Development of Therapeutic and Prophylactic Zinc Compositions for Use against COVID-19: A Glimpse of the Trends, Inventions, and Patents

Zinc is an essential nutrient for human health; it is involved in the catalytic, structural, and regulatory functions of the human cellular system. Different compositions of zinc, as well as its pharmaceutically acceptable salts, are available on the market. Recent studies have demonstrated the role of zinc in combating COVID-19. It has been determined that zinc prevents the entry of SARS-CoV-2 into cells by lowering the expression of ACE-2 receptors and inhibiting the RNA-dependent RNA polymerase of SARS-CoV-2. Zinc also prevents the cytokine storm that takes place after the entry of SARS-CoV-2 into the cell, via its anti-inflammatory activity. The authors believe that no study has yet been published that has reviewed the trends, inventions, and patent literature of zinc compositions to treat/prevent COVID-19. Accordingly, this review has been written in order to fill this gap in the literature. The information about the clinical studies and the published patents/patent applications was retrieved from different databases. This review covers patent literature on zinc compositions up to 31 January 2022. Many important patents/patent applications for zinc-based compositions filed by innovative universities and industries were identified. The patent literature revealed zinc compositions in combination with zinc ionophores, antioxidants, antivirals, antibiotics, hydroxychloroquine, heparin, ivermectin, and copper. Most of these studies were supported by clinical trials. The patent literature supports the potential of zinc and its pharmaceutical compositions as possible treatments for COVID-19. The authors believe that countless zinc-based compositions are still unexplored, and there is an immense opportunity to evaluate a considerable number of the zinc-based compositions for use against COVID-19.


Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative virus for the contagious coronavirus disease of 2019 . The first SARS-CoV-2 infection

Importance of Zinc
Zinc, a brittle and silver/grey metal in its unoxidized form, is represented by the symbol Zn (atomic number 30); it is the second most abundant metal in the human body, after iron [21]. Zinc is an essential nutrient because it is needed in almost all aspects of cellular/biological processes (i.e., catalytic functions, structural functions, and regulatory functions) of the human body [22]. The catalytic functions of zinc are attributed to its antioxidative nature, and to it being an essential component of~3000 catalytic enzymes (e.g., dismutase, dehydrogenase, anhydrase, carboxypeptidase, aminopeptidase, lyase, metalloproteinase, S-methyltransferase, carboxytransferase, deacylase, hydrolase, nuclease, synthase, etc.) [22,23]. The structural functions of zinc include maintenance and stabilization of the intracellular components/cell membranes [22,23]. The regulatory functions of zinc encompass being a component of DNA/RNA polymerase, many kinases, and ribonuclease [22,23].
The human body does not have a zinc store, although it can reutilize some of the zinc released after tissue catabolism [24]. Accordingly, zinc should be consumed regularly in the diet-especially through foods of animal origin (e.g., meat, shellfish, etc.)-or as a supplement/medicine in order to prevent its deficiency [22][23][24]. The absorption of zinc increases in a diet containing protein, histidine, methionine, and citrate. However, some drugs ( Figure 1) and compounds/elements (e.g., phytic acid, cadmium, high doses of iron, and casein) lower the bioavailability of zinc by complexing with it [24][25][26][27]. Accordingly, it is imperative to identify compounds that increase or decrease the absorption of zinc during zinc therapy. The daily zinc requirements for different populations are listed in Table 1 [26,27]. After ingestion, zinc is released as Zn +2 ions and absorbed up to an extent of 33% in a normal healthy person, wherein a decrease in zinc absorption takes place with an increase in age. The zinc is transported to cells through transport proteins [24,25], where it demonstrates its biological effects, including antioxidant, immunostimulant, and antiviral effects ( Figure 1). Zinc deficiency can cause many effects, including growth hindrance, delayed sexual development, skin problems, diarrhea, alopecia, decreased appetite, osteoporosis, and increased susceptibility to viral infections. Accordingly, zinc supplements and zinc-based medicines are effective in the treatment of many illnesses (Figure 1). At the same time, excessive use of zinc can cause many side effects, and can demonstrate drug-drug and drug-disease interactions ( Figure 1) [24][25][26][27].

USFDA-Approved Prescription Zinc Compositions
A search for United States Food and Drug Administration (USFDA)-approved zinc products was conducted on the Orange Book of the USFDA [28] on 1 February 2022, using "zinc" as the keyword. A total of 40 products were obtained, out of which 21 were prescription products and 19 have been discontinued. Among the 21 products, 10 belonged to bacitracin zinc salts, and 11 belonged to zinc sulfate (3 products), zinc chloride (2 products), zinc acetate (2 products), and zinc combinations with other salts/drugs (4 products). The results of the search are provided in Table 2. The USFDA-approved zinc products mentioned in Table 2 are indicated for the parenteral/oral intake of zinc, for maintaining zinc serum levels and avoiding any zinc deficiency syndrome, and for diaper dermatitis (ointment).

Zinc and SARS-CoV-2
SARS-CoV-2 is an RNA virus containing a spike protein. The virus enters human cells after binding its spike protein with the ACE-2 receptors, which are expressed in many human cells (e.g., lung epithelial cells, vascular endothelial cells, etc.) [6,8]. Zinc minimizes the activity of sirtuin-1 (SIRT-1), which regulates ACE-2 expression. Accordingly, zinc prevents the entry of SARS-CoV-2 into the cell by lowering the expression of the ACE-2 receptors [29] (Figure 2). SARS-CoV-2 also needs RNA-dependent RNA polymerase (RdRp) for its replication. Zinc inhibits the RdRp and prevents the replication of SARS-CoV-2 ( Figure 2) [6,8]. The principal hallmark of COVID-19 infection is an imbalance of the immune system. The intracellular presence of SARS-CoV-2 generates a cytokine storm due to the activation of the NF-κB signaling system, and causes ARDS [30,31]. Zinc demonstrates its anti-inflammatory effect by suppressing the NF-κB signaling and attenuating the cytokine storm [30,31] (Figure 2). Zinc also stimulates the generation of interferons that help in the synthesis of antiviral proteins (i.e., latent ribonuclease and protein kinase) that degrade the RNA of SARS-CoV-2 [22]. Zinc increases the activity of natural killer cells, cytotoxic cells, and B-cell receptor signaling, and increases the production of antibodies. All of these factors make zinc an excellent remedy against COVID-19 [32].

Patent Analysis
A patent has two types of claims: independent claims, and dependent claims. The components of the independent claims are the essential parts of the invention. Accordingly, all of the patents/patent applications whose independent claims relating to the use of zinc compositions to treat/prevent COVID-19/SARS-CoV-2 infection were included in this review, and are summarized in Table 4. The patents/patent applications for zinc-based masks, polymers, fabrics, coatings, and devices were excluded from this review.     A synergistic composition comprising one zinc-chelating peptide, one protease inhibitor (9-L-arginine-peptide), and one inhibitor of viral replication enzymes (vitamin B12) [61] (Viral protein synthesis inhibitor; Not present, but in vitro assay present) Our search also revealed some patents/patent applications that implicitly relate to the use of zinc-based compositions to treat/prevent COVID-19/SARS-CoV-2 infection. However, these documents are silent about the anti-COVID-19/antiviral activity of zinc. These documents include US20210244726A1 (a composition of chloroquine/hydroxychloroquine, a macrolide antibiotic, and zinc) [70], IN202021031040A (an Ayurvedic composition contain-ing zinc) [71], CN111450100A (a composition of caffeine, chlorogenic acid, and zinc) [72], WO2021074706A1 (an immunomodulatory composition of many nutrients and zinc) [73], WO2021183456A1 (a composition of lenzilumab and zinc) [74], WO2021186396A2 (a composition of artemisinin and zinc) [75], WO2021195017A1 (an iodine inhalation composition containing zinc) [76], US20210346453A1 (a composition of Uncaria tomentosa extract containing zinc) [77], WO2021224356A1 (a composition of plerixafor/burixafor containing zinc) [78], US20210338765A1 (a composition of ashwagandha, shallaki, ginger, turmeric, and zinc) [79], US20210330587A1 (an oral sanitizer containing zinc) [80], WO2021205242A1 (a composition of a synbiotic and zinc) [81], WO2021205437A1 (a composition of a cholesterol-lowering compound, an S-adenosylhomocysteine hydrolase inhibitor, a DOTH inhibitor, and zinc) [82], and FR3109299A1 (a composition of artemether, azithromycin, and zinc) [83].

Conclusions
Zinc possesses an appreciable antiviral activity, and its effects against SARS-CoV-2 are also well documented. The clinical data of zinc and its compositions show promise against COVID-19. The patent literature also supports the potential of zinc and its pharmaceutical compositions as possible treatments for COVID-19. The identification of the inventive composition of zinc indicates many foreseeable commercially available zinc-based medicines to combat COVID-19. However, the authors trust that many zinc-based compositions are still unexplored, and there is great scope to assess a large number of the zinc-based compositions for use against COVID-19.

Discussion
Zinc, an essential nutrient for human health, has been used in clinical practice as a medicine, immune booster, and food supplement ( Figure 1) [10,14]. SARS-CoV-2 (RNA virus) enters human cells via the ACE-2 receptors, and requires RdRp for its replication [6,8]. RdRp is a major target for antiviral drug research. Studies have shown that increased intracellular concentration of zinc interferes with the proteolytic processing of polyproteins in several RNA viruses. Increased intracellular concentrations of zinc have also demonstrated inhibition of the isolated RdRp complex, purified recombinant RdRp, and the replication of coronavirus in tissue culture [41]. The zinc ions also suppress/lower the expression of the ACE-2 receptors, preventing the entry of SARS-CoV-2 into the cells [29]. Therefore, zinc demonstrates the dual character of prophylactic and therapeutic intervention for COVID-19.
Zinc and its compositions are in clinical trials to prevent and treat COVID-19 (Table 3). The data shown in Table 3 also reveal 3 studies in phase 1, 9 studies in phase 2, 12 studies in phase 3, and 4 studies in phase 4. Among these 28 studies, 18 studies are related to the treatment of COVID-19, 5 are related to the prevention of COVID-19, 4 are related to the use of zinc for supportive care, and 1 study relates to post-COVID-19 smell and taste dysfunction. Seven studies were conducted in the United States; one each in Iraq, Indonesia, Singapore, Thailand, Canada, Australia, and Pakistan; two in India; four each in Saudi Arabia and Egypt; three in Tunisia, and one study's location is undisclosed. Most of the clinical studies [26] have been planned as randomized clinical trials. It is also important to note that only one study (NCT04475588) has revealed its clinical outcomes. Two studies (NCT04590274 and NCT04528927) have been withdrawn. The literature also includes a clinical study (NCT04342728) related to the use of zinc gluconate, vitamin C, and their combination to shorten the treatment of COVID-19 [84]. However, the results of this study were not encouraging; therefore, it has been stopped for ineffectiveness. The compositions of zinc mentioned in Table 3 consist of one or more drugs/elements selected from hydroxychloroquine, azithromycin, vitamin C, vitamin D, N-acetylcysteine, elderberry, quercetin, ivermectin, doxycycline, insulin, gabapentin, itolizumab, heparin, acetaminophen, dexamethasone, chlorine dioxide, famotidine, lactoferrin, green tea extract, vitamin B12, methylene blue solution, phenformin, resveratrol, selenium, extract of Psidii guava, nitazoxanide, ribavirin, chloroquine, darunavir, ritonavir, and bromelain. The results of one clinical study (NCT04322513) have demonstrated the role of vitamin D against COVID-19 [85]. Accordingly, the important combination of zinc and vitamin D may provide synergistic effects to deal with COVID-19.
Our search revealed many patents/patent applications for pharmaceutical compositions of zinc for use against COVID-19 (Table 4). Table 4 provides a summary of 29 patents/patent applications, of which 2 were published in 2020, 26 in 2021, and 1 in 2022. This pattern is expected, because the first COVID-19 case was identified in December 2019, and scientists started working on COVID-19 treatments in 2020. The majority of these patent applications have been filed in the United States (16), followed by India (4), Russia (3), Spain (2), Australia (1), the United Kingdom (1), China (1), and Colombia (1) (Figure 3).
It is interesting to note that most of these compositions or their equivalent compositions are in clinical trials (Table 3). In almost all of the clinical studies and patent specifications, zinc has been used in the form of its salts (zinc acetate, zinc sulfate, zinc lactate, zinc aspartate, zinc undecylenate, zinc pyrithione, zinc gluconate, zinc oxide, zinc picolinate, zinc iodide, zinc chloride, zinc citrate, zinc carbonate, zinc hydroxide, zinc fluoride, zinc bromide, zinc sulfonate, zinc glucuronate, zinc bisglycinate, and zinc pyruvate). Remdesivir [6], Paxlovid [7], and molnupiravir [8] are approved treatments for COVID-19. However, no clinical study or patent literature has been found relating to the specific combination of zinc with remdesivir, Paxlovid, or molnupiravir. This can be considered as an opportunity for further research of treatments for COVID-19. However, the possibility of the interaction of zinc with antiviral drugs must be assessed before COVID-19 treatment, as zinc has been reported to interfere with the absorption of many antivirals (Figure 1). A zinc ionophore helps in the transport of zinc at the target site, such as a cell. Many clinical studies and patent applications have used compositions of zinc with a zinc ionophore (e.g., alpha defensin 5, quercetin, curcumin and epigallocatechin gallate, silymarin, hesperidin, diosmin, neral, geranial, and citronellal). High doses of zinc or its regular intake may cause copper deficiency or side effects [52]. The targeted delivery of zinc utilizing a zinc ionophore may reduce these effects. Hypertensive people are considered to be at risk of COVID-19. ACE-2, a metalloenzyme, is implicated in the pathogenesis of hypertension. Zinc lowers the expression of ACE-2, and is also an immune booster; therefore, it is believed that zinc compositions may provide better therapeutic outcomes when used along with antihypertensive ACE inhibitors (e.g., captopril, lisinopril, ramipril, etc.) [12]. The use of zinc compositions for enriching the human immune system and to prevent the secondary complications of COVID-19 in high-risk populations (e.g., geriatric/immunocompromised patients, patients suffering from chronic diseases, medical and paramedical professionals, etc.) has also been claimed [56].
Despite the many benefits associated with zinc, some studies have warned against the excessive use of zinc among COVID-19 patients [86,87]. Zinc is needed for the growth of many pathological fungi, including Mucorales, which cause fatal mucormycosis [86,88]. Some others have reported that zinc might have a negative impact, and high zinc levels in hepatitis can increase the viral load by blocking the production of interferons (IFN-λ) [89], induce apoptosis in T cells, B cells, and thymocytes [90,91], and lead to copper deficiency, which can cause anemia and leukopenia [92].
Zinc can provide positive or negative effects based on the condition of the consumer/patient. However, zinc supplements are not expensive, and are readily available on the market. This facilitates the overuse of zinc supplements among COVID-19 patients. Accordingly, zinc supplements must be used under medical supervision. Most of the literature supports the notion that zinc can provide beneficial effects among mild-to-moderate COVID-19 patients, wherein the dose, duration of zinc treatment, and condition of the patient are important aspects during COVID-19 therapy. Accordingly, many inventions of zinc-based compositions have been developed for use against COVID-19. The identification of the inventive composition and current clinical trials of zinc-based compositions indicates many foreseeable commercially available zinc compositions to combat COVID-19. However, there is a need to assess the efficacy of zinc supplements and inventive compositions among severe COVID-19 cases requiring intensive care [87].