractable or non-extractable polyphenols that are more strongly or less related to the matrix [3]. Complete and irreversible deactivation of proteins is one means of improving the excretion of phenols. According to the results of a published study, a modification of the classical blueberry anthocyanin extraction was proposed, during which ethanol shock was performed before the final procedures by soaking the blueberry fruit in a 70% ethanol solution for 1 h [37].

When selecting technologies for the extraction of lipophilic compounds, developers must consider two key issues: the efficacy of the extraction process and the complete elimination of non-lipids. Given that phospholipids can form bonds with several biopolymers and that conventional organic solvents are ineffectual in disrupting these interactions, it may be possible to enhance lipid extraction by making adjustments, such as modifying the pH during the extraction process [60]. The development of effective bio-treatment technologies in the field of bio-recycling could allow for cost-effective use of this waste in order to sustainably meet the growing demand for functional ingredients [3,105].

Supercritical CO₂ extraction is an effective method of extracting lipophilic substances. The production of the bioactive compound lycopene using this extraction process has been evaluated in tomato pomace [61]. This technology enables the fractionation of lipids containing various terpenes, phytosterols, or tocopherols [106]. These bioactive compounds have been demonstrated to possess anticholesterolemic, antioxidant, and anti-inflammatory properties [60]. The available literature suggests that supercritical CO₂ extraction is often more effective than the Soxhlet method (using hexane as a solvent) in that more lipophilic substances can be extracted [107,108]. At the same time, carbon dioxide is valued as a greener solvent than hexane. Fatty acids extracted from the seeds and peels of raspberries, blueberries, wild strawberries, pomegranates, blackberries, and blackcurrants using supercritical extraction technology have been proven purer and richer in essential fatty acids than hexane extracts [28]. The utilization of supercritical gases is therefore a viable means of releasing certain phenolic compounds. A study was conducted to evaluate the bio-refinement of waste during the processing of Rubus glaucus. At the herbal biorefinery, phenolic compounds were successfully extracted using a supercritical extraction method. The resulting phenolic compounds were subsequently microencapsulated [3,52].

Alternative appropriate technologies also can increase the recovery of bioactive compounds. A crucial step towards the greater sustainability of the process is the dismantling of complex polymers. Carbohydrates, peptides, and lipids obtained during chemical and physical processing can be used as raw materials in the generation of other commercially beneficial metabolites. This biorefinery process produced profitable products such as organic acids, natural dyes, and other valuable compounds [3,109].

The fermentation of pomace and other by-products is also being pursued. Rai et al. (2021) have announced that it is possible to produce several fermented products with this method, which can have a health-promoting effect [3,110]. The significance of fermentation in the targeted biorefinery of raw materials for health products should be considered in the context of the unique metabolic abilities of unicellular organisms, algae, and microorganisms. These entities can metabolize bio-organic substances present in processing waste. For example, the biotechnological significance of microalgae is attributed to their ability to utilize the carbon, nitrogen, and phosphorus produced by human activity for the biosynthesis of organic molecules (vitamins, carotenoids, phytosterols, polyunsaturated fatty acids, and peptides) [111,112,113]. The secondary metabolites of the microorganisms themselves, formed during the fermentation process, are also a valuable intermediate product. These metabolites play a particularly important role in the competition of microorganisms, in antagonism, and in the mechanisms of self-defense; therefore, they can also be purposefully exploited in pharmaceuticals, cosmetics, or other fields [114,115]. It is appropriate to study and adapt these secondary metabolites in the management of human health problems [116,117].

The advancement of targeted biopolymer substances is also a significant area of interest within the field of pharmacy. As an illustrative example, polyhydroxybutyrate, which is produced by microorganisms, is biodegradable and biocompatible. Naranjo et al. (2014) demonstrated that polyhydroxybutyrate can be produced using by-products derived from the agricultural industry. Such a biopolymer may be a suitable replacement for polypropylene and polyethylene in pharmaceutical containers [118].

The treatment of waste products generated during the metabolic processes of multicellular organisms represents a further potential avenue for the exploitation of secondary raw materials for pharmaceutical purposes. The use of target organisms (e.g., fungi, insect larvae, and worms) allows for natural conversion and the conduction of secretions or parts through these organisms. For example, the use of fly larvae results in the formation of a biomatrix that is rich in compounds with promising biological activity [2]. The offal from fly larvae or other decomposers can subsequently be implemented in accordance with the same principles as secondary herbal raw materials, which are rich in compounds that are beneficial for human health.

In light of the aforementioned considerations, it seems prudent to plan for the utilization of herbal extracts in the context of nano-processing, with a particular focus on the synthesis of nanoparticles [119]. In order to achieve the aforementioned objectives, a variety of natural sources may be employed, including parts of selected plants, isolated phytochemicals of plant origin, fungi, algae, bacteria, marine organisms, and agricultural waste [13,120]. Due to the rich biodiversity of herbal organisms and their possible secondary metabolites, herbals, and herbal parts have recently been adapted for the synthesis of various nanoparticles [121]. Nanoparticles can be synthesized using various physical methods including sonochemistry, microwave radiation, laser ablation, and other methods [13]. Biological methods have advantages because they are not complex in comparison with conventional chemical synthesis techniques, and are economically and ecologically viable because they do not necessitate the use of harmful chemicals or reagents [120]. As a rule, such biogenic synthesis is characterized by minimal environmental impact. Molecules in biological extracts have been adapted to stabilize nanoparticles and stimulate nanoparticulation processes [122]. In addition, extracts can reduce metal precursors, thus stabilizing the nucleus of nanoparticles [119]. Materials of plant origin have recently been successfully utilized in the synthesis of greener nanoparticles of cobalt, copper, silver, gold, palladium, platinum, zinc oxide, and magnetite [123,124]. Khatami and Pourseyedi (2015) announced the synthesis of silver nanoparticles from an aqueous extract of date palm seeds [125]. The resulting silver nanoparticles are distinguished by antibacterial and antifungal effects. Sakthivel et al. (2022) developed and adapted effective zinc oxide nanoparticles from lemon seed extract [126]. These nanoparticles also increased the rate of regrowth of the tail fin of partially amputated zebrafish. Rafique et al. (2021) have shown that nanoparticles can be synthesized using Citrus reticulata Blanco leaf extract [127]. Nisa et al. (2023) synthesized sustainable magnesium oxide nanoparticles using phytochemicals contained in the hydroalcoholic extract of Tamarindus indica L. seeds [128]. Biosynthetic nanoparticles have been studied for their cardioprotective effects in rats; they have proved able to reverse cardiotoxicity caused by doxorubicin. Pre-administration of nanoparticles to Wistar albino rats significantly reduced biomarkers of damage to the heart, such as cardiac troponin-I, aspartate aminotransferase, and creatine kinase.

2. Conclusions

The development of health-promoting products remains minimally integrated into circular models. Furthermore, the loss of high-value health-promoting materials and concurrent increase in waste have negative impacts on the environment. Technological progress in the classification and characterization of secondary raw materials of plant origin, the selection of phytochemical targets, and the development of purification methodologies currently provide the strongest basis for the identification of new research objects, the promotion of more active scientific involvement, and the advancement of scientific tasks in areas related to the development and production of sustainable health-promoting products. In particular, this approach has yielded tangible results, with some forms of waste from fruit processing already being offered as a raw material for the production of value-added products. Extracts produced from herbal residues and agricultural or agro-industrial sources can function as nano-forming agents. Nevertheless, the advancement of this collaborative approach to the development of health-promoting substances and final products and the enhancement of sustainability necessitates not only the involvement of the scientific community but also the implementation of suitable and timely solutions.

3. Future Directions

The development of health-promoting products derived from recovered bioactive compounds represents a significant opportunity within the circular bioeconomy. At present, only a limited number of secondary herbal sources, such as blueberry processing waste, are undergoing partial bio-refinement and being transformed into value-added products. Technological advances in the classification and characterization of secondary raw materials of plant origin, the selection of phytochemical targets, and the development of purification methodologies can facilitate the identification of novel research objects and encourage greater scientific involvement alongside the formulation of new scientific tasks in the field of phytopharmaceuticals and the target branches of medicine and veterinary medicine. Nevertheless, the viability of recycling technologies for valuable waste is influenced by several factors, including the costs associated with their implementation, the quality of the recyclable waste, the efficiency of supply chains, the availability of incentives, and the efficacy of regulatory procedures, which include marketing authorization mandatory for medicine products. It is therefore necessary to conduct a scientific assessment of the current situation and prospects, considering the maturity of society in the transition from linear to circular models in this area. It is crucial that urgent solutions are implemented and the integration of phytopharmaceutical and related industries into circular processes is facilitated. Concurrently, a sustainable regulatory framework must be established to ensure the proper management of novel health-promoting materials. Reducing waste through the efficient reuse of appropriate herbal raw materials and efficient recycling of bioactive phytochemicals is one of the important goals of the nascent circular models of modern and future phytomedicines. By making more extensive use of different resources for the isolation of targeted phytochemicals or fractions enriched with them, it is possible to expand our available range of potential health-promoting final products. The recovery of bioactive compounds can be increased via various modern and targeted technologies, but those with the greatest viability are characterized by green, cost-effective extraction techniques. However, several are only in their initial stages; questions remain unanswered both about the isolation of significant compounds that are found in small quantities or quantitatively unstable quantities in waste and about the exploitation of alternative, less usable secondary raw materials. Furthermore, as with other herbal materials, recycling processes may result in the residual presence of contaminants (including products of vital activity in mold and bacteria) or improperly identified components alongside the active substances. It is, therefore, imperative that a comprehensive quality control process, comprising physicochemical and biological analysis, be implemented throughout the entire production or processing of secondary herbal raw material. This includes the cultivation of herbs, harvesting, drying, and storage, processing procedures, preparation of extracts, and the production of the final product. Nevertheless, despite the implementation of an appropriate preparation process, it is still possible for physicochemical and pharmacological interactions to occur. The detection and investigation of these interactions can only be conducted during the clinical examination (or administration) of the product. The appropriate utilization of non-conventional materials will require further evaluation, although the potential for their incorporation in the development of health-promoting products should be considered favorably.