WO2022219643A1 - Nutraceutical composition comprising molecular complex of lactoferrin and quercetin ('lactocetin') for treatment for sars – cov-2 and related viral infections - Google Patents
Nutraceutical composition comprising molecular complex of lactoferrin and quercetin ('lactocetin') for treatment for sars – cov-2 and related viral infections Download PDFInfo
- Publication number
- WO2022219643A1 WO2022219643A1 PCT/IN2021/050836 IN2021050836W WO2022219643A1 WO 2022219643 A1 WO2022219643 A1 WO 2022219643A1 IN 2021050836 W IN2021050836 W IN 2021050836W WO 2022219643 A1 WO2022219643 A1 WO 2022219643A1
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- WIPO (PCT)
- Prior art keywords
- lactoferrin
- quercetin
- molecular complex
- formulations
- composition
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- REFJWTPEDVJJIY-UHFFFAOYSA-N Quercetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C(O)=C1 REFJWTPEDVJJIY-UHFFFAOYSA-N 0.000 title claims abstract description 219
- CSSYQJWUGATIHM-IKGCZBKSSA-N l-phenylalanyl-l-lysyl-l-cysteinyl-l-arginyl-l-arginyl-l-tryptophyl-l-glutaminyl-l-tryptophyl-l-arginyl-l-methionyl-l-lysyl-l-lysyl-l-leucylglycyl-l-alanyl-l-prolyl-l-seryl-l-isoleucyl-l-threonyl-l-cysteinyl-l-valyl-l-arginyl-l-arginyl-l-alanyl-l-phenylal Chemical compound C([C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 CSSYQJWUGATIHM-IKGCZBKSSA-N 0.000 title claims abstract description 181
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- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23J—PROTEIN COMPOSITIONS FOR FOODSTUFFS; WORKING-UP PROTEINS FOR FOODSTUFFS; PHOSPHATIDE COMPOSITIONS FOR FOODSTUFFS
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
- A23L2/52—Adding ingredients
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Life Sciences & Earth Sciences (AREA)
- Mycology (AREA)
- Health & Medical Sciences (AREA)
- Nutrition Science (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention discloses nutraceutical composition comprising molecular complex of Lactoferrin and Quercetin for use as a prophylactic or in the treatment of early and advanced stage of viral infections including SARS CoV-2 infection and related SARS viral infections. The invention further discloses nutraceutical compositions comprising molecular complex of Lactoferrin and Quercetin suitably formulated for oral, sublingual, subcutaneous, IV & IM and buccal administration such as tablets, fast dissolving tablets, capsules, gummies, oral thin films, liquid formulation for nebulisation, solid / liquid dispersion for inhalation, injections, transdermal formulations, syrups, nasal and eye formulations. The present invention disclosesfast dissolving tablets buccal administration and nebulisation formulation comprising lactoferrinin and quercetin in molar ratio of (Lf)x + quercetin(y) [x:y moles, wherein x = 1,2,3,4 moles and y = 1,10, 20, 30, 40,50, …., 100, 200 moles] solid solution for use in the prevention or treatment of early stage of SARS CoV-2 infection and related viral infections.
Description
“NUTRACEUTICAL COMPOSITION COMPRISING MOLECULAR COMPLEX OF LACTOFERRIN AND QUERCETIN (‘LACTOCETIN’) FOR TREATMENT FOR SARS - COV-2 AND RELATED VIRAL
INFECTIONS”
Technical filed:
The present invention relates to nutraceutical composition comprising molecular complex of Lactoferrin and Quercetin for prophylactic use and in the treatment of, early and advanced stage of SARS CoV-2 infection in COVID patients and related SARS viral infections. The invention further relates to nutraceutical compositions comprising molecular complex of Lactoferrin and Quercetin suitably formulated for oral, subcutaneous, sublingual, IV & IM and buccal administration such as tablets, fast dissolving tablets, capsules, gummies, oral thin films, liquid formulation for nebulisation, solid dispersion for inhalation, injections, transdermal formulations, syrups, nasal drops and eye formulations. The present invention further relates to anti-viral formulation comprising of molecular complex of lactoferrin and quercetin solid solution. The present invention also relates to fast dissolving tablets &oral thin film buccal administration and nebulisation formulation comprising lactoferrin (Lf)x + quercetin^) [x:y moles, wherein x = 1,2, 3, 4 moles and y = 1,10, 20, 30, 40 ,50, ...., 100, 200 moles] solid solution for use in the prevention or treatment of early stage of SARS CoV-2 infection and / or related viral infections.
Background and prior art:
The ideal therapeutic target for a viral infection is the protein critical for infectivity, such as hemagglutinin (HA). HA, a glycoprotein expressed on the viral envelope along with neuraminidase (NA), is pivotal for the interactions between the influenza virus and sialic acid side chains of receptors on the host cell surface and is also required for the final step of viral entry into susceptible cells. HA also plays a significant role in host immune responses by harbouring the major antigenic sites responsible for the production of neutralizing antibodies. Therefore, inhibiting HA
can result in two outcomes: (i) prevention of the interaction between viral surface proteins and cell surface receptors; (ii) blocking of viral envelope fusion with the host cell membrane and thereby the release of viral nucleoproteins into the cytoplasm.
Lactoferrin (Lf) is an 80-kDa multifunctional cationic iron binding glycoprotein belonging to the transferrin family and possessing a variety of biological functions, such as an influence on iron homeostasis, immunomodulation, and inhibitory activity towards different pathogens.
There is ample literature available on lactoferrin and its various therapeutic activities, which is briefly reported herein below.
The use of lactoferrin has been reported as an antibacterial (WO9806425) agent for prevention of infections, inflammations and/or tumours; for the treatment of anemias (W02004060392), as a component of infant food formulas (WO2012091945 and W02010130643), as a livestock supplement (WO03047363) and to prevent spontaneous abortions, premature rupture of membranes and preterm births (IT 1392620).
Composition comprising lactoferrin and to its use in the prevention of preterm delivery is disclosed in EP2931303A1.
Lactoferrin also plays an important role in innate immunity against infections as disclosed in EP1638590A2.
Bovine lactoferrin (Lf) has been recognized as a potent inhibitor of different viruses and has been often reported to exhibit higher antiviral activity than human lactoferrin (hLf). It is reported that selected peptides from bovine lactoferrin C4obe are able to prevent Influenza virus proteins hemagglutination(HA) and cell infection by different HI and H3 viral subtypes (specifically binds the HA2 subunit
of HA). Lactoferrin prevents the early steps of influenza virus infection and its interaction with viral particles is improved at low pH, when the hydrophobic NH2- terminal amino acid residues of HA2 are exposed. Consistent with this result, lactoferrin (and its C-lobe) also blocks virus-induced hemolysis of erythrocytes in a dose-dependent manner.
Lactoferrin (Lf) participates in the host immune response against Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) invasion by enhancing NK cell activity and stimulating neutrophil aggregation and adhesion. Lf inhibits SARS pseudovirus infection in a dose-dependent manner, by inhibiting the viral attachment stage.
Similarity of mechanism of 2019 - nCOV with SARS-COV
Decade-long structural studies by Fang Li of the University of Minnesota, et al. have shown how the SARS virus (SARS-CoV) interacts with animal and human hosts in order to infect them. The mechanics of infection by the Wuhan coronavirus appear to be similar. It is reported that, in addition to ACE2, HSPGs (heparansulfate proteoglycans) are essential cell-surface molecules involved in SARS-CoV cell entry. HSPGs provide the binding sites for SARS-CoV invasion at the early attachment phase. Lactoferrin co-localizes with the widely distributed cell-surface heparin sulfate proteoglycans (HSPGs). Therefore, Lactoferrin will play a protective role in host defence against SARS-CoV infection through binding to HSPGs and blocking the preliminary interaction between SARS-CoV and host cells.
Quercetin and its derivatives are naturally occurring phytochemicals with promising bioactive effects. The antidiabetic, anti-inflammatory, antioxidant, antimicrobial, anti -Alzheimer’s, anti arthritic, cardiovascular and wound-healing effects of Quercetin have been extensively investigated, as well as its anticancer activity against different cancer cell lines has been recently reported.
Quercetin, a naturally occurring dietary flavonoid, is well known to ameliorate chronic diseases and aging processes in humans, and its antiviral properties have been investigated in numerous studies. In silico and in vitro studies demonstrated that quercetin can interfere with various stages of the coronavirus entry and replication cycle such as PLpro, 3CLpro, and NTPase/helicase.
Quercetin seems to have multiple targets of action and may prove to be a better candidate molecule for therapeutic development. Administration of quercetin (1000 mg) showed a decrease in the incidence and extent of upper respiratory tract infections (URTIs). Abian et al identified quercetin as a reasonably potent inhibitor of SARS-CoV-2 3CLpro protease, with the inhibition constant being -Ki ~ 7 mM. Quercetin also modulates the cellular unfolded protein response (UPR). As coronaviruses can utilize the UPR to complete different stages of the viral life cycle during infection, this is an important finding. Early clinical data suggests that quercetin has broad antiviral property and acts at various steps of viral life cycle. As an FDA-approved drug ingredient, with potent antiviral action, quercetin offers great promise as a potential drug candidate in the clinical treatment of SARS. Also, in view of the emerging mutations in SARS CoV-2 virus; there remains a need in the art to develop novel nutraceuticals that can be useful in the prevention or treatment of SARS CoV-2 infection.
Accordingly, it is objective of the present invention to provide a nutraceutical composition comprising molecular complex (solid solution / cocrystal / eutectic)of lactoferrin (Lf) and quercetin in a molar ratio of 1 : 1 to 1 : 200 along with one or more nutraceutical excipients or vehicles or carriers for use in the prevention or treatment of viral infections including SARS CoV-2 and other SARS related infection.
The present invention also includes lactoferrin molecular complex (solid solution / cocrystal / eutectic) along with other polyphenol nutraceuticals including but not limited to luteolin, curcumin, naringenin, apigenin and EGCG.
Summary of the invention:
In accordance with the above objective, in an aspect, the present invention provides nutraceutical compositions comprising a molecular complex of lactoferrin (Lf) and quercetin along with suitable nutraceutical excipients/vehicles/carriers for use in treatment of prophylactic, early and advanced stage of viral infections including SARS CoV-2 and related SARS viral infections.
In another aspect, the molecular complex of lactoferrin (Lf) and quercetin is suitably formulated into solid oral, sublingual or buccal formulations selected from the group consisting of fast dissolving tablets, thin film formulations, gummies, tablets, capsules; liquid formulations for nebulization or a solid / liquid dispersion for inhalation formulation.
In another aspect, the molecular complex of lactoferrin (Lf) and quercetin is suitably formulated into IV, IM, trans-dermal, nasal and eye application formulations.
In another aspect, the invention provides solid form formulation for oral thin film and a solid /liquid dispersion for inhalation comprising molecular complex of lactoferrin (Lf) and quercetin along with suitable nutraceutical excipients, for targeted drug delivery.
In another aspect, the invention provides liquid formulation for nebulization and a solid dispersion for inhalation comprising lactoferrin (Lf) and quercetin in combination with hypothiocyaniteand suitable nutraceutical excipients/vehicles/carriers, for targeted drug delivery.
In yet another aspect, the invention provides nutraceutical compositions comprising molecular complex of lactoferrin (Lf) and quercetin optionally in combination with at least one component selected from natural polyphenols; mono- and di-
saccharides (lactose) and hypothiocyanite having antiviral activity along with suitable nutraceutical excipients/vehicles/carriers, for targeted drug delivery.
In yet another aspect, the invention provides process for preparation of the molecular complex of lactoferrin (Lf) and quercetin, which process comprises; heating Quercetin dihydrate to 150°Cto convert quercetin dihydrate to dehydrate quercetin (anhydrous quercetin) followed by adding lactoferrin (apolactoferrin) and ball milling or neat grinding (using a mortar and pestle) or ball mill grinding for sufficient time to obtain molecular complex of lactoferrin (Lf) and quercetin.
In an alternate embodiment, the process for preparation of the molecular complex of lactoferrin (Lf) and quercetin, which process comprises; heating Quercetin dihydrate to 150°C followed by adding lactoferrin and extruding followed by spheronization for sufficient time using suitable equipments, to obtain molecular complex of lactoferrin (Lf) and quercetin.
In yet another aspect, the invention provides a method for treating prophylactic, early and advanced stage of viral infections including SARS CoV-2 and other SARS infections, which method comprises administering a formulation comprising an effective amount of molecular complex and / or simple mixture of lactoferrin (Lf) and quercetin along with suitable nutraceutical excipients, for targeted drug delivery, wherein, the formulation may be selected from the group consisting of fast dissolving tablets, thin film formulations, gummies, tablets, capsules; liquid formulations for nebulization or a solid dispersion for inhalation; intravenous and intramuscular injections, trans-dermal, nasal and eye application formulations.
Description of drawings:
Figure 1 shows DSC of Lactoferrin Figure 2 shows DSC of Quercetin dehydrate
Figure 3 shows DSC of Lactoferrin + Quercetin (1:10) molecular complex
Figure 4 shows the synergistic therapeutic activity viz., cytopathic effect (CPE) of Lactoferrin + Quercetin (1:10) molecular complex vis-a-vis Lactoferrin, molecular complex of Lactoferrin and lactose as well as molecular complex of Lactoferrin and Arabinogalactan.
Figure 5 depicts SI values of lactocetin and other natural antivirals
Detailed description of the invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
Accordingly, in an embodiment, the present invention provides nutraceutical compositions comprising a molecular complex of lactoferrin (Lf) and quercetin, for use in the treatment of prophylactic, early and advanced stage of viral infections including SARS CoV-2 and other related SARS infections.
While the efficacy of the nutraceutical compositions of the present invention is tested against SARS CoV-2 infection; however, the same can be administered for the treatment of other viral infections such as FLU (Influenza), HIV, Dengue, Chicken guinea and other SARS viral infections.
In an embodiment, the lactoferrin works as "immune booster", in the subjects infected with viral diseases.
In an embodiment, the source of lactoferrin is selected from Bovine source, Goat milk (Caprine), Camel milk, Sheep Milk (Ovain), Yak milk, Donkey milk and Buffalo milk. In one embodiment, the lactoferrin as used in the invention may be bovine lactoferrin.
According to the present invention, the type of lactoferrin includes, Iron Free lactoferrin (Apolactoferrin), half-filled Iron lactoferrin and completely Iron filled lactoferrin (holo lactoferrin).
In an embodiment, the source of quercetin is selected from any natural source or of synthetic origin.
In a preferred embodiment, the molar ratio of lactoferrin (Lf) and quercetin in the molecular complex is 1 : 1 to 1 : 100. For example, the molar ratio of lactoferrin (Lf) and quercetin can be selected from a ratio of 1:1; 1:10; 1:20, 1: 30; 1:40; 1:50; 1:60; 1:70; 1:80; 1:90; 1:100; 1:110; 1:120; 1:130; 1:40; l:-50; 1:160; 1:70; 1:180; 1:190; and 1:200.
In yet another embodiment, the invention provides process for preparation of the molecular complex of lactoferrin (Lf) and quercetin, which process comprises; heating Quercetin dihydrate to 150°C followed by adding lactoferrin and ball milling or neat grinding for sufficient time using a mortar and pestle, to obtain molecular complex of lactoferrin (Lf) and quercetin.
In an alternate embodiment, the process for preparation of the molecular complex of lactoferrin (Lf) and quercetin, which process comprises; heating Quercetin dihydrate to 150°C followed by adding lactoferrin and extruding followed by spheronization for sufficient time using suitable equipment, to obtain molecular complex of lactoferrin (Lf) and quercetin.
In an embodiment, the molecular complex thus obtained comprises Lactoferrin and Quercetin in a molar ratio of 1 :30 [The molecular weight of Lactoferrin is taken as 80,000 Da and Quercetin as 302 Da]
In another embodiment, the molecular complex thus obtained comprises Lactoferrin and Quercetin in a molar ratio of 1 :50.
In another embodiment, the molecular complex thus obtained comprises Lactoferrin and Quercetin in a molar ratio of 1 : 100.
In yet another embodiment, the molecular complex thus obtained comprises Lactoferrin and Quercetin in a molar ratio of 1 :200.
In a further embodiment, the molecular complex of Lactoferrin and Quercetin is characterised by and DSC.
In an embodiment, the molecular complex thus obtained comprises Lactoferrin and Quercetin in a ratio of 1:30 molar, was subjected to differential scanning calorimetry (DSC) which exhibits endotherm at 74.6°C and exotherm at 272.1°C(table 1).
In another embodiment, the 1:50 molar ratio molecular complex of Lactoferrin and Quercetin showed as sharp melting point as follows:
1:50 Molar Lactocetin- 238°C Lactoferrin-246°C Quercetin dehydrate- 316"C
Given the limited diffusion of protein therapeutics from the bloodstream to the lungs (partly due to their high molecular weight), buccal delivery into systemic circulation and pulmonary delivery of aerosolized proteins are the best choice. Drug delivery in the airways by inhalation and / or buccal administration can be used for local and/or systemic action. In view of their advantageous pharmacological features, protein therapeutics has ushered in a new era in sub-lingual and / or respiratory medicine; they provide significant clinical benefit and are becoming increasingly important tools in the therapeutic armamentarium. Either fast dissolving tablets (melt in mouth tablets) for buccal absorption or dry powders for
aerosolization can be made or alternatively liquid formulation suitable for nebulization can be made.
According to an embodiment, the invention provides nutraceutical composition comprising a molecular complex of lactoferrin (Lf) and quercetin along with suitable nutraceutical excipients or carriers or vehicles.
According to an embodiment, the invention provides nutraceutical composition formulated for buccal absorption - Fast Dissolving Tablets (FDTs), formulation for nebulization and a solid dispersion for inhalation, IV and IM, subcutaneous, sublingual, topical, eye-drops or transdermal patch comprising a molecular complex of lactoferrin (Lf) and quercetin along with suitable nutraceutical excipients or carriers or vehicles, for targeted drug delivery.
According to another embodiment, the invention provides a liquid formulation for FDTs and nebulization and a solid dispersion for inhalation comprising molecular complex of lactoferrin (Lf) and quercetin in combination with hypothiocyanite along with suitable nutraceutical excipients, for targeted drug delivery. Hypothiocyanite is a bactericidal agent to obtain synergistic effect of the formulation in the treatment of early stage of SARS CoV-2 infection.
According to yet another embodiment, the invention provides a formulation for oral and buccal formulation comprising molecular complex of lactoferrin (Lf) and quercetin in combination with natural polyphenols, amino acids and / or mono/di/ oligosaccharides having antiviral activity along with suitable nutraceutical excipients, for targeted drug delivery. Prebiotics such as arabinogalactans were used in the formulation along with the molecular complex of lactoferrin and quercetin to provide for better gut health. Glutamine is known to accumulate in the gut, formulations of molecular complex of lactoferrin with quercetin (lactocetin) can be formulated with glutamine to target the gut function.
In yet another aspect, the invention provides a method of treating early and advanced stage of SARS CoV-2 infection, which method comprises administering liquid formulation for nebulization or a solid dispersion for inhalation or oral or buccal formulation comprising an effective amount of molecular complex of lactoferrin (Lf) and quercetin along with suitable nutraceutical excipients, for targeted drug delivery.
In yet another aspect, the invention provides a method of treating early and advanced stage of viral infections selected from the group consisting of Flu, HIV, Dengue, Chicken guinea and SARS CoV-2 and other SARS related infection, which method comprises administering a buccal or oral formulation, or a liquid formulation for nebulization or a solid dispersion for inhalation or intramuscular injections, topical formulations, eye-drops or transdermal patch comprising an effective amount of a molecular complex of lactoferrin(Lf) and quercetin optionally in combination with at least one component selected from polyphenol nutraceuticals and hypothiocyanite along with suitable nutraceutical excipients, for targeted drug delivery.
In yet another aspect, the invention provides a method of treating early and advanced stage of viral infection, which method comprises administering oral or buccal formulation, a liquid formulation for nebulization or a solid dispersion for inhalation or intramuscular injections, topical formulations, eye-drops or transdermal patch comprising an effective amount of molecular complex of lactoferrin(bLf) and quercetin optionally in combination with at least one component selected from polyphenols and oligosaccharides and suitable nutraceutical excipients, for targeted drug delivery.
In a further aspect, the invention provides use of formulations for buccal absorption, oral administration/nebulization or a solid dispersion for inhalation, or intramuscular injections, topical formulations, eye-drops or transdermal patch comprising a therapeutically effective amount of a molecular complex of lactoferrin (Lf) and quercetin, optionally in combination with at least one component selected
from hypothiocyanite, polyphenols and oligosaccharides and suitable nutraceutical excipients, for prevention or treatment of early and advanced stage of viral infection.
The formulations of the present invention can be effectively delivered to the systemic circulation and / or lungs by using suitable formulations or methods or nebulizers so as to convert the formulation into a thin film strip / gummy / fast dissolving tablet / capsule or mist or fine spray.
Solid dispersion formulation can be delivered through the inhalation device.
According to the invention, the lactoferrin (Lf) and quercetin complex present in the solid formulations in an amount of 0.01%- 99 % w/v of the composition. Solid formulations can be selected from tablet, capsule, mouthmelt tablets, dispersible tablets, thin film strips, gummies, candies, solid dispersions for inhalations.
According to the invention, the lactoferrin (Lf) and quercetin complex present in the liquid formulations in an amount of 0.01%- 99 % w/v of the composition. Liquid formulations are selected from solutions, syrups, suspensions and solutions for inhalations.
According to the invention, polyphenols that can be used in the liquid formulations or solid dispersions of the present invention is selected from the group consisting of, but not limited to delphinidin, cyanidine, gallic acid, catechin, epicatechin, epigallocatechin, ellagic acid, rutin, quercetin, luteolin, curcumin, genestien, and the like, to obtain synergistic effect in the treatment of early stage of SARS CoV-2 infection. Ref: Potential Nutraceuticals for COVID-19, NDS, 18 February 2021 Volume 2021:13 Pages 25—51]
According to the invention, the oligosaccharides that can be used in the liquid formulations or solid dispersions of the present invention is selected from the group
consisting of lactose, galactose, mannose, human milk oligosaccharides, chitosan oligos, and the like to obtain synergistic effect in the treatment of early stage of SARS CoV-2 infection.
The molecular complex of lactoferrin (Lf) and quercetin is suitably formulated into solid oral or buccal formulations such as thin film formulations, gummies, fast dissolving tablets, tablets, capsules, liquid formulations for nebulization and the solid dispersions for inhalation. These formulations may comprise a physiologically acceptable organic solvent such as ethanol, acetone, ethyl acetate, isopropyl alcohol, glycerol, propylene glycol, polyethylene glycol, liquid paraffin, triglyceride oil, HFA 134a and / or HFA 227, etc. The nutraceutical excipients/vehicles/carriers that may be added as needed in addition to suitable solvents include controlled release binders, emulsifiers, oily vehicles, emulsion stabilizers, colorants, flavouring agents, sweeteners, bio-adhesive agents, pH modifiers, controller release polymers, viscosity modifiers, stabilizers, surfactants and co-surfactants, plasticizers, preservatives, and the like.
The following examples are presented to further explain the invention with experimental conditions, which are purely illustrative and are not intended to limit the scope of the invention.
Examples:
Example 1:
Preparation of Lactoferrin and Quercetin dehydrate molecular complex
Quercetin dihydrate (heated to 150°C, 300mg, 0.1 mmol) and lactoferrin (800 mg, 0.01 mmol) were neat ground for 3 mins using a mortar and pestle to obtain Lactoferrin and Quercetin dihydrate molecular complex, as a solid. The resultant solid thus obtained was subjected to analytical studies such as DSC to confirm the molecular complex formation,).
Scale up synthesis is performed by ball milling the dehydrate of quercetin (anhydrous quercetin) with lactoferrin.
Characterization:
The molecular complex Lactoferrin and Quercetin dehydrate(l :30 molar ratio) was characterized by DSC, the results of which are provided herein below table 1.
Table 1
The DSC of Quercetin dehydrate; Lactoferrin and the molecular complex of Lactoferrin and Quercetin dehydrate are provided in figure 1, figure 2 and figure 3 respectively. According to these figures, while Lactoferrin shows sharp endotherm at 72.8°C; Quercetin dehydrate shows sharp endotherm at 319°C; the molecular complex of Lactoferrin and Quercetin in a ratio of 1:10, exhibits endotherm at 74.6°C and exotherm at 272.1 °C.
Example 2:
Assay procedure:
The Assay of the molecular complex of Lactoferrin and Quercetin dehydrate; Lactoferrin and Quercetin dehydrate was conducted for determining CC50 and MNTD (Maximum non-toxic dose).
Procedure for MNTD and CC50 determination:
Different dilutions of test compound were added on Vero cell monolayer in triplicate and these plates were incubated at 37 °C in 5% C02. After incubation, development solution was added to the cells followed by incubated at 37 °C in 5% C02. The absorbance was taken. This process was repeated until exact value for
MNTD and CC50 is derived. The time period required for determination of final MNTD and CC50 value was about 2-3 weeks.
EC50: Compound concentration required to achieve 50 % protection from virus- induced cytopathogenicity.
CC50: Compound concentration required to reduce cell viability by 50% .
SI* (selectivity index): ratio by CC50/EC50.
*The higher SI ratio = theoretically more effective and safe drug during in vivo treatment for a given viral infection.
Example 3
In vitro antiviral activity determination of formulation against SARS-CoV-2 virus. This process was conducted in two modes viz., Prophylactic mode and Therapeutic mode.
A. Prophylactic mode:
In this method; based on the MNTD and CC50 value, 6 different concentrations of each drug will be accessed for antiviral potency at 4 different time points in triplicate. Accordingly, theCells were washed and infected with SARS CoV-2 virus. These plates were incubated at 37 °C in 5% C02. After incubation period, quantitative CPE based score were made for EC50 determination.
Virucidal activity determination:
Based on the MNTD and CC50 value, 6 different concentrations of each drug were accessed for its virucidal effect in triplicate, by incubatingwith SARS-CoV-2 virus. Accordingly, virus-test compound mixture was added to the Vero cell monolayer for infection. These plates were then incubated at 37 °C in 5% C02. After incubation, quantitative CPE based score were made for EC50 determination.
Therapeutic mode:
In this method, based on the MNTD and CC50 value, 6 different concentrations of each drug were assessed for antiviral potency at 4 different time points in triplicate. This experiment will determine therapeutic potential of drug at different stage of the virus life cycle (assembly, internalization and replication stage). Accordingly, Vero cells were infected with SARS-CoV2 Virus. Post infection, 6 different concentration of test compound were added to infectVero cells in triplicate at four different time points and these plateswere incubated at 37 °C in 5% C02. After incubation, quantitative CPE based scoreswere made for EC50 determination. Accordingly, various lactoferrin molecular complexes, viz., lactoferrin-lactose, lactoferrin arabinogalactan were also prepared according to the procedure provided in example land in vitro antiviral activity of these complexes and molecular complex ofLactoferrin and Quercetin dihydrate of the present invention were compared with the virucidal activity of lactoferrin. Assessment of these drugs in both prophylactic and therapeutic modes were conducted to identify the antiviral potential of the drug candidate against SARS-CoV-2. The results are shown in below table 2.
Table 2
The therapeutic activity; cytopathic effect (CPE) values of lactoferrin, molecular complexes of Lactoferrin and Quercetin dehydrate (lactocetin); lactoferrin-lactose, lactoferrin arabinogalactan are provided herein below in table 3 and in figure 4.
Table 3
As is evident from the above Table 3and Figure 4, while the molecular complex of Lactoferrin and Quercetin at a concentration of 0.375 mg/ml shows synergistic virucidal activity, with CPE Score of 61.49 at the end of 1st hr, the molecular complex of Lactoferrin and Arabinogalactan shows additive activity at the same concentration and time period.
The Selectivity Index (SI) of Lactoferrin + anhydrous quercetin molecular complex was found to be 78.4, as shown in Table 4 and figure 5. Comparison of SI values with reported Natural Products, indicated that Lactocetin has the highest SI, thereby providing the broadest window for dosing.
Table 4
Example 4:
Clinical study:
A Randomized, Three Treatment, Open Label, Parallel Design pilot study to assess the Comparative Bioavailability of Lactocetin (lactoferrin and quercetin molecular complex with buccal absorption) with that of Lactoferrin formulations in 9 adult male healthy volunteers.
Subjects were randomized into either of these groups;
Group I -3 subjects - Lactocetin (30 mg) (1:30 molar ratio of lactoferrin and quercetin)
Group II -3 subjects - Lactocetin (60 mg) - 2 tablets of 30 mg Lactocetin(l :30molar ratio of lactoferrin and quercetin)
Group III -3 subjects- Lactoferrin (30 mg).
The subjects were screened for inclusion criteria, viz., volunteer aged between 20- 50 years; adhered to all study procedures; provided written informed consent for participation in the trial and agreed to provide blood samples for study analysis and for exclusion criteria viz., history of allergy to known lacto based or herbal products; patients with pre-existing severe systemic disease necessitating long-term
medication, evidence of significant uncontrolled co-morbid disease, like diabetes (Type I or II), which in the investigator's opinion would jeopardize patient participation, history of cancer, including solid tumours, hematologic malignancies and carcinoma, any neurological (congenital or acquired), vascular or systemic disorder which could affect any of the efficacy assessments and participation in the current or previous treatment with any approved or investigational health supplement(s) during the past 1 month. Subjects who cleared the inclusion exclusion criteria were checked-in to the clinical facility from at least 12 hours prior to the Investigational Product administration. After overnight fasting specified dose of the study products were administered orally to each subject in sitting posture, as a single dose in study period. Dosing activity were followed by mouth check to assess the compliance to dosing.
In study Period, total 14 (IX 5 ml each) blood samples were collected from each subject for Pharmacokinetic Analysis. Time points are 0.0 hr (pre-dose) and at 5 min, 10 min, 15 min, 20 min, 30 min, 40 min, 50 min, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr and 12 hr post dose.
Subjects were instructed not to consume alcohol, smoke cigarettes, chew tobacco, and consume any caffeine and any xanthine containing product within 36 hours of in-housing till they leave the facility and also no diet which contains any Lactocetin and Lactoferrin was provided 24 hrs prior to study drug administration till check out from the facility. Other restrictions include subjects are not supposed to consume any OTC medicines prior to 14 days before check in period till the study is over, herbal combinations or prescription medications. Subjects are strictly instructed not to donate blood from the day they are enrolled into the study till the end of the study. They will not be allowed to do any strenuous exercise during study period. Subjects were instructed to be seated upright for the first four hours following drug administration (except as directed by the physician). Regular food free of Lactocetin and Lactoferrin containing food like cow milk, citrus fruits and vegetables. The plasma sample were analyzed using fit-for-purpose method for the
quantification of Lactocetin and Lactoferrin in samples. The calibration curve (CC) for the method will consist of at least 6 non-zero calibration standards along with a blank and blank with internal standard samples. Study samples were analyzed along with quality control samples (low, medium and high QC samples). The pharmacokinetic parameters were calculated using the standard analytical tool. The relative bioavailability of the test formulations were compared and reported for AUC (0-24 h) from the same analysis with respect to standard formulation.
The outcome of the study is shown in below table 5.
Table 5:
• Legend: Vol 1,5 & 9 - lactoferrin 30 mg o Vol 3,4 & 7 - Lactocetin 30 mg o Vol 2, 4 & 6 - Lactocetin 60 mg
The Inference of the above PK data is shown in table 6 below:
Table 6:
Inference from the above study:
Marked increase in Cmax (30%) and Absolute Bioavailability (5 Times) indicate increased permeability of lactoferrin in Lactocetin formulation, which establishes that the quercetin in the formulation enhances the bioavailability of the lactoferrin in lactocetin formulation which further shows that the quercetin enhances the bioavailability of lactoferrin by synergistic action.
Buccal route of administration is a novel faster route of drug / nutraceutical delivery. Shown here by substantial amounts being absorbed by the 5th minute and increased bioavailability.
There is an overall bioavailability increase by 12% in lactocetin buccal formulation as compared to lactoferrin buccal formulation.
The present invention of Lactocetin (a molecular complex of Apolactoferrin with Quercetin dehydrate at 1 :30 molar ratio) has shown substantial improvement in the bioavailability of Lactoferrin. The Fast Dissolving Tablets (FDTs) that the present
inventors have pioneered for lactoferrin delivery, has shown fast absorption and marked improvement in bioavailability and distribution among the various tissues.
Pharmacodynamic study:
The same bioavailability studies were extended to assess few biochemical and physiological parameters. Given below in table 7 is an overall summary of the Pharmacodynamic data:
Table 7:
The above study indicates that Lactocetin has marked Anti-inflammatory action (IL6 & CRP) when compared to lactoferrin at the same concentration. It has also shown to control Random Blood Sugar (RBS) and BP, indicating that Lactocetin can efficiently manage the comorbidities during the viral infection in a subject.
Lactocetin (1:30 molar ratio) is superior formulation of lactoferrin (30mg), and further demonstrated substantial control on viral virulence. Lactocetin is therefore a good therapeutic as well as a prophylactic formulation in the management of COVID 19and related viral infections.
Example 5:
FDT formulation for buccal administration
Example 6:
Both 1:30 molar ratio (Lactoferrin: quercetin) and 1:50 molar ratio (Lactoferrin: Quercetin) were used for making the Fast dissolving Tablets. Both these have shown good antiviral, anti-inflammatory and immunomodulatory actions.
Claims
1. Nutraceutical composition(s) comprising a molecular complex (solid solution / eutectic / cocrystal) of lactoferrin (Lf) and quercetin, in association with one or more suitable nutraceutical carriers or vehicles, for use as prophylactic and in the treatment of early and advanced stage of viral infections.
2. The compositions as claimed in claim 1, wherein, the viral infections are selected from the group consisting of early and advanced stages of Flu (Influenza), HIV, Dengue, Chicken guinea and SARS CoV-2 and related SARS infections.
3. The compositions as claimed in claim 1, wherein, the molar ratio of lactoferrin (Lf) and quercetin in the molecular complex is selected from a ratio of 1:1; 1:10; 1:20, 1: 30; 1:40; 1:50; 1:60; 1:70; 1:80; 1:90; 1:100; 1:110; 1:120; 1:130; 1:40; l:-50; 1:160; 1:70; 1:180; 1:190; and 1:200.
4. The compositions as claimed in claim 1, wherein, the molar ratio of lactoferrin (Lf) and quercetin in the molecular complex is 1 :30, which is characterised by differential scanning calorimetry (DSC) endotherm at 74.6°C and exotherm at 272.1°C.
5. The compositions as claimed in claim 1, wherein, the molar ratio of lactoferrin (Lf) and quercetin in the molecular complex is 1:50 exhibits a sharp melting point at 238°C.
6. The composition as claimed in claim 1, wherein the composition comprises molecular complex of lactoferrin (Lf) and quercetin present in an amount of 0.01%- 99 % w/w of the composition.
7. The composition as claimed in claim 1, wherein the source of lactoferrin is selected from the group consisting of Bovine source, Goat milk (Caprine), Camel milk, Sheep Milk, donkey milk and Buffalo milk.
8. The composition as claimed in claim 1, wherein the type of lactoferrin is selected from the group consisting of Iron Free lactoferrin (Apolactoferrin), half-filled Iron lactoferrin and completely Iron filled lactoferrin (holo lactoferrin).
9. The composition as claimed in claim 1, wherein the source of quercetin(also known as - 5,7,3 ',4'-flavon-3-ol, Sophoretin, Meletin, Quercetine,
Xanthaurine, Quercetol, Quercitin, Quertine, Flavin meletin) is selected from any natural source or of synthetic origin.
10. The composition as claimed in claim 1, wherein, the molecular complex of lactoferrin (Lf) and quercetin is suitably formulated into solid oral, sublingual or buccal formulations selected from the group consisting of thin film formulations, gummies, fast dissolving tablets, tablets, capsules; liquid formulations for nebulization or a solid dispersion for inhalation, intravenous and intramuscular injections, topical transdermal formulations, subcutaneous formulations, eye and ear formulations or transdermal patch.
11. The composition as claimed in claim 1, wherein, the molecular complex (solid solution, eutectic, cocrystal) and / or a simple mixture of lactoferrin (Lf) and quercetin is suitably formulated for Buccal or oral administration.
12. The composition as claimed in claim 1, wherein, the composition is formulated optionally in combination with at least one component selected from natural polyphenols; mono, di or oligosaccharides and hypothiocyanite, having antiviral activity along with suitable nutraceutical excipients/carriers, for targeted drug delivery.
13. The composition as claimed in claim 1, wherein, the natural polyphenol is selected from the group consisting of and not limited to delphinidin, cyanidine, gallic acid, catechin, epicatechin, epigallocatechin, ellagic acid, rutin, quercetin, luteolin, curcumin, genestien and the mono, di or oligosaccharides are selected from the group consisting of lactose, galactose, mannose, human milk oligosaccharides, chitosan oligos, having antiviral activity.
14. A process for preparation of the molecular complex of lactoferrin (Lf) and quercetin, which process comprises; heating Quercetin dihydrate to 150°C followed by adding lactoferrin and ball milling or neat grinding for sufficient time using a mortar and pestle, to obtain molecular complex of lactoferrin (Lf) and quercetin.
15. A process for preparation of the molecular complex of lactoferrin (Lf) and quercetin, which process comprises; heating Quercetin dihydrate to 150°C followed by adding lactoferrin and extruding followed by spheronization of the reaction mass for sufficient time using suitable equipments, to obtain molecular complex of lactoferrin (Lf) and quercetin.
16. A method for treating early and advanced stage of viral infection in a subject, which method comprises administering a formulation comprising an effective amount of molecular complex of lactoferrin (Lf) and quercetin, for targeted drug delivery.
17. The method as claimed in claim 16, wherein the viral infection is selected from the group consisting of early and advanced stages of Flu (influenza), HIV, Dengue, Chicken guinea and SARS CoV-2 infection.
18. The method as claimed in claim 16, wherein the formulation is solid oral, sublingual or buccal formulations selected from the group consisting of thin film formulations, gummies, FDTs, tablets, capsules; liquid formulations for nebulization or a solid dispersion for inhalation, or intravenous and intramuscular injections, topical formulations, nasal and eye formulations or transdermal patch.
19. The method as claimed in claim 16, wherein the method comprises administering the formulation of lactoferrin (Lf) and quercetin optionally in combination with at least one component selected from natural polyphenols, mono, di or oligosaccharides and hypothiocyanite, having antiviral activity, along with suitable nutraceutical excipients, for targeted drug delivery.
20. Use of formulations for buccal absorption, oral administration/nebulization or a solid dispersion for inhalation, or intravenous and intramuscular injections, topical formulations, nasal and eye formulations or transdermal patch comprising a therapeutically effective amount of a molecular complex of lactoferrin (Lf) and quercetin, for prevention or treatment of early and advanced stage of viral infection.
21. The use as claimed in claim 20, wherein the viral infection is selected from the group consisting of early and advanced stages of Flu, HIV, Dengue, Chicken guinea and SARS CoV-2 and related SARS viral infections.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116509821A (en) * | 2023-03-07 | 2023-08-01 | 广州见华医学科技有限公司 | Application of lactoferrin patch in preparing medicine for treating infectious diseases caused by coronaviruses |
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