Compositions for treating human papilloma virus (HPV) infection

Abstract

The present invention relates to a combination or composition for preventing, controlling and treating human papilloma virus infection in a subject comprising epigallocatechin gallate (EGCG) and at least one further agent selected from folic acid, vitamin B12 and low or very low molecular weight hyaluronic acid (1-500 kDa) or derivatives thereof.

Description

Technical Field

[0001] The present invention relates to a combination or composition for preventing, controlling and treating human papillomavirus (HPV) in a subject, comprising epigallocatechin gallate (EGCG) and at least one of the following other agents: folic acid, vitamin B12, low or very low molecular weight hyaluronic acid (1-500 kDa) or a derivative thereof. Background Art

[0002] Human papillomavirus (HPV) is an infection present in sexually active populations worldwide. It is estimated that 80% of people will contract this type of infection at least once in their lifetime [Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209-249. doi:10.3322 / caac.21660]. HPV infection affects both women and men and is mainly acquired after sexual intercourse (vaginal or anal) and occasionally after non-penetrative sex. Viruses of the HPV family have a pronounced tropism for epithelial tissues and mucous membranes, which are subject to microtrauma and abrasions during sexual intercourse. Papillomaviruses (from the Latin word “papilla”, meaning pustule, and the Greek word “oma”, meaning tumor) are a large family of double-stranded DNA viruses (8 kb). They are enveloped and have icosahedral symmetry. The viral genome of HPV viruses is divided into two well-defined regions: 1) early and 2) late. The early genes encode the early proteins E1, E2, E4, E5, E6, and E7, which are responsible for viral DNA replication and cellular transformation. The late genes encode the late proteins L1 and L2, which are required for the formation of the viral capsid [McLaughlin-Drubin, ME; Münger, K. Oncogenic activities of human papillomaviruses. Virus Res. 2009, 143, 195–208]. HPV viruses are classified according to their oncogenicity. Low-risk HPV viruses are associated with proliferative lesions of the skin and mucous membranes that are usually benign. Clinical manifestations include common, flat and plantar warts, genital and flat condyloma acuminatum (anogenital warts), which are the result of sexual transmission of the virus and appear on the penis, anus and female genitals. High-risk HPV viruses integrate into the host genome and cause lesions that may develop into cancer over time.In fact, papillomavirus is the main pathogen of cervical cancer, which is the fourth most common cancer in women and the second most common cancer in people aged 15-14 years [Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. World cancer statistics 2020: GLOBOCAN estimates of global incidence and mortality for 36 cancers in 185 countries. CA Cancer J Clin. 2021 May;71(3):209-249. doi:10.3322 / caac.21660]. HPV infection is also the cause of 50% of penile cancer cases, 33-72% of oral cancers and about 85% of anal cancers in men [Giuliano AR, Anic G, Nyitray AG. Epidemiology and pathology of HPV disease in men. Gynecol Oncol. 2010; 117(2 Suppl): S15-S19. doi: 10.1016 / j.ygyno.2010.01.026]. Most HPV infections are generally temporary and can resolve on their own within 1-2 years. The infection process from initial infection to tumor is a long process consisting of many steps. The persistence of the virus and its integration in the host are the key to determining the "point of no return" (Evander M, Edlund K, Gustafsson A, Jonsson M, Karlsson R, Rylander E, Wadell G. Human papillomavirus infection is transient in young women: a population-based cohort study. J Infect Dis. 1995 April; 171(4): 1026-30. doi: 10.1093 / infdis / 171.4.1026).Initial infection occurs when viral particles enter the basal cells of the epithelium, and then small cuts or trauma expose the basal keratinocytes to the virus (Woodman CB, Collins SI, Young LS. The natural history of cervical HPV infection: unresolved issues. Nat Rev Cancer. 2007 Jan;7(1):11-22. doi:10.1038 / nrc2050. PMID:17186016). When the virus colonizes the basal and parabasal cells of the epithelium, the viral genome replicates in the form of episomes of extrachromosomal circular DNA fragments. At this stage, the expression of viral genes is limited to those involved in stimulating the proliferation and lateral expansion of infected cells. During episomal replication, cells are infected with functionally inactive (latent) viruses, and the cells do not show any signs of neoplastic transformation. During this replication phase, the viral protein E2 plays a fundamental role in regulating the levels of the two major viral oncoproteins E6 and E7. The loss of E2 represents an early stage of tumor transformation. When the viral genome is integrated into the host, the E1 and E2 regions are cut, while the E6 / E7 region remains intact. After this integration, it was observed that both the E2 gene and protein would lose function, resulting in increased expression of viral oncoproteins E6 and E7. These proteins act on cell checkpoints and bind to tumor suppressor proteins pRB and p53, which are cell checkpoint regulators. Specifically, pRB is a negative regulator that normally prevents entry into the S phase of the cell cycle; p53 is known as the "guardian of the genome" and is a major regulator of the cell cycle [Lane DP. Cancer. P53--Guardian of the genome (p53, guardian of the genome). Nature. July 2, 1992; 358 (6381): 15-6. doi: 10.1038 / 358015a0. PMID: 1614522]. The loss of tumor suppressor function promotes tumorigenesis. In fact, the only strategy to limit the spread of infection is a screening program to detect infection and vaccination activities as early as possible. It is important to remember that the vaccine affects only certain strains of the HPV family, it is not without risk, and its effectiveness decreases over time. Currently, there is no specific treatment to prevent or block HPV infection.

[0003] Epigallocatechin gallate (EGCG)

[0004] Epigallocatechin gallate (EGCG) is an ester of epigallocatechin and gallic acid extracted from green tea. The role of EGCG in oncology has been intensively studied and has been shown to have beneficial effects on a variety of tumor types, including cervical cancer [Wang YQ, Lu JL, Liang YR, Li QS. Suppressive Effects of EGCG on Cervical Cancer. Molecules. 2018 Sep 12;23(9):2334. doi:10.3390 / molecules23092334. PMID:30213130; PMCID:PMC6225117]. EGCG has antiproliferative, pro-apoptotic, anti-metastatic, and anti-inflammatory effects on tumor cells and cell lines infected with high-risk HPV. EGCG reduces tumor proliferation in multiple ways: 1) blocking the cell cycle of tumor cells and / or 2) blocking tumor proliferation. A study by Changping Zou et al. [Zou C, Liu H, Feugang JM, Hao Z, Chow HH, Garcia F. Green tea compound in chemoprevention of cervical cancer. Int J Gynecol Cancer. 2010; 20(4): 617-624. doi: 10.1111 / IGC.0b013e3181c7ca5c] demonstrated that EGCG inhibited cell growth and promoted apoptosis, i.e., cell death, in cervical epithelial cell lines infected with high-risk HPV (TLC1) and cervical cancer cell lines such as Hela and Me180 in a dose-dependent manner. In addition, EGCG increased the expression level of p53 protein and reduced the level of viral protein E7 [Zou C, Liu H, Feugang JM, Hao Z, Chow HH, Garcia F. Green tea compound in chemoprevention of cervical cancer. Int J GynecolCancer.2010;20(4):617-624.doi:10.1111 / IGC.0b013e3181c7ca5c].A randomized study showed that green tea extract containing 200 mg EGCG has a chemopreventive effect on cervical cancer [Ahn WS, Yoo J, Huh SW, Kim CK, Lee JM, Namkoong SE, Bae SM, Lee IP. Protective effects of green tea extracts (polyphenon E and EGCG) on human cervical lesions. Eur J Cancer Prev. 2003 Oct; 12(5): 383-90. doi:.

[0005] 10.1097 / 00008469-200310000-00007]. In this study, 88 women with varying degrees of lesions were treated with EGCG tablets (200 mg) for 8-12 weeks. The overall clinical condition of 60% of the treated women improved; after cytological evaluation, colposcopy, histological examination and HPV DNA testing, 100% of women with moderate lesions and 71% of women with severe lesions responded positively to the treatment. In addition, EP0842660A1 describes a pharmaceutical composition containing a tea (Camellia sinensis) extract and its use for treating condyloma acuminatum (genital warts) caused by human papillomavirus, wherein the tea (Camellia sinensis) extract contains catechins (more specifically, (-)-epigallocatechin gallate), and the pharmaceutical composition is in the form of an ointment of 2-20% by weight or a 50-500 mg tea catechin suppository. CN107349197 discloses the use of catechins in the preparation of medicines for treating skin papilloma.

[0006] Folic acid and vitamin B12

[0007] Vitamin B12 (cobalamin), folic acid and folate derivatives are essential water-soluble vitamins that are vital for a variety of functions in living organisms. Specifically, both substances are involved in the metabolism of methionine (an amino acid necessary for protein synthesis), the synthesis of nucleic acids, red blood cells and nervous system function. Deficiency of folate and vitamin B12 leads to elevated plasma homocysteine, which is a risk factor for cardiovascular diseases, Alzheimer's disease and other neurological diseases. A recent meta-analysis suggests that folate deficiency and the consequent elevation of homocysteine ​​increase the risk of cancer [Zhang D, Wen X, Wu W, Guo Y, Cui W. Elevated homocysteine ​​level and folate deficiency associated with increased overall risk of carcinogenesis: meta-analysis of 83 case-control studies involving 35,758 individuals. PLoS One. 2015 May 18;10(5):e0123423. doi:10.1371 / journal.pone.0123423]. In addition, folate and vitamin B12 are essential for the synthesis of S-adenosylmethionine (SAM), a methyl donor and an essential cofactor in a variety of biochemical synthesis pathways. Because folate and vitamin B12 play a role in DNA methylation, and more specifically, in the methylation of the HPV viral genome, they are essential for regulating and inhibiting viral gene expression, proliferation, and persistence [Sedjo RL, Inserra P, Abrahamsen M, Harris RB, Roe DJ, Baldwin S, Giuliano AR. Human papillomavirus persistence and nutrients involved in the methylation pathway among a cohort of young women. Cancer Epidemiol Biomarkers Prev. 2002 Apr; 11(4): 353-9].A study of 315 women with varying degrees of high-risk HPV infection found a correlation between folate and vitamin B12 levels and levels of viral genome methylation. This study showed that folate and vitamin B12 reduced the risk of high-risk lesions, and high levels of both corresponded with high levels of HPV genome methylation and a decrease in the percentage of high-risk lesions [Piyathilake CJ, Macaluso M, Chambers MM, Badiga S, Siddiqui NR, Bell WC, Edberg JC, Partridge EE, Alvarez RD, Johanning GL. Folate and vitamin B12 may play a critical role in lowering the HPV 16methylation-associated risk of developing higher grades of CIN. Cancer Prev Res (Phila). 2014 Nov;7(11):1128-37. doi:10.1158 / 1940-6207.CAPR-14-0143]. A study conducted by Piyathilake et al. verified the protective effect of folate on the occurrence, persistence and disappearance of high-risk HPV infection. 345 women at risk of high-risk lesions were monitored for two consecutive years, their clinical status was assessed every 6 months, and metabolic folate levels were measured. The results of the study showed that patients with higher folate levels had a 73% lower probability of testing positive during regular follow-up; specifically, high folate levels reduced the incidence and persistence of the virus and helped clear the infection [Piyathilake CJ, Henao OL, Macaluso M, Cornwell PE, Meleth S, Heimburger DC, Partridge EE. Folate is associated with the natural history of high-risk human papillomaviruses. Cancer Res. 2004 Dec 1; 64(23):8788-93.doi:10.1158 / 0008-5472.CAN-04-2402].

[0008] Low molecular weight and very low molecular weight hyaluronic acid

[0009] Known hyaluronic acid is an interesting, widely used and useful natural macromolecule. Although its structure is simple, it has specific properties and has different functions according to its molecular weight. Physiologically, hyaluronic acid exists in the form of high molecular weight (HMW-HA) salt (sodium hyaluronate), and plays a structural role as a component of the extracellular matrix. In addition, hyaluronic acid also has a regulatory effect. Specifically, low molecular weight and very low molecular weight hyaluronic acid stimulate the production of proinflammatory cytokines (such as IL-1β, IL-6, IL-12, TNF-α) [Jiang D, Liang J, Noble PW. Hyaluronic acid in human disease immunomodulatory effect (Hyaluronan as an immune regulator in human diseases). Physiol Rev. 2011 January; 91 (1): 221-64. doi: 10.1152 / physrev.00052.2009]. The stimulation of these pro-inflammatory factors is extremely useful in the "wound healing" process [Yang H, Song L, Zou Y, Sun D, ​​Wang L, Yu Z, Guo J. Role of Hyaluronic Acids and Potential as Regenerative Biomaterials in Wound Healing. ACS Appl BioMater. 2021 Jan 18; 4(1): 311-324. doi: 10.1021 / acsabm.0c01364]. Gao F. et al. [Gao F, Yang CX, Mo W, Liu YW, He YQ. Hyaluronan oligosaccharides are potential stimulators to angiogenesis via RHAMM mediated signal pathway in wound healing. Clin Invest Med. 2008; 31(3): E106-16. doi: 10.25011 / cim.v31i3.3467] have demonstrated how low molecular weight and very low molecular weight hyaluronic acid significantly accelerate the wound healing process compared to the control group in an in vitro cell model. In the context of HPV infection, this repair effect can more quickly restore the integrity of the epithelium and mucosa that have been traumatized during sexual intercourse, which allows the virus to enter the epithelial basal layer. The role of hyaluronic acid and its repair effect has been confirmed in vaginal infections and other therapeutic areas.The study of La Galia et al. 2014 [La Galia T., Micali A., Puzzolo D., Cancellieri F. Oral Low-Molecular Weight Hyaluronic Acid in the Treatment of Atrophic Vaginitis. International Journal of Clinical Medicine> Vol. 5, No. 11, May 2014] verified the effect of low molecular weight and very low molecular weight hyaluronic acid on 12 postmenopausal women with vaginal atrophy. Specifically, the study proved that 3 months of hyaluronic acid treatment restored mucosa and significantly alleviated the symptoms (itching, burning and dyspareunia) associated with vaginal atrophy. EP3804696A1 also relates to the use of hyaluronic acid-containing patches to treat warts caused by infection with a certain HPV.

[0010] In the present invention, it has been determined that the combination and / or combination or composition of EGCG with at least one of the following agents has an inhibitory effect on in vitro tumor cell proliferation or HPV-infected cells: folic acid, vitamin B12 and low molecular weight or very low molecular weight hyaluronic acid (1-500kDa). Preferably, the combination and / or combination or composition of the present invention contains all of the above-mentioned active substances. As demonstrated by the present invention, relative to the single action of EGCG alone or the single substances listed above, the combination and / or combination and / or composition of the present invention exhibits a synergistic and / or additive response, reduces tumor cell proliferation or HPV-infected cells, increases the apoptosis (cell death) rate of tumor cells or HPV-infected cells, and induces increased expression or production of p53 and reduced expression of viral E6 and / or E7 genes. Summary of the invention

[0011] The authors found that the administration of EGCG in combination and / or in conjunction with at least one of the following agents or compositions was more effective in preventing and / or blocking HPV infection than the use of these substances alone: ​​folic acid, vitamin B12, and low or very low molecular weight hyaluronic acid (1-500 kDa). Until now, it was known that EGCG could be used to treat tumor cells or cells infected with HPV, but it was not known or suggested that these compounds (i.e., EGCG, folic acid, vitamin B12, and hyaluronic acid) could be used together to treat HPV infection. The evidence of increased tumor suppressor factors provides a novel effect that can be advantageously obtained by combining and / or in conjunction with EGCG and at least one of the following agents: folic acid, vitamin B12, and low or very low molecular weight hyaluronic acid (1-500 kDa).

[0012] It is therefore an object of the present invention to provide a combination comprising or consisting of a compound of formula (I):

[0013]

[0014] Where R1=H or

[0015]

[0016] R2=H or OH,

[0017] or a stereoisomer or a salt thereof;

[0018] and at least one other agent selected from the group consisting of:

[0019] a. folic acid or its salts or derivatives;

[0020] b. Vitamin B12 or its derivatives;

[0021] c. low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa) or a pharmacologically acceptable salt thereof;

[0022] Used to prevent, control and / or inhibit human papillomavirus (HPV) infection.

[0023] Preferably, the combination comprises:

[0024] a. a compound of formula (I) in an amount of 1 mg to 800 mg per day, preferably 50 mg to 600 mg per day, preferably about 200 mg per day;

[0025] b. folic acid or a salt or derivative thereof in an amount of 1 to 400 micrograms per day, preferably 50 to 400 micrograms per day, preferably 200 to 400 micrograms per day, preferably about 400 micrograms per day; and / or

[0026] c. Vitamin B12 or a derivative thereof in an amount of 1 to 1000 micrograms per day, preferably 100 to 1000 micrograms (1 mg) per day, preferably 500 to 1000 micrograms (1 mg) per day, preferably about 1000 micrograms (1 mg) per day; and / or

[0027] d. Very low / low molecular weight hyaluronic acid or a pharmaceutically acceptable salt thereof in an amount of 1 mg to 200 mg per day, preferably 25 mg to 150 mg per day, preferably 50 mg to 100 mg per day, preferably about 50 mg per day.

[0028] Preferably, the combination of the present invention comprises a compound of formula (I) or a stereoisomer or salt thereof and at least two other agents selected from the following:

[0029] a. folic acid or its salts or derivatives;

[0030] b. Vitamin B12 or its derivatives;

[0031] c. Very low / low molecular weight hyaluronic acid or a pharmaceutically acceptable salt thereof.

[0032] More preferably, the combination of the present invention comprises i) a compound of formula (I) or a stereoisomer or salt thereof and ii) folic acid or a salt or derivative thereof and iii) vitamin B12 or a derivative thereof and iv) very low / low molecular weight hyaluronic acid or a pharmaceutically acceptable salt thereof.

[0033] Preferably, the combination comprises or consists of at least a compound of formula (I) and folic acid or a salt or derivative thereof; preferably, the combination comprises or consists of a compound of formula (I) and vitamin B12 or a derivative thereof; more preferably, the combination comprises or consists of at least a compound of formula (I) and low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa) or a pharmacologically acceptable salt; more preferably, the combination comprises or consists of at least a compound of formula (I), folic acid or a salt or derivative thereof and low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa) or a pharmacologically acceptable salt; more preferably, the combination comprises or consists of at least a compound of formula (I), vitamin B12 or a derivative thereof and low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa) or a pharmacologically acceptable salt; more preferably, the combination comprises or consists of at least a compound of formula (I), folic acid or a salt or derivative thereof and vitamin B12 or a derivative thereof.

[0034] Preferably, the combination comprises or consists of at least a compound of formula (I), folic acid or a salt or derivative thereof, vitamin B12 or a derivative thereof, and low or very low molecular weight hyaluronic acid (1-500 kDa) or a pharmacologically acceptable salt thereof.

[0035] As used herein, the expression "folic acid or a salt or derivative thereof" refers to an agent or a mixture of agents selected from the group consisting of folic acid, a salt of folic acid (folate), calcium L-5-methylfolate and (6s)-5-methyltetrahydrofolate, preferably in the form of a glucosamine salt. The agent is also known as pteroyl-L-glutamic acid, vitamin M, vitamin B9, folic acid, pteroyl-L-monoglutamic acid and left methylfolate. Salts other than calcium or glucosamine salts also fall within the meaning of folate according to the present invention. Preferably, the expression "folic acid or a salt or derivative thereof" means calcium L-5-methylfolate.

[0036] As used herein, the expression "vitamin B12 or a derivative thereof" refers to cobalamin, cyanocobalamin, hydroxocobalamin, methylcobalamin; preferably, it refers to cyanocobalamin.

[0037] As defined herein, the expression "low molecular weight or very low molecular weight hyaluronic acid" refers to hyaluronic acid with a molecular weight of 1-500kDa; preferably, the molecular weight is 1-100kDa, more preferably, the molecular weight is 1-20kDa, and more preferably, the molecular weight is 3-10kDa; for example, the pharmacologically acceptable salts of low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) as defined above include salts of sodium hyaluronate, also defined as sodium hyaluronate or sodium hyaluronate salt. Preferably, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) or pharmacologically acceptable salts refer to sodium hyaluronate.

[0038] Preferably, the compound of formula (I) is one of the following: (-)-epigallocatechin gallate (EGCG) and / or (-)-gallocatechin gallate (GCG) and / or (-)-epicatechin gallate (ECG) and / or (-)-catechin gallate (CG) and / or (-)-epicatechin (EC) and / or (+)-catechin (C) and / or (-)-epigallocatechin (EGC) and / or (+)-gallocatechin (GC); or a combination thereof; more preferably, the compound of formula (I) is (-)-epigallocatechin gallate (EGCG).

[0039] EGCG is a polyphenolic catechin and is the most common catechin in tea, particularly green tea, preferably obtained from the Camellia sinensis plant.

[0040] Preferably, the EGCG described in the present invention is a product extracted or obtained from a part of a green tea plant, more preferably, obtained from a wild tea plant, more preferably, obtained from the leaves of the plant, including: (-)-epigallocatechin gallate (EGCG) and / or (-)-gallocatechin gallate (GCG) and / or (-)-epicatechin gallate (ECG) and / or (-)-catechin gallate (CG) and / or (-)-epicatechin (EC) and / or (+)-catechin (C) and / or (-)-epigallocatechin (EGC) and / or (+)-gallocatechin (GC). In addition, EGCG preferably refers to epigallocatechin gallate in an enantiomerically pure form or a racemic mixture.

[0041] Preferably, the human papillomavirus is identified by using the HPV DNA test and the PAP test in women, whose infection shows evidence of changes of various grades (low, medium, high) of cells and / or benign and / or malignant lesions affecting the skin and / or mucous membranes of different gynecological areas (vagina, cervix, vulva, anus and penis). Preferably, the infection is a transitional infection or a persistent infection with HPV. Preferably, the infected benign lesions include common warts, flat and plantar warts, genital and flat condyloma acuminatum, which allow sexual transmission of the virus and appear in the penis, anus, female genitals, urethra, perianal area and rectal area.

[0042] Preferably, the present invention is supplemented with EGCG and an agent selected from at least one of folate, folic acid, L-5-methylfolate calcium or its derivatives, and / or an agent selected from vitamin B12, cobalamin, cyanocobalamin and / or an agent selected from low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) or a pharmaceutically acceptable salt (e.g., sodium hyaluronate or sodium hyaluronate) for preventing, controlling and / or inhibiting HPV infection. Preferably, HPV infection refers to female and male HPV infection. First, preferably, the present invention provides EGCG, L-5-methylfolate calcium, vitamin B12 and low molecular weight / very low molecular weight hyaluronic acid (1-500kDa) for preventing, controlling and / or inhibiting HPV infection.

[0043] Preferably, in the combination and / or combination of the present invention, the amount of EGCG is 1-800 mg / day. More preferably, the amount of EGCG is 50-600 mg / day. More preferably, the amount of EGCG is about 200 mg. Preferably, EGCG is administered twice a day, with each administration of about 100 mg.

[0044] Preferably, in the combination of the present invention, folic acid is administered in an amount of 1-400 μg / day. More preferably, the amount of folic acid is 50-400 μg / day. More preferably, the amount of folic acid is 200-400 μg / day, more preferably, about 400 μg / day. Preferably, folic acid is administered once a day. More preferably, folic acid is administered twice a day, each administration of about 200 μg.

[0045] Preferably, in the combination of the present invention, the amount of vitamin B12 is 1-1000 μg / day. More preferably, the amount of vitamin B12 is 100-1000 μg (1 mg) / day, more preferably, the amount of vitamin B12 is 500-1000 μg (1 mg) / day, more preferably, about 1000 mg (1 mg) / day. Preferably, vitamin B12 is administered once a day. More preferably, vitamin B12 is administered twice a day, each administration of about 500 μg.

[0046] Preferably, in the combination of the present invention, the amount of low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) is 1mg-200mg / days. More preferably, the amount of low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) is 50mg-100mg / days. More preferably, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) is administered once a day, and the dosage is about 50mg. More preferably, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) is administered twice a day, and each administration is about 25mg.

[0047] In a preferred embodiment, the present invention provides a combination of EGCG and at least one of the following agents and / or in combination as described above for preventing, controlling and / or inhibiting HPV infection in women and men: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa). Therefore, in one embodiment, the present invention comprises EGCG, folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) for preventing, controlling and / or inhibiting HPV virus in women and men.

[0048] Preferably, in the combination of the present invention, EGCG is in the form of tea leaves or leaf extracts and / or tea plant parts. More preferably, the leaves and / or plant parts are from leaves and / or parts of green tea plants (more preferably Camellia Sinesis). Preferably, the amount of EGCG contained in the leaves and / or tea plant parts and / or the extract is from about 30% by weight to about 95% by weight, preferably about 30% by weight, about 45% by weight, about 50% by weight or about 95% by weight.

[0049] In a preferred embodiment, the combination and / or combination of EGCG and at least one of the following agents has a synergistic / additive effect and / or is more effective in preventing and / or blocking HPV infection in women and men and increasing the expression of tumor suppressors compared to the use of a single substance: folic acid, vitamin B12, and low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa). Preferably, relative to the effect of using EGCG alone or other agents alone, the combination of EGCG, folic acid, vitamin B12, and low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa) reduces the proliferation of tumor cells and cells infected with HPV, increases apoptosis (cell death) of tumor cells and cells infected with HPV, and leads to a significant increase in p53 protein expression or production, and a significant decrease in viral E6 and / or E7 gene expression.

[0050] Preferably, the human papillomavirus is identified in women using the HPV DNA test and the PAP test, the infection showing evidence of changes of various grades (low, medium, high) of cells and / or benign and / or malignant lesions affecting the skin and / or mucous membranes of different gynecological areas (vagina, cervix, vulva, anus and penis). Preferably, the infected benign lesions include common warts, flat and plantar warts, genital and flat condyloma acuminatum, which allow sexual transmission of the virus and appear in the penis, anus and female genital area.

[0051] Preferably, EGCG is combined and / or associated with at least one of folic acid, vitamin B12, and low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa) for simultaneous oral administration and / or topical administration once or twice daily.

[0052] Another object of the present invention is to provide such a composition, which comprises or consists of the compound of formula (I) as described above or its stereoisomer or salt and at least one other agent selected from the following:

[0053] a. folic acid or its salts or derivatives;

[0054] b. Vitamin B12 or its derivatives;

[0055] c. low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa) or a pharmaceutically acceptable salt thereof;

[0056] Preferably, the compound of formula (I) is one of the following: (-)-epigallocatechin gallate (EGCG) and / or (-)-gallocatechin gallate (GCG) and / or (-)-epicatechin gallate (ECG) and / or (-)-catechin gallate (CG) and / or (-)-epicatechin (EC) and / or (+)-catechin (C) and / or (-)-epigallocatechin (EGC) and / or (+)-gallocatechin (GC); or a combination thereof; more preferably, the compound of formula (I) is (-)-epigallocatechin gallate (EGCG).

[0057] Preferably, the composition of the invention comprises folic acid or a salt thereof and / or L-5-methylfolate calcium (commonly known as L-methylfolate) or another salt of (6s)-5-methyltetrahydrofolate, such as the glucosamine salt.

[0058] Preferably, in the composition of the present invention, the low molecular weight or very low molecular weight hyaluronic acid is sodium hyaluronate with a molecular weight between 1 and 100 kDa, more preferably between 1 and 20 kDa, and more preferably between 3 and 10 kDa.

[0059] Preferably, the vitamin B12 or its derivative in the composition of the present invention is cyanocobalamin.

[0060] Preferably, the composition contains at least a compound of formula (I) and folic acid or a salt or derivative thereof; more preferably, the composition contains at least a compound of formula (I) and vitamin B12 or a derivative thereof; more preferably, the composition contains at least a compound of formula (I) and low or very low molecular weight hyaluronic acid (1-500 kDa) or a pharmaceutically acceptable salt thereof.

[0061] Preferably, the composition comprises at least a compound of formula (I), folic acid or a salt or derivative thereof and vitamin B12 or a derivative thereof or consists of the same; more preferably, the composition comprises at least a compound of formula (I), folic acid and low or very low molecular weight hyaluronic acid (1-500 kDa) or a pharmaceutically acceptable salt thereof or consists of the same; more preferably, the composition comprises at least a compound of formula (I), vitamin B12 or a derivative thereof and low or very low molecular weight hyaluronic acid (1-500 kDa) or a pharmaceutically acceptable salt thereof or consists of the same.

[0062] In a preferred embodiment, the composition of the present invention comprises or consists of the following substances: i) a compound of formula (I) or a stereoisomer or salt thereof; and ii) folic acid or a salt or derivative thereof; and iii) vitamin B12 or a derivative thereof; and iv) very low / low molecular weight hyaluronic acid or a pharmaceutically acceptable salt thereof.

[0063] Preferably, the composition of the present invention comprises:

[0064] a. the compound of formula (I) in an amount of 1 mg to 800 mg, preferably 50 mg to 600 mg, preferably about 200 mg, preferably about 100 mg;

[0065] b. folic acid or a salt or derivative thereof in an amount of 1 to 400 micrograms, preferably 50 to 400 micrograms, preferably 200 to 400 micrograms, preferably about 400 micrograms, preferably about 200 micrograms; and / or

[0066] c. Vitamin B12 or a derivative thereof in an amount of 1 to 1000 micrograms, preferably 100 to 1000 micrograms (1 mg), preferably 500 to 1000 micrograms (1 mg), preferably about 1000 micrograms (1 mg), preferably about 500 micrograms; and / or

[0067] d. Very low / low molecular weight hyaluronic acid or a pharmaceutically acceptable salt thereof in an amount of 1 mg to 200 mg, preferably 25 mg to 150 mg, preferably 50 to 100 mg, preferably about 50 mg, preferably about 25 mg.

[0068] Preferably, the composition is used in a transient or sustained state to prevent, control and / or inhibit HPV infection, preferably, the human papillomavirus is identified by using HPV DNA test and PAP test in women, whose infection shows evidence of various grades (low, medium, high) of changes in cells and / or benign and / or malignant lesions affecting the skin and / or mucous membranes of different gynecological areas (vagina, cervix, vulva, anus and penis). Preferably, the infected benign lesions include common warts, flat warts and plantar warts, genital and flat condyloma acuminatum, which allow sexual transmission of the virus and appear in the penis, anus and female genital area.

[0069] Still preferably, the EGCG in the composition is in the form of tea leaves or tea extracts, preferably, the tea leaves are green tea leaves, preferably wild tea leaves, more preferably the tea leaves contain 30 wt % to 95 wt % EGCG, even more preferably about 30 wt %, 45 wt %, 50 wt % or 95 wt % EGCG.

[0070] Preferably, the composition comprises EGCG in an amount of 1 to 800 mg / day. More preferably, the amount of EGCG is 50 to 600 mg. More preferably, the amount of EGCG is about 200 mg. More preferably, the EGCG in the composition is administered once a day; more preferably, the EGCG in the composition is administered twice a day, each administration of about 100 mg.

[0071] Preferably, the composition comprises 1 to 400 μg of folic acid or a salt or derivative thereof. More preferably, the amount of folic acid is 50 to 400 μg. More preferably, the amount of folic acid is 200 to 400 μg, more preferably, the amount of folic acid is about 400 μg, even more preferably, the amount of folic acid is about 200 μg. Preferably, the folic acid in the composition is administered once a day. More preferably, the folic acid in the composition is administered twice a day, each administration of about 200 μg.

[0072] Preferably, the amount of vitamin B12 in the composition is 1-1000 μg. More preferably, the amount of vitamin B12 is 100 to 1000 μg (1 mg), more preferably, the amount of vitamin B12 is 500 to 1000 μg (1 mg), more preferably about 1000 μg (1 mg), and even more preferably an amount of 500 μg. Preferably, the vitamin B12 in the composition is administered once a day. More preferably, vitamin B12 is administered twice a day, with each administration of about 500 μg.

[0073] Preferably, the composition contains 1mg to 200mg of low molecular weight or very low molecular weight hyaluronic acid (1-500kDa). More preferably, the amount of low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) is 50mg to 100mg, preferably about 50mg, preferably about 25mg. More preferably, the low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) contained in the present composition is administered once a day, and dosage is about 50mg. More preferably, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) is administered twice a day, and each administration is about 25mg.

[0074] Preferably, the composition is administered orally and / or topically. Preferably, the composition is administered once or twice a day.

[0075] Preferably, the composition is in the form of tablets, hard capsules, soft capsules, powders, syrups, drinking liquids, gels, ointments, creams.

[0076] Optionally, the composition is used in combination with other therapeutic inventions. Preferably, the therapeutic invention is selected from the following surgeries, the purpose of which is to remove lesions caused by infection with any variant of human papillomavirus.

[0077] Another object of the present invention is to provide a composition comprising or consisting of the following substances:

[0078] The compound of formula (I) as defined above is preferably selected from the following substances: (-)-epigallocatechin gallate (EGCG) and / or (-)-gallocatechin gallate (GCG) and / or (-)-epicatechin gallate (ECG) and / or (-)-catechin gallate (CG) and / or (-)-epicatechin (EC) and / or (+)-catechin (C) and / or (-)-epigallocatechin (EGC) and / or (+)-gallocatechin (GC) or mixtures thereof; more preferably, EGCG refers to gallocatechin gallate;

[0079] and at least one, preferably at least two of the following reagents:

[0080] - folic acid or a salt or derivative; preferably calcium L-5-methylfolate or another salt of (6s)-5-methyltetrahydrofolate, such as the glucosamine salt;

[0081] - an agent selected from the group consisting of: cobalamin or cyanocobalamin or methylcobalamin or hydroxocobalamin; preferably, cyanocobalamin;

[0082] - an agent selected from the following: low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa) and pharmacologically acceptable salts (e.g. sodium hyaluronate or sodium hyaluronate salt); preferably, the molecular weight of low molecular weight or very low molecular weight hyaluronic acid and sodium hyaluronate or sodium hyaluronate salt is between 1-500 kDa; more preferably, the molecular weight is between 1-100 kDa, more preferably, the molecular weight is between 1 and 20 kDa, more preferably, the molecular weight is between 3-10 kDa;

[0083] and a pharmaceutically acceptable excipient or diluent.

[0084] Preferably, the excipient and / or diluent is selected from the group consisting of calcium phosphate, dicalcium phosphate, microcrystalline cellulose, magnesium stearate (or generally magnesium salt of fatty acid), silicon dioxide, sucrose, gum arabic, corn starch, medium chain triglycerides, tricalcium phosphate, cross-linked sodium carboxymethylcellulose, hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, polyvinyl pyrrolidone, talc, erythritol, xylitol, steviol glycosides and sucralose.

[0085] Preferably, the composition is used to prevent, control and / or inhibit HPV infection, preferably, the human papillomavirus is identified in women by using HPV DNA test and PAP test, the infection showing evidence of changes of various grades (low, medium, high) of cells and / or benign and / or malignant lesions affecting the skin and / or mucous membranes of different gynecological areas (vagina, cervix, vulva, anus and penis). Preferably, the infected benign lesions include common warts, flat warts and plantar warts, genital and flat condyloma acuminatum, which allow sexual transmission of the virus and appear in the area of ​​penis, anus and female genitalia.

[0086] More preferably, in the above-identified composition, EGCG is contained in powdered leaves of the tea plant or an extract thereof, preferably in the form of tea leaves or tea leaf extracts, more preferably, the tea leaves are green tea leaves, more preferably, the tea leaves contain the agent in an amount of 30% to 95% by weight, preferably about 30%, about 45%, about 50% or about 95% by weight.

[0087] Preferably, the amount of EGCG is 1 to 800 mg. More preferably, the amount of EGCG is 50 to 600 mg. More preferably, the amount of EGCG is about 200 mg. Even more preferably, the amount of EGCG is about 100 mg. More preferably, in the composition of the present invention, EGCG is administered twice a day, with each administration of about 100 mg.

[0088] Preferably, the composition comprises folic acid in an amount of 1 to 400 μg. More preferably, the amount of folic acid is 50 to 400 μg. More preferably, the amount of folic acid is 200 to 400 μg, more preferably about 400 μg, even more preferably 200 μg. Preferably, the folic acid in the composition is administered once a day. More preferably, in the composition of the present invention, folic acid is administered twice a day, each administration being about 200 μg.

[0089] Preferably, the composition comprises an amount of vitamin B12 of 1 to 1000 μg. More preferably, the amount of vitamin B12 is 100 to 1000 μg (1 mg), more preferably, the amount of vitamin B12 is 500 to 1000 μg (1 mg), more preferably about 1000 μg (1 mg), even more preferably, the amount of vitamin B12 is about 500 μg. Preferably, in the composition of the present invention, vitamin B12 is administered once a day. More preferably, vitamin B12 is administered twice a day, each administration of about 500 μg.

[0090] Preferably, the amount of low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) included in the composition is 1mg to 200mg. More preferably, the amount of low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) is 25mg to 100mg, preferably about 50mg, more preferably about 25mg. More preferably, in the composition of the present invention, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) is administered once a day, and consumption is about 50mg. More preferably, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) is administered twice a day, and each administration is about 25mg.

[0091] Preferably, the composition is administered orally and / or topically. Preferably, the composition is administered once or twice a day.

[0092] Preferably, the composition is in the form of tablets, hard capsules, soft capsules, powders, syrups, drinking liquids, gels, ointments, creams.

[0093] Optionally, the composition is used in combination with other therapeutic inventions. Preferably, the therapeutic invention is selected from the following surgeries, the purpose of which is to remove lesions caused by infection with any variant of human papillomavirus.

[0094] Another object of the present invention is to provide a pharmaceutical composition, or a skin cosmetic, or a medical device, or a supplement, or a dietary product, preferably, a food for special medical purposes, or a drinkable product, or an external preparation, which contains a compound of formula (I) as defined above and at least one of the following ingredients:

[0095] - folic acid or a salt or derivative; preferably calcium L-5-methylfolate or another salt of (6s)-5-methyltetrahydrofolate, such as the glucosamine salt;

[0096] - an agent selected from the group consisting of: cobalamin or cyanocobalamin or methylcobalamin or hydroxocobalamin; preferably, cyanocobalamin;

[0097] - an agent selected from the following: low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa) and pharmacologically acceptable salts (e.g. sodium hyaluronate or sodium hyaluronate salt); preferably, the molecular weight of low molecular weight or very low molecular weight hyaluronic acid and sodium hyaluronate or sodium hyaluronate salt is between 1-500 kDa; more preferably, the molecular weight is between 1-100 kDa, more preferably, the molecular weight is between 1 and 20 kDa, more preferably, the molecular weight is between 3-10 kDa;

[0098] - A pharmaceutically acceptable excipient or diluent.

[0099] Preferably, the compound of formula (I) is selected from: epigallocatechin gallate (EGCG), catechin, epicatechin and epicatechin gallate (ECG). More preferably, in the composition, the agent is selected from the group consisting of EGCG, epigallocatechin-3-gallate, (-)-epigallocatechin-3-gallate, (-)-gallocatechin-3-O-gallate (GCG), (-)-gallocatechin-3-gallate, (+)-catechin (C), (-)-epicatechin (EC), (+)-gallocatechin (GC), (-)-epigallocatechin, (-)-epicatechin-3-gallate, (-)-catechin-3-gallate and (+)-catechin-3-gallate. More preferably, the agent is epigallocatechin gallate (EGCG) in the form of a green tea extract.

[0100] Preferably, the pharmaceutical composition, or dermocosmetic, or medical device, or supplement, dietary product, preferably medical food, drinkable product or topical preparation is used for the prevention, control and / or inhibition of HPV infection, which is identified by using HPV DNA test and PAP test in women, whose infection shows evidence of various grades (low, medium, high) of changes in cells and / or benign and / or malignant lesions of the skin and / or mucous membranes affecting different gynecological areas (vagina, cervix, vulva, anus and penis). Preferably, the infection is a transitional infection or a persistent infection of HPV. Preferably, the infected benign lesions include common warts, flat warts and plantar warts, genital and flat condyloma acuminatum, which allow sexual transmission of the virus and appear in the penis, anus, female genitals, urethra, perianal area and rectal area.

[0101] Preferably, in the pharmaceutical composition, or dermocosmetic, or medical device, or supplement, dietary product, preferably medical food, drinkable product or topical preparation, EGCG is in the form of tea leaves or leaf extracts and / or tea plant parts. Preferably, the leaves and / or plant parts are from leaves and / or parts of green tea plants (more preferably Camellia Sinesis). Preferably, the leaves and / or tea plant parts and / or the extract contain 30% to 95% by weight of EGCG, more preferably about 30%, 45%, 50% or 95% by weight of EGCG.

[0102] Preferably, the pharmaceutical composition, or skin cosmetic, or medical device, or supplement, dietary product, preferably medical food, drinkable product or topical preparation contains 1 to 800 mg of EGCG. More preferably, the amount of EGCG is 50 to 600 mg. More preferably, the amount of EGCG is about 200 mg, and even more preferably, the amount of EGCG is about 100 mg. More preferably, EGCG is administered twice a day, with each administration of about 100 mg.

[0103] Preferably, the pharmaceutical composition, or dermocosmetic, or medical device, or supplement, dietary product, preferably medical food, drinkable product or external preparation contains 1 to 400 μg of folic acid. More preferably, the amount of folic acid is 50 to 400 μg. More preferably, the amount of folic acid is 200 to 400 μg, more preferably about 400 μg. Preferably, folic acid is administered once a day. More preferably, folic acid is administered twice a day, each administration of about 200 μg.

[0104] Preferably, the pharmaceutical composition, or dermocosmetic, or medical device, or supplement, dietary product, preferably medical food, drinkable product or topical preparation contains 1 to 1000 μg of vitamin B12. More preferably, the amount of vitamin B12 is 100 to 1000 μg (1 mg), more preferably, the amount of vitamin B12 is 500 to 1000 μg (1 mg), more preferably about 1000 μg (1 mg), even more preferably about 500 μg. Preferably, vitamin B12 is administered once a day. More preferably, vitamin B12 is administered twice a day, each administration of about 500 μg.

[0105] Preferably, the pharmaceutical composition, or skin cosmetics, or medical equipment, or supplements, dietary products, preferably medical foods, or drinkable products or topical preparations contain 1mg to 200mg of low molecular weight or very low molecular weight hyaluronic acid (1-500kDa). More preferably, the amount of low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) is 25mg to 100mg, preferably 50mg, preferably 25mg. More preferably, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) is administered once a day, and consumption is about 50mg. More preferably, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) is administered twice a day, and each administration is about 25mg.

[0106] Preferably, the excipient and / or diluent is selected from the group consisting of calcium phosphate, dicalcium phosphate, microcrystalline cellulose, magnesium stearate (or generally magnesium salt of fatty acid), silicon dioxide, sucrose, gum arabic, corn starch, medium chain triglycerides, tricalcium phosphate, cross-linked sodium carboxymethylcellulose, hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, polyvinyl pyrrolidone, talc, erythritol, xylitol, steviol glycosides and sucralose.

[0107] Preferably, the pharmaceutical composition, supplement or medical food or drinkable product is administered orally. Preferably, the formulation is administered topically. Preferably, the supplement or medical food or drinkable product or topical medical device is administered once or twice daily. Preferably, the pharmaceutical composition, supplement, medical food or drinkable product or topical formulation is in the form of a tablet, hard capsule, soft capsule, powder, syrup, drinkable liquid, dietary supplement, edible bar or edible snack, gel, cream, ointment.

[0108] Specifically, the supplement can be any type of dietary supplement. In addition, the dietary supplement preferably includes special medical purpose foods. Special medical purpose foods are foods prepared or formulated for dietary management of patients (including infants) for use under medical supervision; they are designed for patients with limited feeding capacity or impaired ability to ingest, digest, absorb or excrete ordinary food or nutrients or metabolites contained therein, or patients with other nutritional needs determined by clinical conditions or that cannot be achieved by simply changing the normal diet.

[0109] Optionally, the supplement or food or drinkable product or topical preparation for special medical purposes is used in combination with a therapeutic intervention selected from the following surgeries, the purpose of which is to remove lesions caused by infection with any human papillomavirus variant.

[0110] Another object of the invention is the non-therapeutic use of the composition as defined previously, or the pharmaceutical composition, or the dermocosmetic, or the medical device, or the supplement, or the dietary product, preferably the medical food, or the beverage product, or the topical preparation in the field of nutraceuticals or as a base ingredient in the preparation of supplements and / or dietary products and / or special medical foods. The supplements and / or dietary products and / or special medical foods are non-therapeutic products for the prevention, control and / or inhibition of human papillomavirus (HPV), preferably the human papillomavirus, whose infection shows evidence of various grades (low, medium, high) of alterations of cells and / or benign and / or malignant lesions of the skin and / or mucous membranes affecting different gynecological areas (vagina, cervix, vulva, anus and penis). Preferably, the infected benign lesions include common warts, flat and plantar warts, genital and flat condyloma acuminatum, which allow sexual transmission of the virus and appear in the area of ​​the penis, anus and female genitalia.

[0111] Another object of the present invention is a combination or composition, or a pharmaceutical composition, or a skin cosmetic, or a medical device, or a supplement, or a dietary product, preferably a medical food, or a drinkable product or a topical preparation, each of which comprises a compound of formula (I) and at least one other agent, preferably at least two other agents selected from the following: a) folic acid or a salt or derivative, b) vitamin B12 or a derivative, c) a low molecular weight or very low molecular weight hyaluronic acid or a pharmaceutically acceptable salt; wherein the compound of formula (I) and the other one or more agents reduce the proliferation of tumor cells or HPV-infected cells, increase apoptosis (cell death) of tumor cells or HPV-infected cells, show a significantly increased expression or production of protein p53 and / or a significantly reduced expression of viral proteins E6 and / or E7 compared to a single agent.

[0112] The invention will now be described by way of non-limiting embodiments with reference to the following drawings.

[0113] BRIEF DESCRIPTION OF THE DRAWINGS

[0114] Figure 1 : Percentage of apoptosis in HeLa cells treated with EGCG, Fol, B12, and Hyal. ANOVA Bonferroni post hoc test; compared with control, *p<0.05, ***p<0.001, ****p<0.0001; compared with EGCG, ##### p<0.0001; compared with EGCG+Fol+B12+Hyal, §§§§ p<0.0001.

[0115] Figure 2: P53 expression in HeLa cells treated with EGCG, Fol, B12, and Hyal. ANOVA Bonferroni post hoc test was performed; compared with the control, *p<0.05, ****p<0.0001; relative to EGCG, #### p<0.0001; relative to EGCG+Fol+B12+Hyal, @@ p<0.01, @@@ p<0.001; relative to EGCG+Fol+B12+Hyal, §§ p<0.001, §§§§ p<0.0001.

[0116] Figure 3 : E6 / E7 expression in HeLa cells after EGCG, Fol, B12 and Hyal treatment. ANOVA Bonferroni post hoc test was performed; *p<0.05, **p<0.01, ***p<0.001 relative to the control.

[0117] Figure 4 : Rb expression in HeLa cells after EGCG, Fol, B12 and Hyal treatment. DETAILED DESCRIPTION

[0118] The following describes the definitions of various terms and expressions used in this application to describe the present invention. It should be understood that the definitions of terms and expressions used in one aspect or form of the present invention also apply to any aspect or form of the present invention described herein in which these terms and expressions appear.

[0119] This is true regardless of where in this application these terms are defined or discussed.

[0120] In addition, if the present application refers to an embodiment alone, it should be understood that any embodiment and its features can be freely combined with any other embodiment and its respective features, even if not explicitly mentioned in the text. Therefore, as understood by those skilled in the art, the combination of an embodiment with another embodiment, and one or more features of an embodiment with one or more features of another embodiment is part of the specification submitted by the present application.

[0121] In this application, unless otherwise specified, the use of the singular (such as "a" and "an") may include the plural. In addition, the use of the term "(including)" and other grammatical forms (such as "including") are not limiting. In this context, the term "including" has a broad meaning and can be used to mean "including", "covering" and "comprising".

[0122] Including one or more elements explicitly states and allows but does not require the presence of another one or more elements that are not explicitly stated. In addition to its broader meaning, the term "comprising" herein also includes a limited meaning of "consisting of", according to which only the one or more elements explicitly stated are present, and no other elements are present. In addition, the term "comprising" also includes "consisting essentially of", which means that in addition to the elements explicitly stated, one or more elements may also be present, provided that the additional one or more elements do not change the technical effect obtained from the one or more elements explicitly stated.

[0123] In this context, the term "approximately" or the term "about" is used interchangeably herein, and when it refers to a specific value (such as one or more endpoints of a time interval), in addition to the specified value, it also includes and describes the degree of variation around the specified value. For example, this variation can be derived from normal variation in measurement, for example, when weighing or distributing various materials using methods known to those skilled in the art. The term "approximately" should be understood to include and describe a series of variations above or below the specified value, and the percentage value is relative to the same specified value below. The term "approximately" can be understood to include and describe a variation of ±5.0%. The term "approximately" can be understood to include and describe a variation of ±4.9%. The term "approximately" can be understood to include and describe a variation of ±4.8%. The term "approximately" can be understood to include and describe a variation of ±4.7%. The term "approximately" can be understood to include and describe a variation of ±4.6%. The term "approximately" can be understood to include and describe a variation of ±4.5%. The term "approximately" can be understood to include and describe a variation of ±4.4%. The term "approximately" can be understood to include and describe a variation of ±4.3%. The term "approximately" may be understood to include and describe variations of ±4.2%. The term "approximately" may be understood to include and describe variations of ±4.1%. The term "approximately" may be understood to include and describe variations of ±4.0%. The term "approximately" may be understood to include and describe variations of ±3.9%. The term "approximately" may be understood to include and describe variations of ±3.8%. The term "approximately" may be understood to include and describe variations of ±3.7%. The term "approximately" may be understood to include and describe variations of ±3.6%. The term "approximately" may be understood to include and describe variations of ±3.5%. The term "approximately" may be understood to include and describe variations of ±3.4%. The term "approximately" may be understood to include and describe variations of ±3.3%. The term "approximately" may be understood to include and describe variations of ±3.2%. The term "approximately" may be understood to include and describe variations of ±3.1%. The term "approximately" may be understood to include and describe variations of ±3.0%. The term "approximately" may be understood to include and describe variations of ±2.9%. The term "approximately" may be understood to include and describe variations of ±2.8%. The term "approximately" may be understood to include and describe variations of ±2.7%. The term "approximately" may be understood to include and describe variations of ±2.6%. The term "approximately" may be understood to include and describe variations of ±2.5%. The term "approximately" may be understood to include and describe variations of ±2.4%. The term "approximately" may be understood to include and describe variations of ±2.3%. The term "approximately" may be understood to include and describe variations of ±2.2%. The term "approximately" may be understood to include and describe variations of ±2.1%. The term "approximately" may be understood to include and describe variations of ±2.0%. The term "approximately" may be understood to include and describe variations of ±1.9%.The term "approximately" may be understood to include and describe variations of ±1.8%. The term "approximately" may be understood to include and describe variations of ±1.7%. The term "approximately" may be understood to include and describe variations of ±1.6%. The term "approximately" may be understood to include and describe variations of ±1.5%. The term "approximately" may be understood to include and describe variations of ±1.4%. The term "approximately" may be understood to include and describe variations of ±1.3%. The term "approximately" may be understood to include and describe variations of ±1.2%. The term "approximately" may be understood to include and describe variations of ±1.1%. The term "approximately" may be understood to include and describe variations of ±1.0%. The term "approximately" may be understood to include and describe variations of ±0.9%. The term "approximately" may be understood to include and describe variations of ±0.8%. The term "approximately" may be understood to include and describe variations of ±0.7%. The term "approximately" may be understood to include and describe variations of ±0.6%. The term "approximately" may be understood to include and describe variations of ±0.5%. The term "approximately" may be understood to include and describe variations of ±0.4%. The term "approximately" may be understood to include and describe variations of ±0.3%. The term "approximately" may be understood to include and describe variations of ±0.2%. The term "approximately" may be understood to include and describe variations of ±0.1%. When referring to a specific value, the term "approximately" may be understood to include and describe the referenced value itself, whether or not the value is explicitly mentioned; furthermore, in the absence of an explicit indication that the term "approximately" includes the referenced value, the specific referenced value is still included in the range of variation resulting from the term "approximately" and is described accordingly.

[0124] As described above, the present invention relates to a combination and / or combination of epigallocatechin gallate (EGCG) as defined above for preventing, controlling and / or inhibiting HPV infection in women and men with at least one of the following agents: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa). In a related aspect, the present invention relates to a method for preventing, controlling and / or inhibiting HPV infection in women and men who need or may need it, comprising administering EGCG, folic acid, vitamin B12 and low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa) to the subject.

[0125] In another related aspect, the present invention relates to the use of EGCG, folic acid, vitamin B12 and low / or very low molecular weight hyaluronic acid (1-500 kDa) in the manufacture of a product for preventing, controlling and / or inhibiting HPV infection in a subject (female and male).

[0126] In this context, the term "subject" refers to a mammal, preferably a human. The subject needs, potentially needs or is suspected of needing to prevent, control and / or inhibit HPV infection. The subject needs treatment for HPV infection.

[0127] In these cases, this need is usually determined based on a previous diagnosis of HPV infection. In cases where one or more pathological conditions have been diagnosed or diagnosed, the invention described herein can be used to treat the existing pathology (e.g., a curable HPV infection) while preventing another infection (e.g., persistence of infection; the appearance of symptoms such as common warts, flat warts and plantar warts, genital flat warts and condyloma acuminatum; neoplastic diseases). However, it is foreseeable that the subject matter of the invention described herein can be applied to subjects with suspected needs. Such subjects may be at risk of developing such a condition (e.g., sexually active people without a stable partner, immunocompromised subjects, subjects using oral contraceptives).

[0128] Thus, in this document, the term "treat" or grammatically correct variants such as "cure", "treatment" and the like refers to improvement, also temporary improvement, which includes but does not require complete elimination of the pathological state. In the broadest sense, treatment of HPV infection means that in this case at least regression, at least partial regression, of the infection is observed. Specifically, the proposed treatment includes restoration of the correct structure and function of the affected epithelium and / or mucosa and regression of lesions associated with HPV infection.

[0129] In this context, the term "infection" refers to a process that causes microorganisms (viruses or bacteria) to enter and multiply in host tissues. Infectious diseases are manifestations of infection.

[0130] As used herein, the term "human papillomavirus infection" refers to a condition in which benign lesions are formed in various tissue cells in different areas of the gynecological and urinary systems (vagina, cervix, vulva, anus, penis) after the virus invades host cells and genome and successfully replicates and / or integrates. The benign lesions include common warts, flat warts and plantar warts, genital and flat condyloma acuminatum and / or lesions of various grades (low, medium, high).

[0131] HPV infection can be diagnosed by using HPV DNA testing and PAP testing in women. Generally speaking, treatment of HPV infection may include various types of surgery such as scalpel treatment, laser, cryotherapy, diathermy, which aims to remove lesions caused by infection with any strain of HPV.

[0132] According to the present invention, treatment of any such HPV infection may be combined with EGCG, folic acid, vitamin B12 and low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa).

[0133] As used herein, the term "prevent" or grammatically correct variants such as "prevent" refer to situations where the possibility, suspicion or expected occurrence of HPV infection is avoided using the methods described herein. These suspected cases are due to the infection possibly originating from the medical history of the subject (even if there is no corresponding diagnosis), such as the subject having had sexual relations with an HPV-positive subject. In this case, one may suspect that the subject is HPV-positive. This suspicion that HPV infection may occur (even if there is no corresponding diagnosis) is also applicable to subjects at risk of developing the condition, such as sexually active subjects without a stable partner, subjects with low immunity, and subjects using oral contraceptives.

[0134] In this context, the term "EGCG" includes and describes the 22 H 18 O 11 In the present context, the term "epigallocatechin gallate" includes and describes substances having the chemical formula C 22 H 18 O 11 In this context, the term "catechin" includes and describes substances having the chemical formula C 15 H 14 In this context, the term "gallic acid" includes and describes substances having the chemical formula C 15 H 14 O7 substances, namely gallic acid, (+)-gallic acid (GC), and (-)-epigallocatechin (EGC).

[0135] EGCG is contained in various foods, and various foods or any combination thereof can be used as the source of EGCG in the present invention. Specifically, in the present invention, the source of EGCG can be green tea, white tea, oolong tea, black tea, carob powder, blackberry, apple, raspberry, pecan, hazelnut, blueberry, prune, peach, avocado, strawberry and / or onion. Carob powder can be obtained from the fruit of Ceratonia plant.

[0136] Preferably, the source of EGCG is tea, and the preferred source of EGCG includes tea, specifically: green tea, white tea, oolong tea and black tea. As the source of EGCG in the present invention, any tea source can be used. More preferably, wild tea tree (Camellia sinensis) is used. As the source of EGCG in the present invention, any part of the tea tree, or the whole of the tea tree can be used. More preferably, the leaves of the tea tree are used. More preferably, the leaves of the wild tea tree are used in the present invention. Tea leaves can contain different amounts of EGCG, specifically, 30% to 95% by weight. For example, 30% by weight, 45% by weight, 50% by weight and 95% by weight. Such amounts can be determined by titration and depend on the purity and processing level of the raw material. More preferably, EGCG is used as a dry tea extract in the present invention, more preferably, a dry green tea extract.

[0137] In the present context, the expression "folic acid or a salt or a derivative" includes and describes a compound of formula C 19 H 19 N7O6 (Folic acid, folate, vitamin B9, pteroyl-L-glutamic acid, vitamin M, folic acid, pteroyl-L-monoglutamic acid), C 20 H 23 The term "folic acid or a salt or a derivative thereof" refers to calcium L-methylfolate (CAS No. 151533-22-1), also commonly referred to as calcium methylfolate, calcium L-5-methyltetrahydrofolate, L-5-methyltetrahydrofolate, and L-methylfolate. Also included are addition salts of folate and L-5-methyltetrahydrofolate, such as sodium, potassium, magnesium, and organic salts, such as glucosamine, galactosamine, and methylamine. Preferably, the expression "folic acid or a salt or a derivative thereof" refers to calcium L-methylfolate (CAS No. 151533-22-1), also commonly referred to as calcium methylfolate, calcium L-5-methylfolate, L-5-methyltetrahydrofolate, and L-methylfolate.

[0138] In the present context, the expression "vitamin B12 or a derivative" includes and describes a vitamin B12 having the chemical formula C 63 H 88 CoN 14 O 14 P (vitamin B12, cobalamin, cyanocobalamin), C 62 H 89 CoN 13 O 15 P (Hydroxocobalamin), C 63 H 91 CoN 13 O 14 Preferably, vitamin B12 refers to cyanocobalamin.

[0139] In the present context, the expression "low molecular weight or very low molecular weight hyaluronic acid or a pharmacologically acceptable salt thereof" includes and describes a hyaluronic acid having the chemical formula (C 14 H 21 NO11 ) n (Hyaluronic acid, hyaluronic acid), (C 14 H 20 NO 11 Na) n (sodium hyaluronate, sodium hyaluronate, sodium hyaluronate). As defined above, "low molecular weight or very low molecular weight" refers to hyaluronic acid, whose molecular weight is between 1 and 500 kDa, preferably in the range of 1 to 100 kDa or 1 to 20 kDa or 3 to 10 kDa. Preferably, the hyaluronic acid according to the present invention is sodium hyaluronate.

[0140] Embodiments of the present invention include combinations and / or associations of EGCG with at least one of the following agents: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa).

[0141] Embodiments of the present invention include combinations and / or associations of EGCG with folic acid, vitamin B12, low or very low molecular weight hyaluronic acid (1-500 kDa).

[0142] Embodiments of the present invention relate to the following corresponding quantities:

[0143] Green tea extract, 444.5 mg (containing 45% epigallocatechin gallate (EGCG) 200 mg)

[0144] Hyaluronic acid, 50mg

[0145] Vitamin B12, 1000 μg (1 mg)

[0146] Folic acid, 400 μg

[0147] The reagents of the invention may exist or be used according to the invention in any form of salts, solvates, stereoisomers, zwitterions and / or isotopes.

[0148] The salt of the reagent in the present invention is preferably pharmaceutically acceptable. Pharmaceutically acceptable salts include conventional non-toxic salts obtained by the salt-forming reaction of the reagent of the present invention with an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid) or an organic acid (e.g., acetic acid, propionic acid, succinic acid, benzoic acid, p-aminobenzoic acid, 2-acetoxybenzoic acid, cinnamic acid, mandelic acid, salicylic acid, glycolic acid, lactic acid, oxalic acid, malic acid, maleic acid, malonic acid, fumaric acid, tartaric acid, citric acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid or naphthalenesulfonic acid). For a review of pharmaceutically acceptable acids, please refer to Berge SM et al., J. Pharm. Sci. 1977, 66, 1-19.

[0149] In addition, inorganic or organic bases, such as triethylamine, ethanolamine, triethanolamine, dicyclohexylamine, ammonium hydroxide, pyridine, glucosamine, galactosamine can be used to form addition salts with pharmaceutically acceptable bases. The term "inorganic base" herein has its ordinary meaning for those of ordinary skill in the art, generally referring to inorganic compounds that can serve as proton acceptors. In addition, the term "organic base" herein has its ordinary meaning for those of ordinary skill in the art, generally referring to organic compounds that can serve as proton acceptors. Other pharmaceutically acceptable salts include pharmaceutically acceptable salts of alkali metals or alkaline earth metals, such as sodium, potassium, calcium and magnesium. The present invention relates to the use of all possible stoichiometric and non-stoichiometric forms of the salts of the reagents of the present invention. In addition, the reagents of the present invention can exist in the form of solvates or non-solvates with pharmaceutically acceptable solvents (such as water, ethanol and other similar solvents).

[0150] Some agents of the invention, in particular EGCG, folic acid and hyaluronic acid, may exist in different stereoisomers or polymeric forms (e.g., they may contain one or more asymmetric carbon atoms, or exist as molecules with different molecular weights). In the treatment of HPV infection according to the invention, they may be all stereoisomers of the agents of the invention, in particular EGCG and folic acid. In particular, R1 and R2 in the compounds of formula (I) have the meanings given above, with chiral centers indicated by asterisks.

[0151]

[0152] Each of these chiral centers can exist in R or S form, therefore, compounds of formula (I) include stereoisomers (R, R), (R, S), (S, R), (S, S) and mixtures thereof. The use of single stereoisomers (enantiomers and diastereomers) and mixtures thereof is also included within the scope of the present invention. Using methods known to those skilled in the art, racemic mixtures can be separated using preparative HPLC using a column with a chiral stationary phase or a column designed to produce a single enantiomer to obtain a single enantiomer. Polymerized hyaluronic acid in different forms can be used, with a molecular weight in the range of 1-500 kDa, preferably between 1-100 kDa or 1-20 kDa, or between 3-10 kDa.

[0153] The agents of the present invention may exist in the form of zwitterions, and these agents may be used in the present invention to prevent, control and / or inhibit HPV infection. Likewise, it should be understood that the agents of the present invention may exist in the form of tautomers and their use is also encompassed within the scope of the present invention.

[0154] The present invention includes the use of all suitable isotopic variations of the reagents of the present invention. An "isotopic variation" of a reagent of the present invention is defined as a reagent in which one atom is replaced by another atom having the same atomic number mass as the atom usually found in nature, but having a different atomic mass. Examples of isotopes that can be incorporated into the reagents of the present invention include 2 H. 3 H. 13 C. 14 C. 15 N. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 36 Cl. Some isotopic variants of the present invention, for example, incorporate 3 H or 14 Isotopic variants of radioactive isotopes such as deuterium can be used to study the distribution of substrates and / or drugs in tissues. 2 Isotopic substitution such as H may provide certain therapeutic advantages resulting from improved metabolic stability. Isotopic variations of the agents of the invention can generally be prepared using conventional procedures or following the preparations described in the examples below using appropriate isotopic variations of the appropriate reagents.

[0155] In this context, the term "combination" refers to EGCG accompanied by at least one of the following agents as part of a given treatment regimen and co-administered to a subject: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa). The treatment regimen may include repeated and co-administered EGCG, folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) in a predetermined time period, such as 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months or longer, preferably 6 to 9 months in the range of time period. The co-administration of EGCG, folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) can be repeated multiple times a day, such as once a day, twice a day, three times a day, four times a day, five times a day or more, preferably repeated about once / twice a day. In other words, the combined administration of EGCG, folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa) should be repeated for a predetermined amount of time and a predetermined number of times per day, which constitutes a preventive or therapeutic regimen.

[0156] The concomitant administration of EGCG, folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa) is understood as a "combination" of these substances, which need not be physical and does not imply simultaneous administration. Therefore, the "combination" of EGCG, folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa) includes and describes a variety of possible routes and times of administration of the corresponding substances.

[0157] For example, the term "combination" includes and describes at least one of EGCG accompanied by folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa), for simultaneous administration by the same route, simultaneous administration by different routes, staggered administration (non-simultaneously) in time by the same route, or staggered administration (non-simultaneously) in time by different routes. Various routes of administration as described herein can be combined in any way, and if generally speaking, preferred routes are oral and / or topical administration. It is particularly preferred to simultaneously administer EGCG, folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) with oral administration or topical administration, such as EGCG, folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) present in the composition, such as present in one of the compositions shown herein, such as in the form of tablets, hard capsules, soft capsules, powders, syrups, drinking liquids, lozenges, ointments, creams, gels.

[0158] EGCG, folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) can be administered simultaneously with the same route of administration. For example, EGCG, folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) can be included in the same physical administration composition, such as by ingestion or topical application of the subject, so that EGCG, folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) enter the body simultaneously through the same route of administration (e.g., oral or topical). It is also possible that the term "combination" includes and describes a combination of EGCG, folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) for staggered administration (non-simultaneous) in a given co-administration. The order of administration of EGCG, folic acid, vitamin B12, and low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) is not particularly important. The timing of staggered administration (non-simultaneous) of EGCG, folic acid, vitamin B12, and low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) may include first administering EGCG, followed by sequential administration of at least one of the following agents: folic acid, vitamin B12, and low molecular weight or very low molecular weight hyaluronic acid; or first administering one of the following agents: folic acid, vitamin B12, and low molecular weight or very low molecular weight hyaluronic acid (1-500kDa), followed by sequential administration of EGCG. For example, staggered administration (non-simultaneous) of folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa) and EGCG for the same route of administration can be oral and / or topical administration of at least one of the following agents: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid; and accompanied by administration of EGCG and at least one of the following agents: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa); such administration falls within the meaning of "combination" as described herein.

[0159] Alternatively, staggered administration (non-simultaneous) of EGCG and at least one of folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa) for different routes of administration may, for example, include initial topical administration of EGCG, followed by administration of at least one of the following agents in the form of, for example, tablets: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa); in this manner, simultaneous administration of EGCG and at least one of the following agents: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa) also falls within the definition of "combination" described herein.

[0160] In this context, "non-simultaneous" refers to EGCG and at least one of the following agents being given at different times in a temporally staggered manner: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa). Administration / administration refers to the combined administration of EGCG and at least one of the following agents as part of a treatment or prevention regimen: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa). For example, one embodiment predicts that EGCG is administered to an object before at least one of the following agents is administered to the object: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa). Another embodiment predicts that EGCG is administered to an object after at least one of the following agents is administered to the object: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa). It should be understood that this "non-simultaneous" includes administering EGCG and at least one of the following agents separately in the context of a complete treatment regimen: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa). As described herein, regardless of the order of administration, i.e., first administering EGCG and then administering at least one of folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa), or vice versa, the respective combined administration can be carried out by the same or different routes of administration.

[0161] Another embodiment involves administering EGCG and at least one of the following agents to the subject simultaneously: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa). As described above, the simultaneous administration of EGCG and at least one of the following agents can be administered by the same or different routes of administration: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa). Generally, it is more advantageous and convenient to simultaneously administer EGCG and at least one of the following agents by the same route of administration: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa); preferably by an oral / topical route of administration. The most common is to combine EGCG with at least one of the following agents: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa), which is administered in the same composition, for example in the form of tablets, including but not limited to effervescent tablets, powders (especially in the form of sachets), hard capsules, soft capsules, syrups, drinking liquids, lozenges, soft candies, or in ointments, creams, gels.

[0162] In the case of staggered administration, i.e., non-simultaneous administration, the time interval between the administration of EGCG and at least one of the following agents is not particularly limited: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa); however, if the time intervals between the administration of EGCG and at least one of the agents of folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) are short, close to simultaneous, such as on the order of a few minutes, then it is usually more effective and convenient. In some cases, such time intervals can be extended to one or several hours between each administration. Therefore, in some cases, the combined administration of EGCG and at least one of the following agents is staggered in time order: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa); the time interval can be up to 12 hours. In addition, in the case where EGCG and at least one of folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) are administered in a time-staggered manner via the same or different routes of administration, the term "combination" means that the combined administration of EGCG and one of the following agents: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) has been completed as part of the regimen; that is, these substances have been administered before the combined administration of EGCG and at least one of folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) (which in turn can be administered simultaneously or in a time-staggered manner and through the route of previous combined administration) as part of the regimen.

[0163] In this context, the term "composition" includes and describes any physical entity that includes or consists of the corresponding substances listed or consists essentially of the corresponding substances listed, for example, includes or consists of EGCG and at least one of the following agents or consists essentially of EGCG and at least one of the following agents: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa). The physical form of the composition is not limited. For example, the term "composition" includes and describes a powder, wherein the various substances listed are present in powder form. As another example, the term "composition" includes and describes a liquid solution, wherein the listed substances are present in dissolved form. As another example, the term "composition" also includes and describes an emulsion in which the listed substances are present. In another example, the term "composition" also includes and describes a suspension in which the listed substances are present. In another example, the term "composition" also includes and describes a mixture, wherein EGCG is in the form of, for example, a powdered solid, and at least one of the following agents is in another form, such as a liquid: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa). Specifically, the term "composition" can be a "pharmaceutical composition" as defined below, and can be formulated for the route of administration. Therefore, as used and described herein, the term "composition" can be a composition suitable for oral administration, such as a tablet form, including but not limited to effervescent tablets or multilayer tablets, powders, such as sachets, hard capsules, soft capsules, syrups, drinking liquids, lozenges, soft lozenges, balms or other liquid preparations, ointments, creams, gels. In some particularly preferred embodiments of the present invention, the "composition" includes EGCG and at least one of the following agents: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa), and can be in the form of a soft capsule. In certain other particularly preferred embodiments of the present invention, the "composition" includes EGCG and at least one of the following agents: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa), and can be in the form of a powder. In certain other preferred embodiments, the "composition" includes EGCG and at least one of the following agents: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa), and can be in the form of creams, gels, and ointments. The term "composition" can also be a composition suitable for non-oral administration, such as suppositories, tablets, hard capsules, soft capsules, creams, gels, plasters, and liquids. Other dosage forms of the composition and their routes of administration are given below. Therefore, the composition of the present invention (including pharmaceutical compositions) may contain at least one pharmaceutically acceptable ingredient.Although the compositions (including pharmaceutical compositions) of the present invention can be administered to a subject by themselves, it should be understood that, in addition to at least one of EGCG and folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa), the addition of one or more pharmaceutically acceptable ingredients can be beneficial to make the composition more suitable for direct administration by a given predetermined route. Therefore, a "pharmaceutical composition" can be formulated to include at least one of EGCG and folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa), a pharmaceutically acceptable ingredient; the pharmaceutically acceptable ingredient makes the composition more suitable or particularly suitable for direct administration by a given predetermined route without further testing. This suitability can involve a range of different routes of administration, such as oral, parenteral, transmucosal, vaginal or perivaginal, topical, transdermal or intravesical, as further explained below. If present, and in a non-limiting exemplary manner, such ingredients and their positive effects on the suitability of the compositions of the present invention for various routes of administration will be further reported below.

[0164] a) Formulations suitable for oral administration

[0165] Compositions suitable for oral administration can be prepared, packaged or sold in the form of a single solid dose, including a pouch (e.g., a powder in a pouch), a tablet, a hard capsule or a soft capsule, each of which contains a predetermined amount of EGCG as described herein and at least one of the following agents: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa). Other formulations suitable for oral administration include powder or granular form, aqueous or oily suspension, aqueous or oily solution or emulsion. In this article, "oily" liquids include carbon-containing liquid molecules that are less polar relative to water.

[0166] Particularly preferably, a single solid dose of the composition of the present invention is in powder form, which is present in a pouch. In this article, the term "pouch" refers to a sealed bag containing the composition of the present invention. The bag can be made of paper, wax paper, laminated paper or a combination of paper and foil. The material of the pouch is preferably impermeable to ambient humidity and other potential environmental pollutants, so that by sealing the pouch, the composition of the present invention is kept in a free-flowing powder form until use.

[0167] For example, a tablet containing at least one of EGCG and folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) of any concentration listed above can be prepared by compressing at least one of EGCG and folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) with one or more added ingredients. The tablet obtained by compression can be obtained by compressing at least one of EGCG and folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) in a suitable device in a free-flowing powder or granular form, optionally, with one or more of a binder, a lubricant, an excipient, a surfactant and a dispersant. Molded tablets can be obtained by molding, and can be obtained by molding at least one of EGCG and the following reagents in a suitable device: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa), a pharmaceutically acceptable carrier and a liquid that fully wets the mixture.

[0168] Pharmaceutically acceptable excipients for producing tablets include, but are not limited to, inert diluents, granulating agents and disintegrants, binders and lubricants. Notable dispersants include, but are not limited to, potato starch and sodium starch glycolate. Notable surfactants include, but are not limited to, sodium lauryl sulfate. Notable diluents include, but are not limited to, calcium carbonate, sodium carbonate, lactose, microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, and sodium phosphate. Notable granulating agents and disintegrants include, but are not limited to, corn starch and alginic acid. Notable binders include, but are not limited to, gelatin, gum arabic, pregelatinized corn starch, polyvinyl pyrrolidone, and hydroxypropyl methylcellulose. Notable lubricants include, but are not limited to, magnesium stearate, stearic acid, silicon dioxide, and talc.

[0169] The tablets may be uncoated or coated by known methods to achieve delayed disintegration in the gastrointestinal tract of the subject, thereby prolonging the release and absorption of EGCG and at least one of the following agents: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa). For example, materials such as monostearate or distearate may be used to coat the tablets. Thus, the tablets may contain sweeteners, flavoring agents, colorants, preservatives, or some combination to provide pharmaceutically interesting and acceptable formulations.

[0170] Physiologically degradable compositions (e.g., gelatin or cellulose derivatives) can be used to obtain hard capsules containing EGCG and at least one of the following agents: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa). Therefore, hard capsules containing EGCG and at least one of folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa) may contain other ingredients, including, for example, inert solid diluents, such as calcium carbonate, calcium phosphate or kaolin.

[0171] Physiologically degradable compositions, such as gelatin and plasticizer (i.e., glycerol) can be used as the matrix component of soft gelatin capsules to obtain soft gelatin capsules containing EGCG and at least one of the following agents: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa). Soft gelatin capsules can contain pre-concentrated solutions or suspensions or liquid microemulsions or semisolids. The soft capsule contains EGCG and at least one of the following substances: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa), which can be mixed with water or an oily medium, such as peanut oil, liquid paraffin, olive oil, soybean oil, sunflower oil, lecithin, such as soybean lecithin or sunflower lecithin, medium chain triglycerides, polyglycerol oleate, beeswax, monoglycerides and diglycerides of fatty acids, or any combination of any of the above substances.

[0172] Some liquid preparations suitable for oral administration can be prepared, packaged and sold in liquid or solid form, and they are designed to be reconstituted with water or other carriers suitable for ingestion. Liquid suspensions can be prepared by conventional methods to obtain a suspension of one or more active ingredients in an aqueous or oily vehicle. For example, aqueous vehicles include water and isotonic saline. For example, oily vehicles include almond oil, oily esters, ethanol, vegetable oils, such as peanut oil, olive oil, sesame oil or coconut oil, fractionated vegetable oils and mineral oils, such as liquid paraffin.

[0173] Therefore, liquid suspensions may contain one or more other ingredients, including but not limited to suspending agents, dispersants or wetting agents, emulsifiers, emollients, preservatives, buffers, salts, flavoring agents, colorants and sweeteners. Oily suspensions also contain thickeners. Notable suspending agents include but are not limited to sorbitol syrup, hydrogenated edible fats, sodium alginate, polyvinyl pyrrolidone, tragacanth gum, gum arabic and cellulose derivatives, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose. Notable dispersants or wetting agents include but are not limited to naturally occurring phospholipids, such as lecithin, condensation products of alkylene oxides with fatty acids, with long-chain fatty alcohols, with partial esters derived from fatty acids and hexyl groups, or with partial esters derived from fatty acids and hexyl anhydrides (e.g., polyoxyethylene stearate, 17ethyleneoxyethanol, polyoxyethylene sorbitol monooleate and polyoxyethylene dehydrated sorbitan monooleate, respectively). Notable emulsifiers include but are not limited to lecithin and gum arabic. Notable preservatives include, but are not limited to, methyl, ethyl or n-propyl parabens, ascorbic acid and sorbic acid. Notable sweeteners include, for example, glycerol, propylene glycol, sorbitol, sucrose and saccharin. For example, notable thickeners for oily suspensions include beeswax, paraffin and cetyl alcohol. Powder or granular powder preparations suitable for the compositions of the present invention can be prepared by known methods. Such preparations can be directly administered to the subject, for example, using sachets or tablets, for filling capsules or for preparing suspensions, or for adding to aqueous or oily solutions in aqueous or oily carriers. Each of these preparations can include one or more dispersants or wetting agents, suspending agents and preservatives. In these preparations, other excipients, such as fillers and sweeteners, fragrances and colorants, can be included. The composition can also be prepared, packaged and sold in the form of water-in-oil emulsions or oil-in-water emulsions. The oil phase can be a vegetable oil, such as olive oil or peanut oil or a mineral oil, such as liquid paraffin, or a combination of these. Such compositions may also include one or more emulsifiers, such as naturally occurring rubbers, such as gum arabic or tragacanth, naturally occurring phospholipids, such as soybean lecithin or lecithin, esters or partial esters derived from a combination of fatty acids and hexyl anhydride, such as sorbitan monooleate, and condensation products of such partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. These emulsifiers may include other ingredients, such as sweeteners or fragrances. Methods for inserting chemical compositions into materials or applying them to materials are known in the art, including but not limited to methods for depositing or bonding chemical compositions to surfaces, methods for incorporating chemical compositions into material structures during material synthesis (e.g., using physiologically degradable materials), and methods for absorbing solutions or aqueous or oily suspensions into absorbent materials with or without subsequent drying.

[0174] b) Preparations suitable for parenteral administration

[0175] For parenteral administration, a composition containing at least one of EGCG and folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa) can be formulated for injection or infusion, such as injection or intravenous infusion, intramuscular or subcutaneous injection or as a bolus dose and / or continuous infusion. Suspensions, solutions and emulsions can be used in oily or aqueous vehicles, optionally containing other agents, such as suspending agents, stabilizers and / or dispersants as described above.

[0176] By using a pharmaceutically acceptable carrier, such as sterile water or isotonic saline, a composition containing EGCG and at least one or more of the following agents can be made particularly suitable for parenteral administration: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa). These preparations can be prepared, packaged and sold in the form of a bolus dose or continuous administration. Injectable preparations can be prepared and packaged as a single dose (e.g., in an unbreakable or non-unbreakable ampoule) or in multiple doses containing a preservative. Compositions particularly suitable for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous carriers, sustained-release or biodegradable pastes and implantable preparations. These compositions may also include one or more additional ingredients, including, but not limited to, suspending agents, stabilizers or dispersants. In other embodiments of compositions particularly suitable for parenteral administration, the active ingredient is provided in a dry form (e.g., a powder or granular powder) for reconstitution with a suitable carrier (e.g., sterile pyrogen-free water) before parenteral administration of the reconstituted composition. Compositions suitable for use in the present invention can be prepared, packaged and sold in the form of sterile injectable aqueous or oily suspensions or solutions. The suspension or solution can be prepared according to known techniques and, in addition to one or more active ingredients, can also include added ingredients, such as dispersants, wetting agents or suspending agents as described herein. Such sterile injectable compositions for parenteral administration routes include, but are not limited to, Ringer's solution, isotonic sodium chloride solution and fixed oils, such as synthetic monoglycerides or diglycerides. Other common preparations for parenteral administration routes include preparations that include active ingredients in microcrystalline form, liposome preparations or as part of a biodegradable polymer system.

[0177] Compositions for sustained release or implantation may include polymers or pharmaceutically acceptable hydrophobic materials, such as emulsions, ion exchange resins, poorly soluble polymers or poorly soluble salts.

[0178] c) Preparations suitable for transmucosal administration

[0179] Compositions including EGCG and at least one of the following agents can be formulated to be suitable for transmucosal administration: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa). The formulation may include any substance or dosage unit suitable for administration to mucosal tissue. For example, the selected active agent can be administered to the buccal mucosa in the form of an adhesive tablet or patch, administered sublingually with a sublingual solid dose, administered through the tongue by placing a solid dose on the tongue, administered through the nose in the form of drops or nasal sprays, liquid non-aerosols or dry powders, placed in or near the rectum (rectal formulations) or administered through the urethra in the form of suppositories, ointments or the like.

[0180] d) Preparations suitable for vaginal or perivaginal administration

[0181] Compositions including EGCG and at least one of the following agents suitable for vaginal or perivaginal administration can be formulated: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa). Dosage units suitable for this application include vaginal suppositories, creams, ointments, liquid preparations, vaginal suppositories, tampons, gels, pastes, foams or sprays. Suppositories, creams, ointments, liquid preparations, vaginal suppositories, tampons, gels, pastes, foams or sprays for vaginal or perivaginal release include a certain amount of therapeutically effective active agents or selected active agents and one or more non-toxic conventional carriers for vaginal or perivaginal administration. Vaginal or perivaginal administration in the present invention can be carried out in a conventional manner, for example, as described in Remington: The Science and Practice of Pharmacy. Vaginal or perivaginal dosage units can be products that disintegrate rapidly or products that disintegrate for several hours. The time for complete disintegration can be an interval of about 10 minutes to 6 hours, for example, less than about 3 hours.

[0182] e) Preparations suitable for topical administration

[0183] Compositions comprising EGCG and at least one of the following agents may also be formulated to be suitable for topical administration: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa). Dosage forms suitable for this application include forms suitable for application to body surfaces, and may include, for example, ointments, creams, gels, lotions, solutions, pastes, etc., and / or they may be prepared to contain liposomes, micelles and / or microspheres. In some embodiments, the topical formulations reported herein are ointments, creams or gels.

[0184] f) Preparations suitable for transdermal administration

[0185] Compositions including at least one of EGCG and the following agents can be formulated to be suitable for transdermal administration: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa). As known to those skilled in the art, transdermal administration involves releasing drug compounds through transdermal channels, thereby delivering compounds to the patient's systemic circulation. For example, this can be achieved by transdermal patches or using iontophoresis devices. For example, in addition to at least one of EGCG and folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa), transdermal patches can also incorporate other components. For example, compositions and / or transdermal patches can include preparations with one or more preservatives or antibacterial agents, including but not limited to methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkonium chloride, etc. The dosage form of the composition of the present invention for topical administration of at least one of EGCG and folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) can include creams, sprays, lotions, gels, ointments, eye drops, nose drops, ear drops, etc. In such dosage forms, the ingredients of the composition of the present invention can be mixed with, for example, 1% or 2% (w / w) benzyl alcohol, emulsifying wax, glycerol, isopropyl palmitate, lactic acid, purified water and sorbitol solution as preservatives to form a smooth, uniform white opaque cream or lotion. In addition, the composition may contain polyethylene glycol 400. They can be mixed with, for example, 2% (w / w) benzyl alcohol, white vaseline, emulsifying wax and TenoxII (butylated hydroxyanisole, propyl gallate, citric acid, propylene glycol) as preservatives to form an emulsion. Tampons or dressing rolls (e.g., gauze) can also be used for topical applications, in which compositions in the form of solutions, emulsions, creams, ointments, etc. can be inserted. The composition may also be topically applied via a transdermal system, for example as a resin crosslinker and acrylic-based polymer adhesive containing the composition and laminated to an impermeable substrate. Examples of suitable skin contact adhesive materials include, but are not limited to, polyethylene, polysiloxane, polyisobutylene, polyacrylate, polyurethane, and the like. Alternatively, the drug-containing reservoir and the skin contact adhesive are separate and distinct, with the adhesive being located beneath the reservoir, in which case the reservoir may be a polymer matrix as described above, or may be a liquid or hydrogel reservoir, or may take other forms.

[0186] g) Preparations suitable for intravesical administration

[0187] The term "intravesical administration" is used herein in its conventional sense to refer to the release of a drug directly into the bladder. Suitable methods for intravesical administration can be found, for example, in U.S. Pat. Nos. 6,207,180 and 6,039,967.

[0188] The combination of EGCG and at least one of folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) can be administered in the form of a dietary product or beverage according to the purposes and methods described herein, wherein the dietary product or beverage contains EGCG and at least one of the following agents: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa). In this context, the term "dietary product" refers to an ingestible substance that is solid or semi-solid at a temperature for correct storage and ingestion and will be chewed before swallowing. In this context, the term "drinkable product" refers to an ingestible substance that is in a free-flowing liquid at a temperature for correct storage and injection and will not be chewed before swallowing. In principle, a dietary product can be any dietary product to be administered, which is processed to include a combination of EGCG and at least one of the following products: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa). In the case where a combination of at least one of EGCG and folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) must be administered, the dietary product will contain the desired concentration of EGCG and at least one of the following agents: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa). Examples of such dietary products include dietary bars, such as chocolate bars, cereal bars, ice cream bars, or energy bars; chewing gum; candy; mints; yogurt; edible gels; ready-to-eat foods, such as instant foods; spreadable creams; puddings; or processed fruit products, such as fruit rolls or fruit bars. Examples of such drinkable products include juices or beverages containing juice, milk beverages, such as milk-containing beverages or buttermilk-containing beverages, whey-containing beverages, yogurt beverages, energy drinks, non-alcoholic beverages, flavored water beverages, etc. The applicant has found that the composition of the present invention contains a certain minimum amount of EGCG and at least one of folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) which may be beneficial to ensure the desired treatment or prevention effect, and can be obtained by a reasonable number of administrations. Typically, a total of about 200mg EGCG, about 400μg folic acid, about 1mg vitamin B12, and about 50mg low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) are administered daily to achieve the purpose of preventing, controlling and / or inhibiting HPV.

[0189] However, from the perspective of the effect of such repeated administration on the patient's quality of life, it may be advantageous to ensure a minimum amount of EGCG and at least one of folic acid, vitamin B12, and low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa), wherein the minimum amount corresponds to the number of daily administrations required to achieve a target amount of at least one of EGCG and folic acid, vitamin B12, and low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa), such as the target amount of at least one of EGCG and folic acid, vitamin B12, and low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa) mentioned above.

[0190] Therefore, one embodiment of the purposes and methods described herein can provide a total of about 200 mg EGCG, about 400 μg folic acid, about 1 mg vitamin B12, about 50 mg low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa) to the subject. Another embodiment of the purposes and methods described herein can provide a total of about 100 mg EGCG, about 200 μg folic acid, about 0.5 mg vitamin B12, about 25 mg low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa) to the subject. Another embodiment of the purposes and methods described herein can provide a total of about 65 mg EGCG, about 130 μg folic acid, about 330 μg vitamin B12, about 15 mg low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa) to the subject. Another embodiment of the purposes and methods described herein can provide a total of about 50 mg EGCG, about 100 μg folic acid, about 250 μg vitamin B12, about 12.5 mg low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa) (e.g., in powder form, e.g., in sachets) to be administered to the subject. Another embodiment of the purposes and methods described herein can provide a total of about 40 mg EGCG, about 80 μg folic acid, about 200 μg vitamin B12, about 10 mg low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa) to be administered to the subject. For example, such medical uses and treatment methods can provide a total of about 30 mg EGCG, about 60 μg folic acid, about 140 μg vitamin B12, about 7 mg low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa) to be administered to the subject.

[0191] Another embodiment of the uses and methods described herein can provide for co-administering to a subject a total of about 800 mg EGCG, about 400 μg folic acid, about 1000 μg vitamin B12, and about 200 mg low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa).

[0192] Another embodiment of the uses and methods described herein can provide for co-administering to a subject a total of about 600 mg EGCG, about 400 μg folic acid, about 1000 μg vitamin B12, and about 200 mg low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa).

[0193] One embodiment of the purposes and methods described herein can provide that a total of about 200 mg EGCG, about 400 μg folic acid, about 1000 μg vitamin B12, about 50 mg low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa) or 50-300 mg EGCG, 200-400 μg folic acid, 500-1000 μg vitamin B12 and 100-200 mg low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa) are administered to the subject in any administration mode (e.g., in any co-administration mode). One embodiment of the purposes and methods described herein can provide that 1-800 mg EGCG, 1-400 μg folic acid, 1-1000 μg vitamin B12 and 1-200 mg low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa) are administered to the subject in any administration mode (e.g., in any co-administration mode).

[0194] Another embodiment of the uses and methods described herein can provide for administering 200 mg EGCG, about 400 μg folic acid, about 1000 μg vitamin B12, and about 50 mg low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa) to a subject in any administration manner (e.g., in any combined administration manner).

[0195] Another embodiment of the uses and methods described herein can provide for administering 800 mg EGCG, about 400 μg folic acid, about 1000 μg vitamin B12, and about 200 mg low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa) to a subject in any administration manner (e.g., in any combined administration manner).

[0196] In embodiments where the combination of EGCG, folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) must be administered to a subject in a powder form (e.g., in a sachet), it may include or consist of a total of about 200 mg EGCG, a total of about 400 μg folic acid, a total of about 1000 μg vitamin B12, and a total of about 50 mg low molecular weight or very low molecular weight hyaluronic acid (1-500kDa), and it may be administered to a subject. In a related embodiment, the total combination of EGCG, folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) may be administered to a subject in a powder form (e.g., as a sachet), and may include a total of about 100 mg EGCG, a total of about 200 μg folic acid, a total of about 500 μg vitamin B12, and a total of about 25 mg low molecular weight or very low molecular weight hyaluronic acid (1-500kDa), and it may be administered to a subject. In an alternative embodiment in which the combination of EGCG, folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) must be administered to a subject in the form of a soft capsule, it may include or consist of a total of about 200 mg EGCG, a total of about 400 μg folic acid, a total of about 1000 μg vitamin B12, and a total of about 50 mg low molecular weight or very low molecular weight hyaluronic acid (1-500kDa), and it may be administered to a subject. In a related embodiment, the total combination of EGCG, folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500kDa) may be administered to a subject in the form of a liquid gel capsule, and may include a total of about 100 mg EGCG, a total of about 200 μg folic acid, a total of about 500 μg vitamin B12, and a total of about 25 mg low molecular weight or very low molecular weight hyaluronic acid (1-500kDa), and it may be administered to a subject.

[0197] Most importantly, the final embodiment comprises administering a total of about 200 mg EGCG, a total of about 400 μg folic acid, a total of about 1000 μg vitamin B12, and a total of about 50 mg low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa), or administering a total of about 100 mg EGCG, a total of about 200 μg folic acid, a total of about 500 μg vitamin B12, and a total of about 25 mg low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa), which are particularly advantageous because in order to achieve the daily target amount, such combined administration is required once or twice a day, respectively. The following quantities and combinations represent preferred embodiments of the present invention:

[0198] About 1-800mg EGCG and about 1-400μg folic acid

[0199] About 50-600mg EGCG and about 50-400μg folic acid

[0200] About 100-300mg EGCG and about 200-400μg folic acid

[0201] About 160-240 mg EGCG, specifically about 200 mg EGCG ± 20%

[0202] About 400 μg folic acid

[0203] About 1-800mg EGCG and about 1-1000μg vitamin B12

[0204] About 50-600mg EGCG and about 100-1000μg vitamin B12

[0205] About 100-300mg EGCG and about 500-1000μg vitamin B12

[0206] About 1000 μg vitamin B12

[0207] About 1-800 mg EGCG and about 1-200 mg low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa)

[0208] About 50-600mg EGCG and about 25-150mg low molecular weight or very low molecular weight hyaluronic acid (1-500kDa)

[0209] About 100-300mg EGCG and about 50-100mg low molecular weight or very low molecular weight hyaluronic acid (1-500kDa)

[0210] About 50mg low molecular weight or very low molecular weight hyaluronic acid (1-500kDa)

[0211] About 800mg EGCG, about 400μg folic acid, about 1000μg vitamin B12 and about 200mg low molecular weight or very low molecular weight hyaluronic acid (1-500kDa)

[0212] About 600mg EGCG, about 400μg folic acid, about 1000μg vitamin B12 and about 200mg low molecular weight or very low molecular weight hyaluronic acid (1-500kDa)

[0213] About 100 mg EGCG, about 200 μg folic acid, about 500 μg vitamin B12, and about 25 mg low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa)

[0214] About 50mg EGCG, about 100μg folic acid, about 250μg vitamin B12 and about 12.5mg low molecular weight or very low molecular weight hyaluronic acid (1-500kDa)

[0215] About 200mg EGCG, about 400μg folic acid, about 1000μg vitamin B12 and about 50mg low molecular weight or very low molecular weight hyaluronic acid (1-500kDa)

[0216] Various embodiments are provided below to illustrate various embodiments of the present invention and technical effects and advantages. It should be understood that the examples given below are illustrative only and do not limit the claimed invention. In fact, those skilled in the art can easily recognize other embodiments within the spirit and scope of the claimed invention, while also understanding the technical advantages.

[0217] Example

[0218] In order to provide a more favorable effect in preventing, controlling and inhibiting HPV infection relative to the use of a single substance, the present invention provides a combination and / or composition of EGCG with at least one of the following agents: folic acid, vitamin B12, low molecular weight or very low molecular weight hyaluronic acid (1-500 kDa). This represents a new and unexpected method for preventing / treating HPV infection.

[0219] Example 1

[0220] A first exemplary composition of the present invention is an oval tablet (diameter: 19 x 8 mm), weighs about 900 mg, has a reported shelf life of 24 months (if stored in a cool, dry, dark place), and has the following composition:

[0221] Table 1. Composition of Example 1

[0222]

[0223] It can be noted in this example that the tolerance interval of EGCG titer is 160-240 mg / tablet (200±20%).

[0224] The amount of ingredients reported in the "mg / tablet" column in Table 1 refers to the amount of the ingredient used to prepare the tablet. The amount of ingredients reported in the "Contribution per tablet" column in Table 1 refers to the amount of the nutrient present in the tablet. Overdosage of 5-MTHF and sodium hyaluronate has been associated with the following factors:

[0225] - Titer of raw materials

[0226] - the chemical form of the starting molecular substrate;

[0227] -Material losses during the production process.

[0228] It is recommended to take one tablet per day.

[0229] Example 2

[0230] A second exemplary composition of the present invention is an oval tablet (diameter: 19 x 8 mm), weighs about 900 mg, has a reported shelf life of 24 months (if stored in a cool, dry, dark place), and has the following composition:

[0231] Table 2. Composition of Example 2

[0232]

[0233]

[0234] It can be noted in this example that the tolerance interval of EGCG titer is 160-240 mg / tablet (200±20%).

[0235] The amounts of ingredients reported in the "mg / tablet" column in Table 2 refer to the amount of ingredient used to prepare the tablet. The amounts of ingredients reported in the "Contribution per tablet" column in Table 2 refer to the amount of nutrient present in the tablet. Overdosage of L-5-methylfolate and sodium hyaluronate has been associated with:

[0236] - Titer of raw materials

[0237] - the chemical form of the starting molecular substrate;

[0238] -Material losses during the production process.

[0239] It is recommended to take one tablet per day.

[0240] Example 3 - In vitro experiments

[0241] Experimental design

[0242] The combined effects of epigallocatechin gallate (EGCG) and at least one of folic acid, vitamin B12, and hyaluronic acid were tested in vitro in an immortalized cervical cancer cell line (HeLa) relative to the single substances.

[0243] The cells were seeded in 25 cm 3 The flask was added with 10% FBS (fetal bovine serum), 1% L-Glu (L-glutamine), and 1% Pen / Strep (penicillin / streptomycin). The cells were placed in an incubator at 37°C, 5% carbon dioxide, and 95% humidity, and cultured as described above until the cells reached 50% confluence.

[0244] On the day of the experiment, cells were treated as follows:

[0245] 1. Control (cells in culture medium without other stimulation)

[0246] 2.EGCG 50mcg / ml

[0247] 3. L-Methylfolate Calcium (900nM)

[0248] 4. Vitamin B12 (1000nM)

[0249] 5. Hyaluronic acid (10mcg / ml)

[0250] 6. Combination therapy (EGCG + folic acid; EGCG + vitamin B12; EGCG + hyaluronic acid)

[0251] 7. Combination therapy (EGCG + folic acid + vitamin B12 + hyaluronic acid

[0252] EGCG was used in the form of green tea extract with a polyphenol titer of 95% and an EGCG content of 45%. The given concentration refers to the active ingredient EGCG.

[0253] After 48 hours of treatment, apoptosis (cell death) was assessed using the Annexin V kit.

[0254] After 48 hours of treatment, the expression of tumor suppressor genes (p53 and / or pRB) and / or viral E6 and / or E7 genes was evaluated by real-time PCR and statistical analysis was performed.

[0255] Cell culture

[0256] The human HeLa cervical cancer cell line was obtained from the European Collection of Cell Cultures (ECACC). The cells were seeded in 25 cm 2 Monolayer culture was performed in flasks (Falcon, Becton Dickinson, Franklin Lakes, NJ, USA) in a 1:1 mixture of Dulbecco's modified Minimum Essential Medium (DMEM) and Ham's F12 medium containing 5% fetal bovine serum (FBS), antibiotics (penicillin 100 IU / mL, streptomycin 100 μg / mL, gentamicin 200 μg / mL, all from Euroclone Ltd, Cramlington, UK). Cells were cultured at 37°C in an atmosphere of 5% CO2. The medium was changed every three days. After confluence, cells were removed with 0.05% trypsin-0.01% EDTA and then subcultured.

[0257] Annexin V / 7-AAD staining

[0258] After confluence, HeLa cells were placed in a 25 cm 2Flasks (Falcon, BD, Franklin Lakes, NJ, USA) were cultured in complete medium. Then, the medium was replaced with fresh complete medium containing EGCG (50mcg / ml) or folic acid (Fol) (900nM) or vitamin (B12) (1000nM) or low molecular weight or very low molecular weight hyaluronic acid (Hyal) (10mcg / ml) or EGCG (50mcg / ml) + Fol (900nM) + B12 (1000nM) + Hyal (10mcg / ml). After 48 hours of treatment, the cells were cultured according to the manufacturer (BD Pharmingen TM ) instructions, and the cell status was assessed using FITC Annexin V Cell Apoptosis Detection Kit I.

[0259] Expression of p53, E6 / E7, and Rb messenger RNA

[0260] After confluence, HeLa cells were placed in a 25 cm 2 Flask (Falcon, BD, Franklin Lakes, New Jersey, USA), cultured in complete medium. Then, after 24 hours, the culture medium was replaced with fresh complete medium containing EGCG (50mcg / ml) or Fol (900nM) or B12 (1000nM) or Hyal (10mcg / ml) or containing EGCG (50mcg / ml) + Fol (900nM) + B12 (1000nM) + Hyal (10mcg / ml). After 48 hours of treatment, total RNA was isolated using RNeasy Plus Mini kit (Qiagen, Germany) according to the manufacturer's instructions. 1 μg of total RNA was reverse transcribed into its complement (cDNA) using Fast GeneScriptase II cDNA kit (Nippon Genetics Europe, Germany). qPCR was performed on 1 μg of total cDNA using iTaq Universal SYBR Green Supermix (BioRad, Hercules, CA, USA). mRNA levels were normalized using β-actin cDNA. Ratios between treated and control conditions were compared and analyzed in triplicate. Results are expressed as fold change relative to control values. Previously published commercial primers for qRT-PCR of Rb, E6 / E7 mRNA and β-actin were used.

[0261] p53: forward primer 5′-ACATGACGGAGGTTGTGA-3′ (SEQ ID No. 1), and reverse primer 5′-CGCAAATTTCCTTCCACTC-3′ (SEQ ID No. 2);

[0262] Rb: forward primer 5'-GCTAGCCTATCTCCGGCTAAA-3' (SEQ ID No. 3), and reverse primer 5'-CTGGAAAAGGGTCCAGATGA-3' (SEQ ID No. 4);

[0263] E6 / E7: forward primer 5'-ATGCATGGACCTAAGGCAAC-3' (SEQ ID No. 5), and reverse primer 5'-AGGTCGTCTGCTGAGCTTTC-3' (SEQ ID No. 6);

[0264] β-actin: forward primer 5'-CAACCGCGAGAAGATGACC-3' (SEQ ID No. 7), and reverse primer 5'-AGAGGCGTACAGGGATAGCA-3' (SEQ ID No. 8);

[0265] (Darnell GA, Antalis TM, Johnstone RW, Stringer BW, Ogbourne SM, Harrich D, Suhrbier A. Inhibition of retinoblastoma protein degradation by interaction with the serpin plasminogen activator inhibitor 2 via a novel consensus motif. Mol Cell Biol. 2003 Sep; 23(18): 6520-32. doi: 10.1128 / MCB.23.18.6520-6532.2003) (Fuso A, Cavallaro RA, Zampelli A, D'Anselmi F, Piscopo P, Confaloni A, Scarpa S. Gamma-Secretase is differentially modulated by alterations of homocysteine ​​cycle in neuroblastoma and glioblastoma cells. J Alzheimers Dis 2007; 11: 275-90. doi: 10.3233 / jad-2007-11303).

[0266] Statistical analysis

[0267] Statistical analysis GraphPad Prism 8 (GraphPad Inc., La Jolla, CA, USA) was used for statistical and graphical analysis. One-way ANOVA was calculated and Bonferroni post hoc test was used to evaluate any significant differences reported in this article (p < 0.05). The assay was repeated three times and the histograms report the mean ± SD. The differences observed between experimental conditions are expressed as fold increase.

[0268] result

[0269] In HeLa cervical cancer cells, EGCG ( #### p<0.0001, Fol, B12 and Hyal alone (§§§§§ p<0.0001), the combination of EGCG, folic acid, vitamin B12 and hyaluronic acid synergistically increased cell death (apoptosis). In our cell model, no differences in apoptosis levels were observed between the EGCG and control groups. B12 and Hyal alone significantly increased apoptosis compared to the control (*p<0.05), although this increase was not as significant as in samples treated with the combination of all substances (****p<0.0001). Fol alone significantly reduced apoptosis compared to the control (***p<0.001)( Figure 1 ).

[0270] The combination of EGCG, FA, B12, and HA modulated the gene expression levels of p53 and E6 / E7.

[0271] After 48 hours of treatment, EGCG alone ( #### p<0.0001) and single administration of Fol, Hyal and B12 ( §§§§ p<0.0001 and §§ p<0.01), the combination of EGCG, Fol, B12 and Hyal synergistically increased the expression of p53. Except for B12 which showed a slight increase (*p<0.05), the use of each listed substance alone did not increase p53 expression compared with the control. @@@ p<0.001) and EGCG+Fol( @@ The combination of EGCG, Fol, B12 and Hyal induced a significant increase in p53 compared to the combination of EGCG, Fol, B12 and Hyal (***p<0.01). The difference between EGCG+Fol+B12+Hyal and EGCG+B12 was not significant, however, it must be emphasized that even though EGCG+B12 was significantly higher than the control (***p<0.001) and EGCG alone ( # p<0.05) significantly increased p53, but its significance was lower than that caused by the combination of EGCG+Fol+B12+Hyal (****p<0.0001)( Figure 2 ).

[0272] The combination of EGCG+Fol+B12+Hyal significantly and synergistically reduced the expression of E6 / E7 (***p<0.001), which is partially responsible for the persistence of tHPV. In our experimental model, the combination of EGCG+Fol+B12+Hyal showed the most significant reduction in E6 / E7 ( Figure 3 After 48 hours of treatment, Rb expression did not change ( Figure 4 ).

[0273] in conclusion

[0274] The present invention demonstrates for the first time that the combination of EGCG, Fol, B12 and Hyal significantly and synergistically up-regulates apoptosis in HeLa cells, a model of HPV infection persistence. The combination of EGCG, Fol, B12 and Hyal increases apoptosis through the expression of p53 (known as the "guardian of the genome"), and p53 is inhibited by the E6 / E7 viral proteins that are partially associated with HPV persistence.

[0275] In addition, the combination of EGCG, Fol, B12, and Hyal significantly downregulated the expression of E6 / E7, but had no effect on Rb expression.

Claims

1. A combination comprising a compound of formula (I): in, R1 is H or and R2 is H or OH; or a stereoisomer or a salt thereof; and at least one other agent selected from the group consisting of: a. folic acid or its salts or derivatives; b. Vitamin B12 or its derivatives; c. Very low / low molecular weight hyaluronic acid or a pharmaceutically acceptable salt thereof; Used to prevent, control and / or inhibit human papillomavirus infection (HPV).

2. The combination for use as claimed in claim 1, wherein: The compound of formula (I) is selected from: (-)-epigallocatechin gallate (EGCG) and / or (-)-gallocatechin gallate (GCG) and / or (-)-epicatechin gallate (ECG) and / or (-)-catechin gallate (CG) and / or (-)-epicatechin (EC) and / or (+)-catechin (C) and / or (-)-epigallocatechin (EGC) and / or (+)-gallocatechin (GC), or a combination thereof; preferably, the compound of formula (I) is (-)-epigallocatechin gallate (EGCG).

3. A combination for use as claimed in any one of the preceding claims, comprising: a. a compound of formula (I) in an amount of 1 mg to 800 mg per day, preferably 50 mg to 600 mg per day, preferably about 200 mg per day; b. folic acid or a salt or derivative thereof in an amount of 1 to 400 micrograms per day, preferably 50 to 400 micrograms per day, preferably 200 to 400 micrograms per day, preferably about 400 micrograms per day; and / or c. Vitamin B12 or a derivative thereof in an amount of 1 to 1000 micrograms per day, preferably 100 to 1000 micrograms (1 mg) per day, preferably 500 to 1000 micrograms (1 mg) per day, preferably about 1000 micrograms (1 mg) per day; and / or d. Very low / low molecular weight hyaluronic acid or a pharmaceutically acceptable salt thereof in an amount of 1 mg per day To 200 mg per day, preferably 25 mg to 150 mg per day, preferably 50 mg to 100 mg per day, preferably about 50 mg per day.

4. A combination for use as claimed in any one of the preceding claims, comprising a compound of formula (I) or a stereoisomer or salt thereof and at least two other agents selected from the group consisting of: a. folic acid or its salts or derivatives; b. Vitamin B12 or its derivatives; c. Very low / low molecular weight hyaluronic acid or a pharmaceutically acceptable salt thereof.

5. A combination for use as claimed in any one of the preceding claims comprising i) a compound of formula (I) or a stereoisomer or salt thereof and ii) folic acid or a salt or derivative thereof and iii) vitamin B12 or a derivative thereof and iv) very low / low molecular weight hyaluronic acid or a pharmaceutically acceptable salt thereof.

6. A combination for use as claimed in any one of the preceding claims, wherein: The compound of formula (I) is contained in powdered leaves of tea plants or in an extract thereof, preferably the leaves of the tea plants are green tea plant leaves, preferably wild tea plants (Camellia Sinensis) leaves, and more preferably the extract contains about 30% to about 95% by weight of EGCG, preferably about 30%, about 45%, about 50% or about 95% by weight of EGCG.

7. A combination for use as claimed in any of the preceding claims, wherein the human papillomavirus infection exhibits varying degrees (low, medium, high) of changes in cells and / or benign and / or malignant lesions of the skin and / or mucous membranes of different gynecological and urological areas (vagina, cervix, vulva, anus, penis), preferably wherein the benign lesions of the infection include common warts, flat warts and plantar warts, genital warts and flat condylomata caused by sexual transmission of the virus and appearing in the penis, anus and female genitalia.

8. A combination for use as claimed in any one of the preceding claims, wherein: The compound of formula (I) and one or more other agents are administered simultaneously and / or orally and / or topically once and / or twice daily.

9. A composition comprising a compound of formula (I): in, R1 is H or and R2 is H or OH; or a stereoisomer or a salt thereof; and at least one other agent selected from the group consisting of: a. folic acid or its salts or derivatives; b. Vitamin B12 or its derivatives; c. Very low / low molecular weight hyaluronic acid or a pharmaceutically acceptable salt thereof; Preferably, the compound of formula (I) is selected from: (-)-epigallocatechin gallate (EGCG) and / or (-)-gallocatechin gallate (GCG) and / or (-)-epicatechin gallate (ECG) and / or (-)-catechin gallate (CG) and / or (-)-epicatechin (EC) and / or (+)-catechin (C) and / or (-)-epigallocatechin (EGC) and / or (+)-gallocatechin (GC); or a combination thereof; preferably, the compound of formula (I) is (-)-epigallocatechin gallate (EGCG).

10. The composition of claim 9, comprising a compound of formula (I): in, R1 is H or and R2 is H or OH; or a stereoisomer or a salt thereof; and at least two other agents selected from the group consisting of: a. folic acid or its salts or derivatives; b. Vitamin B12 or its derivatives; c. Very low / low molecular weight hyaluronic acid or a pharmaceutically acceptable salt thereof.

11. A composition as claimed in any one of claims 9 or 10 comprising i) a compound of formula (I) or a stereoisomer or salt thereof and ii) folic acid or a salt or derivative thereof and iii) vitamin B12 or a derivative thereof and iv) very low / low molecular weight hyaluronic acid or a pharmaceutically acceptable salt thereof.

12. A composition as described in any one of claims 9 to 11, comprising: a. the compound of formula (I) in an amount of 1 mg to 800 mg, preferably 50 mg to 600 mg, preferably about 200 mg, preferably about 100 mg; b. folic acid or a salt or derivative thereof in an amount of 1 to 400 micrograms, preferably 50 to 400 micrograms, preferably 200 to 400 micrograms, preferably about 400 micrograms, preferably about 200 micrograms; and / or c. Vitamin B12 or a derivative thereof in an amount of 1 to 1000 micrograms, preferably 100 to 1000 micrograms (1 mg), preferably 500 to 1000 micrograms (1 mg), preferably about 1000 micrograms (1 mg), Preferably about 500 micrograms; and / or d. Very low / low molecular weight hyaluronic acid or a pharmaceutically acceptable salt thereof in an amount of 1 mg to 200 mg, Preferably 25 mg to 150 mg, preferably 50 to 100 mg, preferably about 50 mg, preferably about 25 mg.

13. The composition of any one of claims 9 to 12, wherein The compound of formula (I) is contained in powdered leaves of the tea plant or in an extract thereof, preferably the leaves of the tea plant are green tea plant leaves, preferably wild tea leaves, and more preferably the extract contains 30% to 95% by weight of EGCG, preferably about 30% by weight, about 45% by weight, about 50% by weight or about 95% by weight of EGCG.

14. A pharmaceutical composition, a dermocosmetic or a medical device or a supplement or a food, preferably a food for special medical purposes, or a drink, or a topical preparation, comprising the composition according to any one of claims 9 to 13.

15. The composition of any one of claims 9 to 13, further comprising at least one excipient or diluent, preferably for oral and / or topical administration, preferably in the form of lozenges, hard capsules, soft capsules, powders, syrups, cachets, pills, tablets, pastilles, gels, creams, ointments, preferably, the excipient and / or diluent is selected from the group consisting of calcium phosphate, dicalcium phosphate, microcrystalline cellulose, silicon dioxide, sucrose, gum arabic, corn starch, medium chain triglycerides, tricalcium phosphate, cross-linked sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, polyvinyl pyrrolidone, talc, erythritol, xylitol, steviol and sucralose, magnesium salts of fatty acids, preferably, the magnesium salts of fatty acids are magnesium stearate.

16. A pharmaceutical composition or a dermocosmetic or a medical device or a supplement or a food according to claim 14, preferably a food or a drink or a topical preparation for special medical purposes, or a composition according to claim 15, for preventing, controlling and / or inhibiting human papillomavirus infection (HPV), preferably wherein the human papillomavirus infection exhibits different degrees (low, medium, high) of changes in cells and / or benign and / or malignant lesions of the skin and / or mucous membranes of different gynecological and urological areas (vagina, cervix, vulva, anus, penis), preferably wherein the benign lesions of the infection include common warts, flat warts and plantar warts, genital warts and flat condylomata caused by viral sexual transmission and appearing in the penis, anus and female genitalia.

17. A composition according to any one of claims 9 to 13 or 15 or a pharmaceutical composition according to claim 14 or a dermocosmetic or medical device or supplement or food, preferably a food or beverage product for special medical purposes or a topical preparation in the field of nutrition and health care or as a basic ingredient in the preparation of supplements and / or topical devices and / or foods and / or foods for special medical purposes for non-therapeutic use.

18. The combination for use as claimed in any one of claims 1 to 8 or the composition as claimed in any one of claims 9 to 13 or 15, or the pharmaceutical composition or the dermocosmetic or the medical device or the supplement or the food, preferably the food for special medical purposes, or the drink or the topical preparation as claimed in claim 14, for use in combination with other therapeutic interventions, preferably surgery whose purpose is to remove lesions caused by infection with any human papillomavirus strain.

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