Diphenylethylene compounds and their compositions

Abstract

This application relates to the use of diphenylethylene compounds, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, and / or pterostilbene, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, in the treatment of papillomavirus infection and diseases, disorders, or conditions resulting from papillomavirus infection, such as cancer, as well as compositions containing them, and further combinations with curcuminoids and catechins.

Description

Technical Field

[0001] Field of the Invention This application relates to the use of diphenyl ethylene compounds and compositions thereof in therapy. In certain embodiments, this application relates to the use of diphenyl ethylene compounds and compositions thereof in the treatment of papillomavirus infections and diseases, disorders, or conditions caused by papillomavirus infections, such as cancer.

[0002] All publications, patents, patent applications, and other references cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application, or other reference were specifically and individually indicated to be incorporated by reference in its entirety for all purposes. The citation of references herein is not to be construed as an admission that such references are prior art to the present invention. Cross - Reference to Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 526,122, filed on July 11, 2023, the content of which is hereby expressly incorporated by reference herein.

Background Art

[0003] Background Diphenyl ethylene compounds have aromatic groups attached to each end of a carbon - carbon double bond, are versatile, and are involved in various biochemical, photochemical, and photochromic reactions. Plants produce extremely diverse and bioactive forms characterized by the presence of a 1,2 - diphenyl ethylene nucleus, and (E) - stilbene is the most biologically relevant stereoisomer.

[0004] There are over 400 naturally occurring stilbenes, many of which are phytoalexins produced by plants in response to damage from pathogenic bacteria, fungi, and viruses. These abundant bioactive compounds form the basis for treating human diseases using numerous medicinal plants and are the source of drug discovery for antiviral and antimicrobial therapies.

[0005] Human papillomavirus (HPV) is a group of viruses that infect the skin and mucous membranes, causing a wide range of epithelial lesions, from benign growths (e.g., warts) to cancer. There are more than 400 types of HPV, classified into five different genera: alpha, beta, gamma, mu, and new papillomavirus. Approximately 80% of men and women acquire HPV at some point in their lives.

[0006] The Papillomaviridae family is a family of small, non-enveloped DNA viruses. They infect a variety of species, such as birds, reptiles, and mammals, such as dogs, cats, rabbits, mice, and humans. Collectively, these viruses are known as papillomaviruses. They are host-specific and not cross-species. Therefore, human papillomavirus (HPV) is transmitted only among humans and infects the skin or mucous membranes. HPV can cause papillomas (verrucae) in the skin, larynx, or urogenital area, but some genotypes induce malignant transformation and cause overt cancer. There are more than 400 types of HPV, many of which are classified as either low-risk or high-risk HPV depending on their likelihood of causing cancer.

[0007] Most HPV infections are transient, but 10-15% become chronic, and these persistent infections can lead to malignancies. HPV is a leading cause of cervical cancer. In the United States, 1.8 million women have chronic cervical HPV, which accounts for 200,000 cases of precancerous cervical cancer each year. Globally, more than 28 million women have persistent cervical HPV infection and are at risk of developing cervical cancer. These patients have no specific treatment options. HPV vaccines can prevent HPV and cervical cancer. However, they are not effective in treating those with established infections.

[0008] Furthermore, only 15% of eligible women worldwide have completed the full HPV vaccination regimen. With no cure for HPV, the standard medical practice is to offer a “watchful care” approach, which allows patients infected with high-risk HPV strains to simply follow up with the development of precancerous lesions. Surgical interventions and resections are only an option to treat precancerous lesions after they have developed. For these reasons, HPV infection remains one of the most challenging viral infections in women, and cervical cancer remains the fourth most common malignancy in women worldwide.

[0009] HPV infection also causes widespread disease in men and women, leading to higher prevalence and mortality rates. 25 percent of men in the United States carry genital oncogenic HPV infection, which is currently untreatable and a major cause of the virus's continued spread. HPV infection also induces other malignancies, such as cancers of the mouth, anus, vagina, and penis. Low-risk HPV genotypes cause various difficult-to-treat and painful papillary growths (verrucae) on the skin and vulva, as well as laryngeal papillomas and lesions on the body surface. The CDC estimates there are 14 million new HPV infections each year. The annual cost to the US healthcare system for diagnosing and treating cervical HPV alone reaches billions, making it the second most devastating sexually transmitted infection. Currently, there are no known antiviral drugs, and the infection remains incurable.

[0010] Resveratrol (trans-3,5,4'trihydroxystilbene) is a polyphenolphytoalexin first isolated and identified from the roots of Veratrum grandiflorum O.Loes, possessing anticancer and antiviral properties. In preclinical studies, resveratrol modulates numerous cellular signaling and regulatory proteins, including Wnt, nuclear factor-κB (NF-κB), cytokines, caspases, Notch, matrix metalloproteinases (MMPs), 5'-AMP-activated protein kinase (AMPK), sirtuin type 1 (SIRT1), and tumor necrosis factor α (TNF-α). These promising studies led to clinical trials using resveratrol to treat a variety of diseases or disorders. However, the successes seen in laboratory studies have not translated into success in clinical settings. Most clinical trials have yielded little to minimal positive results. This is attributed to resveratrol's low solubility, rapid degradation in aqueous environments, and generally low target tissue concentrations for achieving biological effects. A further problem is that cancer cells have been observed to acquire resveratrol resistance (Colin DJ et al., Cell Death Dis. 2014 Nov 20;5(11):e1533; Aires V, et al. Nutrients. 2019 Sep 4;11(9):2098; Park D, et al. Sci Rep. 2016 Feb 23;6:21772; Nie JH, et al. Int J Mol Sci. 2019 Jan 7;20(1):191; Amintas S, et al. Journal of Functional Foods, Volume 99, December 2022, 105345. doi.org / 10.1016 / j.jff.2022.105345). Although promising in preclinical studies, resveratrol has not been effective in patients due to its low systemic bioavailability. Even if the compound reaches diseased cells, resistance to resveratrol develops. Over millennias, plants have evolved robust defenses against pathogenic microorganisms, including viruses. The plant immune system is mediated by chemical messengers. Selective pressures have allowed some plant species to thrive by producing unique phytochemicals. These small molecules activate potent antiviral mechanisms that confer a robust immune response. Plants lack immune cells and rely solely on these bioactive compounds. Similar to mammals, the plant immune response is "polyclonal." Multiple phytoalexins are activated and released in response to viral infection. Numerous plant species possess diverse polyphenols with unique and potent biological properties. A pharmaceutical mixture of curcumin, (-)-epicatechin gallate, and resveratrol was found to be synergistic in eliminating various HPV(+) cancer cell lines, cancerous and precancerous tissues. (Mukherjee et al., 2017 Oncotarget. 2017 Mar 29;8(37), International Publication No. 2015 / 081319, U.S. Patent Application Publication No. 2016 / 0287533, Einbond et al. 2021, Br J Cancer. 2021 Mar; 124(5):901-913). However, cancer cells develop resistance to resveratrol, which contributes to the limited clinical efficacy of resveratrol-based drugs (Colin DJ et al., Cell Death Dis. 2014 Nov 20;5(11):e1533, Aires V, et al. Nutrients. 2019 Sep 4;11(9):2098; Park D, et al. Sci Rep. 2016 Feb 23;6:21772; Nie JH, et al. Int J Mol Sci. 2019 Jan 7;20(1):191; Amintas S, et al. Journal of Functional Foods, Volume 99, December 2022, 105345. doi.org / 10.1016 / j.jff.2022.105345). [Prior art documents]

Patent Document

[0011]

Patent Document 1

Patent Document 2

[0014] The application also includes a method for treating or preventing a disease, disorder, or condition caused by a papillomavirus infection, comprising the step of administering a therapeutically effective amount of one or more compounds of formula I as defined in claim 1, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, to a subject in need.

[0015] In some embodiments, the method includes the step of administering an effective amount of two or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, in combination with curcuminoids and catechins.

[0016] This application includes a method for treating or preventing resveratrol-resistant cancer in a subject who needs treatment or prevention of resveratrol-resistant cancer, the method comprising administering to the subject an effective amount of pterostilbene, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

[0017] In some embodiments, the method includes administering to the subject an effective amount of pterostilbene, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, in combination with curcuminoids and catechins.

[0018] This application includes a method for treating or preventing papillomavirus infection in a subject who needs treatment or prevention of papillomavirus infection, the method comprising administering to the subject an effective amount of one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof,

Chemical formula

Chemical formula

[0019] The application also includes a method for treating or preventing a disease, disorder, or condition caused by a papillomavirus infection, comprising the step of administering a therapeutically effective amount of one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, in combination with pterostilbene, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, to a subject in need.

[0020] In some embodiments, the method includes administering to a subject an effective amount of one or more compounds of formula I, in combination with pterostilbene, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, and further in combination with curcuminoids and catechins.

[0021] This application also relates to a pharmaceutical composition comprising one or more compounds of formula I, or pharmaceutically acceptable salts thereof, prodrugs, and / or solvates, curcuminoids, and catechins, [ka] During the ceremony, X 1 ~X 4 This includes pharmaceutical compositions as defined above.

[0022] In some embodiments, the pharmaceutical composition comprises one or more compounds of formula I, or pharmaceutically acceptable salts thereof, prodrugs, and / or solvates, curcuminoids, and catechins.

[0023] In some embodiments, the composition comprises two or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof.

[0024] This application relates to a pharmaceutical composition for treating or preventing resveratrol-resistant cancer in subjects requiring treatment or prevention of resveratrol-resistant cancer, comprising an effective amount of pterostilbene or a pharmaceutically acceptable salt thereof, a prodrug, and / or a solvate, a curcuminoid, and a catechin.

[0025] This application relates to pharmaceutical compositions comprising one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, in combination with pterostilbene, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof.

[0026] Other features and advantages of this application will become apparent from the detailed description below. However, it should be understood that the detailed description and specific examples illustrate embodiments of this application, but are provided for illustrative purposes only, and the claims should not be limited by these embodiments, but rather given the broadest possible interpretation consistent with the description as a whole. [Modes for carrying out the invention]

[0027] Detailed explanation I. Definition Unless otherwise indicated, the definitions and embodiments set forth in this section and other sections are intended to apply to all embodiments and aspects of this application as described herein, to the extent appropriate, as can be understood by those skilled in the art.

[0028] All characteristics disclosed herein, including the claims, abstract, and drawings, and all steps in any disclosed method or process, may be combined in any combination, except where at least some of such characteristics and / or steps are mutually exclusive. Each characteristic disclosed herein, including the claims, abstract, and drawings, may be replaced by an alternative characteristic serving the same, equivalent, or similar purpose, unless otherwise expressly stated.

[0029] As used herein, terms such as “composition of the application” or “composition of the present application” refer to compositions comprising one or more compounds of formula I, or their salts, prodrugs, and / or solvates, curcuminoids, and catechins; pterostilbene, or its salts, prodrugs, and / or solvates, curcuminoids, and catechins; or one or more compounds of formula I, or its salts, prodrugs, and / or solvates, pterostilbene, or its salts, prodrugs, and / or solvates, and optionally combinations of curcuminoids and catechins.

[0030] When used herein, the term "consisting of" or its derivatives is intended to be a closed term that specifies the existence of the mentioned characteristics, elements, components, groups, integers, and / or steps, and excludes the existence of other unmentioned characteristics, elements, components, groups, integers, and / or steps.

[0031] When used herein, the term “essentially derived from” is intended to specify the presence of the properties, elements, components, groups, integers, and / or steps mentioned, as well as those that do not substantially affect the fundamental and novel characteristics of the properties, elements, components, groups, integers, and / or steps.

[0032] Terms of degree such as “substantially,” “about,” and “approximately,” as used herein, mean a reasonable deviation of the modified term that does not significantly alter the final result. These terms of degree should be interpreted as including a deviation of at least ±5% of the modified term, unless this deviation negates the meaning of the word it modifies.

[0033] As used in this application, the singular forms “a,” “an,” and “the” include plural references unless otherwise clearly indicated by the context.

[0034] In embodiments including “additional” or “second” components, the second component used herein is chemically different from the other components or the first component. The “third” component is different from the other components, the first component, and the second component, and the further listed or “additional” components are similarly different.

[0035] Where used herein, the term “preferred” means that the selection of a particular compound or state depends on the specific synthetic operation to be performed, the identity of the molecule to be transformed, and / or the specific use of the compound, but the selection is well within the skill of a person skilled in the art. All process / method steps described herein should be carried out under conditions sufficient to obtain the indicated product. A person skilled in the art will understand that all reaction conditions, including, for example, the reaction solvent, reaction time, reaction temperature, reaction pressure, reactant ratio, and whether the reaction should be carried out under an anhydrous or inert atmosphere, can be modified to optimize the yield of the desired product, and that doing so is within the skill of a person skilled in the art.

[0036] Where used herein, the term "and / or" means that the listed items exist or are used individually or in combination. In practice, the term means that "at least one" or "one or more" of the listed items are used or exist.

[0037] As used herein, the term "cell" refers to a single cell or a group of cells, including cells in a cell culture or a subject.

[0038] The term "subject," as used herein, includes all members of the animal kingdom, including mammals. Therefore, the methods and uses of this application are applicable to both human therapeutic and veterinary applications.

[0039] The term "pharmaceutically acceptable" means that the treatment of the subject is compatible with the treatment.

[0040] The terms “pharmaceutically acceptable carrier” or “vehicle” mean a non-toxic solvent, dispersion medium, excipient, adjuvant, or other material that is mixed with the active ingredient (e.g., one or more compounds of this application) to enable the formation of a pharmaceutical composition, i.e., a dosage form that can be administered to a subject.

[0041] "Pharmacologically acceptable salt" means either an acid addition salt or a base addition salt that is suitable or compatible with the treatment of the subject.

[0042] An acid addition salt suitable or compatible for the treatment of a subject is any non-toxic organic or inorganic acid addition salt of any basic compound.

[0043] Suitable or compatible base addition salts for the treatment of the subject are any non-toxic organic or inorganic base addition salts of any acidic compound.

[0044] As used herein, the term "solvate" means a compound or salt of a compound in which molecules of a preferred solvent are incorporated into the crystal lattice. The preferred solvent is physiologically tolerable at the administered dosage.

[0045] As used herein, the term "prodrug" means a compound or a salt of a compound that is converted into an active drug after administration.

[0046] As used herein, the term "viral infection" refers to an invasion of cells or body tissues by one or more foreign, unwanted viruses.

[0047] When used herein, the term "administered" means the administration of a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, prodrug, and / or solvate thereof, or a composition comprising the compound, or a pharmaceutically acceptable salt thereof, prodrug, and / or solvate thereof, to cells in either a cell culture or a subject.

[0048] As used herein, the terms “effective dose,” “therapeutic effective dose,” or “antiviral effective dose” mean the amount of a compound, or a pharmaceutically acceptable salt thereof, prodrug, and / or solvate thereof, or a composition comprising the compound, or a pharmaceutically acceptable salt thereof, prodrug, and / or solvate thereof, that is effective in the dose and duration required to achieve the desired outcome, including therapeutic and prophylactic results.

[0049] The term "subject," as used herein, includes all members of the animal kingdom, including mammals, and preferably refers to humans. Therefore, the methods and uses of this application are applicable to both human therapeutic and veterinary applications.

[0050] When used herein, the term "pharmaceutical composition" refers to a composition intended for pharmaceutical use.

[0051] When used herein, the term "parenteral" means that the substance is taken into or administered to the body by means other than through the gastrointestinal tract.

[0052] The terms “to treat” or “treatment,” as used herein and as is well understood in the art, mean an approach to obtain beneficial or desired outcomes, including clinical outcomes. Beneficial or desired clinical outcomes may include, but are not limited to, relief or improvement of one or more symptoms or conditions, whether detectable or undetectable; a reduction in the severity of a disease, disability, or condition; a stabilization of a disease, disability, or condition (i.e., no worsening); prevention of the spread of a disease, disability, or condition; delay or slowing of the progression of a disease, disability, or condition; improvement or temporary relief of a disease, disability, or condition; a reduction in the recurrence of a disease, disability, or condition; inhibition or reduction of a disease, disability, or condition; and remission (whether partial or whole). “To treat” and “treatment” may also mean extending survival compared to the survival expected if treatment is not received. “To treat” and “treatment,” as used herein, also include prophylactic treatment.

[0053] To “temporarily alleviate” an infection and / or disease means that the severity of the infection and / or disease and / or undesirable clinical signs are reduced and / or the progression over time is slowed or gradual compared to when the infection and / or disease is not treated.

[0054] When used herein, terms such as "prevention," "prophylaxis," or "prophylactic" refer to a reduction in the risk or probability that a subject will contract a viral infection and / or a disease caused by a viral infection, or that symptoms associated with a viral infection or a disease caused by a viral infection will appear.

[0055] As used herein, the terms “effective dose” or “therapeutic dose” mean the amount of a compound or one or more compounds that is effective in the dosage and duration required to achieve the desired result.

[0056] The term “disease, disorder, or condition caused by papillomavirus infection” means that the disease, disorder, or condition being treated is directly or indirectly affected and / or modulated by papillomavirus infection.

[0057] For example, when used in connection with the treatment methods, uses, compositions, and kits of this application, subjects, for example, subjects who "need it," are subjects diagnosed with papillomavirus infection or a disease caused by papillomavirus infection, subjects suspected of having it, subjects who may come into contact with it, and / or subjects who have previously received treatment in relation to it.

[0058] As used herein, the term "papillomavirus" refers to viruses of the family Papillomaviridae.

[0059] The term "human papillomavirus infection" or "HPV infection" refers to an infection caused by the human papillomavirus.

[0060] When used herein, the term "resveratrol" refers to a chemical name having: (E)-5-(4-hydroxystyryl)benzene-1,3-diol or trans-3,5,4'-trihydroxystilbene, and the following chemical structure and numbering [ka] This refers to compounds that possess [a certain characteristic].

[0061] The term "resveratrol-resistant cancer" refers to cancer that exhibits very low sensitivity to treatment with resveratrol, and as a result, its symptoms are neither improved, reduced, alleviated, nor treated by resveratrol. Resveratrol-resistant cancer may be cancer that was originally resistant to treatment with resveratrol, or it may be cancer that was not originally resistant to resveratrol. II. Method and Use of the Application

[0062] The applicant has identified a specific plant species containing trans-resveratrol, such as the medicinal rhubarb plant, and has further investigated other diphenylethylene compounds present in the plant species for their anti-papillomavirus activity, such as anti-human papillomavirus (HPV) activity. To the best of the applicant's knowledge, the medicinal rhubarb plant has not been previously investigated for its anti-papillomavirus compounds.

[0063] In one embodiment, drug screening was performed for other identified natural diphenylethylene compounds present in medicinal rhubarb plant species (including Rheum rhaponticum and Rheum rhabarbarum) known to contain resveratrol. Among the other identified compounds, candidate diphenylethylene plant chemicals having a 1,2-diphenylethylene scaffold in a trans configuration were selected. The selected diphenylethylene compounds were tested, and dose-response curves were constructed based on their ability to eliminate HPV-18(+) HeLa cells. This HPV-18(+) HeLa cervical cancer lineage was also used to develop a subclonal population of HeLa cells, which showed potent resistance to resveratrol and was designated HeLa-GS1. The most active (IC) of the identified compounds was selected. 50 The diphenylethylene compound (<30 μM) was then tested on a newly developed resveratrol-resistant cell line, HeLa-GS1. The applicants identified a diphenylethylene compound that exhibits unexpectedly good cytotoxicity against HPV(+) cells.

[0064] The applicant then investigated the activity of the identified diphenylethylene compound combinations, and further combinations with curcuminoids, e.g., curcumin, and catechins, e.g., (-)-epigallocatechin gallate (EGCg), and found compound combinations that exhibit high and synergistic anti-papillomavirus activity. i) Method and use of compound of formula I

[0065] This application relates to a method for treating or preventing papillomavirus infection in a subject requiring treatment or prevention of papillomavirus infection, the method comprising the step of administering to the subject an effective amount of one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof. [ka] During the ceremony, X 1 and X 2 These are independently OH and OR 1 Selected from, X 3 and X 4 These are independently selected from OH and OCH3, R 1 teeth, [ka] This includes methods.

[0066] The application also includes the use of one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, for treating or prophylactic papillomavirus infection in subjects; the use of one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, for the preparation of pharmaceuticals for treating or prophylactic papillomavirus infection in subjects; and the use of one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, for use in treating or prophylactic papillomavirus infection in subjects.

[0067] In some embodiments, a papillomavirus infection is an infection with at least one papillomavirus. In some embodiments, a papillomavirus infection is a human papillomavirus (HPV) infection. In some embodiments, HPV infections are 1 (HPV-1), 2 (HPV-2), 3 (HPV-3), 4 (HPV-4), 5 (HPV-5), 6 (HPV-6), 8 (HPV-8), 11 (HPV-11), 16 (HPV-16), 18 (HPV-18), 21 (HPV-21), 22 (HPV-22), 23 (HPV-23), 27 (HPV-27), 29 (HPV-29), 31 (HPV-31), 33 (HPV-33), 35 (HPV-35), 39 (HPV-39), 45 (HPV-45), 51 (HPV-51), 52 (HPV-52), 56 (HPV-56), 57 (HPV-57) HPV infection is an infection of one or more HPV genotypes selected from 58 (HPV-58), 59 (HPV-59), and 68 (HPV-68). In some embodiments, HPV infection is an infection of one or more HPV genotypes selected from 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. In some embodiments, HPV genotypes selected from 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68 cause cancer. In some embodiments, HPV infection is an infection of one or more HPV genotypes selected from HPV genotypes 16 and 18. In some embodiments, HPV infection is an infection of HPV genotype 16. In some embodiments, HPV infection is an infection of HPV genotype 18. In some embodiments, HPV infection is an infection with one or more HPV genotypes selected from 1, 3, 27, 29, and 57. In some embodiments, the HPV genotype is selected from 1, 3, 27, 29, or 57 and causes common warts. In some embodiments, HPV infection is an infection with one or more HPV genotypes selected from 1, 2, 3, 4, 27, 29, and 57. In some embodiments, the HPV genotype selected from 1, 2, 3, 4, 27, 29, and 57 causes plantar warts, for example, deep palmoplantar warts.

[0068] Because the compound of formula I has shown activity against HPV-16(+) and HPV-18(+) cervical cancer cell lines and resveratrol-resistant cancer cell lines, the compound of formula I is useful in treating diseases, disorders, or conditions caused by papillomavirus infection.

[0069] Accordingly, the present application also includes a method for treating or preventing a disease, disorder, or condition caused by a papillomavirus infection, comprising the step of administering a therapeutically effective amount of one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, to a subject in need.

[0070] This application also includes the use of one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, for the treatment or prevention of diseases, disorders, or conditions caused by papillomavirus infections, and the use of one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, for the preparation of pharmaceuticals for the treatment or prevention of diseases, disorders, or conditions caused by papillomavirus infections. This application further includes one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, for use in the treatment or prevention of diseases, disorders, or conditions caused by papillomavirus infections.

[0071] In some embodiments, the disease, disorder, or condition caused by papillomavirus infection is papillomavirus-associated cancer or precancerous (dysplasia). In some embodiments, the disease, disorder, or condition caused by papillomavirus infection is papillomavirus-associated cancer. In some embodiments, papillomavirus-associated cancer is selected from cervical cancer, anal cancer, oropharyngeal cancer, penile cancer, vaginal cancer, vulvar cancer, oral cancer, and skin cancer, and combinations thereof. In some embodiments, papillomavirus-associated cancer is cervical cancer.

[0072] In some embodiments, papillomavirus-associated cancer is cancer caused by one or more HPV genotypes selected from 16(HPV-16), 18(HPV-18), 31(HPV-31), 33(HPV-33), 35(HPV-35), 39(HPV-39), 45(HPV-45), 51(HPV-51), 52(HPV-52), 56(HPV-56), 58(HPV-58), 59(HPV-59), and 68(HPV-68). In some embodiments, papillomavirus-associated cancer is cancer caused by one or both of HPV genotypes 16(HPV-16) and 18(HPV-18). In some embodiments, papillomavirus-associated cancer is cancer caused by HPV genotype 16(HPV-16). In some embodiments, papillomavirus-associated cancer is cancer caused by HPV genotype 18 (HPV-18).

[0073] In some embodiments, papillomavirus-associated cancer is a resveratrol-resistant papillomavirus-associated cancer as defined above. Therefore, in some embodiments, papillomavirus-associated cancer is a resveratrol-resistant cancer. Therefore, in some embodiments, a disease, disorder, or condition caused by a papillomavirus infection is a resveratrol-resistant cancer.

[0074] In some embodiments, the disease, disorder, or condition caused by papillomavirus infection is selected from verrucae and laryngeal papillomas, and combinations thereof. In some embodiments, the disease, disorder, or condition caused by papillomavirus infection is verrucae. In some embodiments, the verrucae are caused by one or more of HPV-1, HPV-2, HPV-3, HPV-4, HPV-6, HPV-8, HPV-11, HPV-27, HPV-29, and HPV-57. In some embodiments, the verrucae are selected from common verrucae, flat verrucae, filiform verrucae, mosaic verrucae, plantar verrucae, perineal verrucae, anal verrucae, and genital verrucae, and combinations thereof. In some embodiments, genital verrucae are selected from vaginal and anal verrucae, and combinations thereof. In some embodiments, the verrucae are plantar verrucae.

[0075] In some embodiments, compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, treat or prevent papillomavirus infections, or treat or prevent diseases, disorders, or conditions caused by papillomavirus infections, by inhibiting papillomavirus replication.

[0076] In some embodiments, X 1 and X 2 One of them is OR 1 X 1 and X 2 The other of these is OH. In some embodiments, X 1 is OR 1 X 2 It is OH.

[0077] In some embodiments, R 1 The configuration is as follows: [ka] It holds.

[0078] In some embodiments, X 1 and X2 All of these are OH groups.

[0079] In some embodiments, X 3 and X 4 In some embodiments, X 3 and X 4 These are all OCH3. In some embodiments, X 3 and X 4 One of them is OH, and X 3 and X 4 The other of these is OCH3. In some embodiments, X 3 OH and X 4 This is OCH3.

[0080] In some embodiments, one or more compounds of formula I are one or more compounds listed below. [Table 26-1] [Table 26-2] or selected from pharmaceutically acceptable salts, prodrugs, and / or solvates thereof.

[0081] The applicants have shown that combinations of two or more compounds of formula (I), or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, have improved activity or act synergistically against various cancer cell lines. Accordingly, in some embodiments, the above methods and uses involve administering to a subject an effective amount of two or more compounds of formula (I), or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof.

[0082] In some embodiments, two compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, are administered or used in molar ratios of about 0.5:1 to about 1:10, about 0.5:1 to about 1:8, about 0.5:1 to about 1:5, about 0.5:1 to about 1:4, about 0.5:1 to about 1:3.75, about 0.5:1 to about 1:4, about 1:1 to about 1:4, about 1:1 to about 1:3.75, about 1:1 to about 1:3, or about 1:1 to about 1:2. In some embodiments, two compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, are administered or used in molar ratios of about 0.5:1 to about 1:3.75, about 0.5:1 to about 1:4, about 1:1 to about 1:4, about 1:1 to about 1:3.75, about 1:1 to about 1:3, and about 1:1 to about 1:2. In some embodiments, two compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, are administered or used in molar ratios of about 1:8, about 1:5, about 1:4, about 1:3.75, about 1:3, about 1:2, or about 1:1. In some embodiments, two compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, are administered or used in molar ratios of about 1:4, about 1:3.75, about 1:3, about 1:2, or about 1:1. In some embodiments, two compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, are administered or used in a molar ratio of about 1:1.

[0083] The applicants have further demonstrated that combinations of one or more compounds of formula (I), or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, when further combined with curcumin and catechin, exhibit improved activity in various cancer cell lines. Accordingly, in some embodiments, the above methods and uses involve administering to a subject an effective amount of one or more compounds of formula (I), or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, in combination with curcuminoids and catechin.

[0084] In exemplary embodiments, the applicants have shown that combinations of two or more compounds of formula (I), or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, when further combined with curcumin and catechin, have further improved activity against various cancer cell lines and act synergistically. Accordingly, in some embodiments, the above methods and uses involve administering to a subject an effective amount of two or more compounds of formula (I), or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, in combination with curcuminoids and catechin.

[0085] In some embodiments, curcuminoids, catechins, and one or more, preferably two or more, compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates are administered or used in a molar ratio of curcuminoids to catechins to one or more, preferably two or more, compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates of about 1-16:0.25-4:1-40, about 1-16:1-4:10-40, about 1-10:1-3:1-30, about 4-12:1-3:15-35, or about 6-8:2-3:20-30. In some embodiments, curcuminoids, catechins, and one or more, preferably two or more, compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates are administered or used in a molar ratio of curcuminoids to catechins to one or more, preferably two or more, compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates of about 1 to 16:1 to 4:10 to 40, about 1 to 10:1 to 3:1 to 30, about 4 to 12:1 to 3:15 to 35, or about 6 to 8:2 to 3:20 to 30. In some embodiments, curcuminoids, catechins, and one or more, preferably two or more, compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates are administered or used in a molar ratio of curcuminoids to catechins to one or more, preferably two or more, compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates of about 16:2:25, about 8:4:25, about 4:1:20, about 4:2:25, about 8:1:25, about 4:1:6, or about 8:2:25. In some embodiments, curcuminoids, catechins, and one or more, preferably two or more, compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof are administered or used in a molar ratio of curcuminoids to catechins to one or more, preferably two or more, compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof of about 8:2:25.

[0086] In some embodiments, two compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, are administered or used in molar ratios of about 0.5:1 to about 1:10, about 0.5:1 to about 1:8, about 0.5:1 to about 1:5, about 0.5:1 to about 1:4, about 0.5:1 to about 1:3.75, about 0.5:1 to about 1:4, about 1:1 to about 1:4, about 1:1 to about 1:3.75, about 1:1 to about 1:3, or about 1:1 to about 1:2. In some embodiments, two compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, are administered or used in molar ratios of about 0.5:1 to about 1:3.75, about 0.5:1 to about 1:4, about 1:1 to about 1:4, about 1:1 to about 1:3.75, about 1:1 to about 1:3, and about 1:1 to about 1:2. In some embodiments, two compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, are administered or used in molar ratios of about 1:8, about 1:5, about 1:4, about 1:3.75, about 1:3, about 1:2, or about 1:1. In some embodiments, two compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, are administered or used in molar ratios of about 1:4, about 1:3.75, about 1:3, about 1:2, or about 1:1. In some embodiments, two compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, are administered or used in a molar ratio of about 1:1.

[0087] In some embodiments, the curcuminoid is selected from curcumin (diferuloylmethane), tetrahydrocurcumin, demethoxycurcumin, tetrahydrodemethoxycurcumin, bisdemethoxycurcumin, tetrahydrobisdemethoxycurcumin, or curcumin esters, and combinations thereof. In some embodiments, the curcuminoid is curcumin.

[0088] In one embodiment, the curcuminoid is tetrahydrocurcumin.

[0089] In some embodiments, the catechin is selected from epicatechin gallate (ECG), epigallocatechin gallate (EGCG or EGCg), epicatechin (EC), epigallocatechin (EGC), (-)-epigallocatechin gallate, ((-)-EGCG), (-)-epicatechatechin gallate ((-)-ECG), (-)-epigallocatechin ((-)-EGC), (+)-gallogallate ((+)-GCG), (-)-epicatechin ((-)-EC), (+)gallocatechin ((+)-GC), and (+)-catechin ((+)-C). In some embodiments, the catechin is (-)-epigallocatechin gallate.

[0090] In exemplary embodiments, the compound of formula I, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, is selected from I-1 (isorapontigenin) and I-3 (piceatannol), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

[0091] In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, is I-3 (piceatannol), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof. In some embodiments, curcuminoids, catechins, and I-3 (piceatannol), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, are administered or used in molar ratios of curcuminoids to catechins to I-3 or a pharmaceutically acceptable salt, prodrug, and / or solvate of about 16:2:25, about 8:4:25, about 4:1:20, about 4:2:25, about 8:1:25, about 4:1:6, or about 8:2:25. In some embodiments, one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, is I-3(piceatannol), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, the curcuminoid is curcumin, the catechin is (-)-epigallocatechin gallate, and the molar ratio of curcumin to (-)-epigallocatechin gallate to I-3(piceatannol), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof is about 8:2:25. Accordingly, in exemplary embodiments, the present application provides a method for treating or preventing a papillomavirus infection in a subject requiring treatment or prevention of a papillomavirus infection, the method comprising the step of administering to the subject an effective amount of one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, in combination with a curcuminoid and a catechin, wherein the one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, is I-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, the curcuminoid is curcumin, the catechin is (-)-epigallocatechin gallate, and the molar ratio of curcumin to (-)-epigallocatechin gallate to I-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof is about 8:2:25.

[0092] In another exemplary embodiment, two or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, are I-1 (isorapontigenin), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, and I-3 (piceatannol), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof. In some embodiments, two or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, are I-1 (isorapontigenin), or its pharmaceutically acceptable salts, prodrugs, and / or solvates, and I-3 (piceatannol), or its pharmaceutically acceptable salts, prodrugs, and / or solvates, the curcuminoid is curcumin, the catechin is (-)-epigallocatechin gallate, and the molar ratio of curcumin to (-)-epigallocatechin gallate to I-3 (piceatannol), or its pharmaceutically acceptable salts, prodrugs, and / or solvates, and I-1 (isorapontigenin), or its pharmaceutically acceptable salts, prodrugs, and / or solvates, is approximately 8:2:25. In some embodiments, I-3 (piceatannol), or a pharmaceutically acceptable salt thereof, prodrug, and / or solvate thereof, and I-1 (isorapontigenin), or a pharmaceutically acceptable salt thereof, prodrug, and / or solvate thereof, are further administered or used in a molar ratio of I-3 (piceatannol), or a pharmaceutically acceptable salt thereof, prodrug, and / or solvate to I-1 (isorapontigenin), or a pharmaceutically acceptable salt thereof, prodrug, and / or solvate of about 1:3.75. Thus, in exemplary embodiments, the present application relates to a method for treating or prophylactically treating a papillomavirus infection in a subject requiring treatment or prophylactic treatment of a papillomavirus infection, the method comprising the step of administering to the subject an effective amount of two compounds of formula I, or pharmaceutically acceptable salts thereof, prodrugs, and / or solvates thereof, in combination with curcuminoids and catechins. Two compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, are I-1 (isorapontigenin), or its pharmaceutically acceptable salt, prodrug, and / or solvate, and I-3 (piceatannol), or its pharmaceutically acceptable salt, prodrug, and / or solvate, where the curcuminoid is curcumin, the catechin is (-)-epigallocatechin gallate, and curcumin vs (-)-epigallocatechin gallate vs I-3 (piceatannol) The method comprises a molar ratio of I-1 (isorapontigenin), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, and I-1 (isorapontigenin), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, being approximately 8:2:25, and a molar ratio of I-3 (piceatannol), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof to I-1 (isorapontigenin), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, being approximately 1:3.75. ii) Methods and uses of pterostilbene compounds

[0093] In some embodiments, the applicants have shown that pterostilbene is active against resveratrol-resistant cell lines. Therefore, the application relates to a method for treating or preventing resveratrol-resistant cancer in subjects requiring treatment or prevention of resveratrol-resistant cancer, comprising administering an effective amount of pterostilbene to the subjects. [ka] The method includes the step of administering a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

[0094] The application also includes the use of pterostilbene or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof for the treatment of resveratrol-resistant cancer in subjects; the use of pterostilbene or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof for the preparation of a medicament for the treatment or prevention of resveratrol-resistant cancer in subjects; and pterostilbene or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof for use for the treatment or prevention of resveratrol-resistant cancer in subjects.

[0095] In some embodiments, resveratrol-resistant cancer is a papillomavirus-associated cancer or precancerous (dysplasia). Therefore, in some embodiments, methods and uses of pterostilbene, or its pharmaceutically acceptable salts, prodrugs, and / or solvates, are intended for treating or preventing resveratrol-resistant papillomavirus-associated cancer or precancerous conditions.

[0096] In some embodiments, the resveratrol-resistant cancer is a papillomavirus-associated cancer. In some embodiments, the papillomavirus-associated cancer is selected from cervical cancer, anal cancer, oropharyngeal cancer, penile cancer, vaginal cancer, vulvar cancer, oral cancer, and skin cancer, as well as combinations thereof. In some embodiments, the papillomavirus-associated cancer is cervical cancer.

[0097] In some embodiments, papillomavirus-associated cancer is cancer caused by one or more HPV genotypes selected from 16(HPV-16), 18(HPV-18), 31(HPV-31), 33(HPV-33), 35(HPV-35), 39(HPV-39), 45(HPV-45), 51(HPV-51), 52(HPV-52), 56(HPV-56), 58(HPV-58), 59(HPV-59), and 68(HPV-68). In some embodiments, papillomavirus-associated cancer is cancer caused by one or both of HPV genotypes 16(HPV-16) and 18(HPV-18). In some embodiments, papillomavirus-associated cancer is cancer caused by HPV genotype 16(HPV-16). In some embodiments, papillomavirus-associated cancer is cancer caused by HPV genotype 18 (HPV-18).

[0098] In some embodiments, pterostilbene, or a pharmaceutically acceptable salt thereof, prodrug, and / or solvate thereof, treats or prevents resveratrol-resistant papillomavirus-associated cancer or precancerous disease by inhibiting papillomavirus replication.

[0099] The applicants have further demonstrated that pterostilbene, or a pharmaceutically acceptable salt thereof, a prodrug, and / or solvate thereof, when combined with curcumin and catechin, exhibits further improved activity against various cancer cell lines. Accordingly, in some embodiments, the above methods and uses involve administering to a subject an effective amount of pterostilbene, or a pharmaceutically acceptable salt thereof, a prodrug, and / or solvate thereof, in combination with curcuminoids and catechin.

[0100] In some embodiments, curcuminoids, catechins, and pterostilbene, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, are administered or used in molar ratios of curcuminoids to catechins to pterostilbene, or their pharmaceutically acceptable salts, prodrugs, and / or solvates of about 1-16:0.25-4:1-40, about 1-16:1-4:10-40, about 1-10:1-3:1-30, about 4-12:1-3:15-35, or about 6-8:2-3:20-30. In some embodiments, curcuminoids, catechins, and pterostilbene, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, are administered or used in molar ratios of curcuminoids to catechins to pterostilbene, or their pharmaceutically acceptable salts, prodrugs, and / or solvates of about 1 to 16:1 to 4:10 to 40, about 1 to 10:1 to 3:1 to 30, about 4 to 12:1 to 3:15 to 35, or about 6 to 8:2 to 3:20 to 30. In some embodiments, curcuminoids, catechins, and pterostilbene, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, are administered or used in molar ratios of curcuminoids to catechins to pterostilbene, or their pharmaceutically acceptable salts, prodrugs, and / or solvates of about 6:2:25, about 8:4:25, about 4:1:20, about 4:2:25, about 8:1:25, about 4:1:6, or about 8:2:25.

[0101] In some embodiments, the curcuminoid is selected from curcumin (diferuloylmethane), tetrahydrocurcumin, demethoxycurcumin, tetrahydrodemethoxycurcumin, bisdemethoxycurcumin, tetrahydrobisdemethoxycurcumin, or curcumin esters, and combinations thereof. In some embodiments, the curcuminoid is curcumin.

[0102] In some embodiments, the catechin is selected from epicatechin gallate (ECG), epigallocatechin gallate (EGCG or EGCg), epicatechin (EC), epigallocatechin (EGC), (-)-epigallocatechin gallate ((-)-EGCG), (-)-epikecatechin gallate ((-)-ECG), (-)-epigallocatechin ((-)-EGC), (+)-gallogallate ((+)-GCG), (-)-epicatechin ((-)-EC), (+)gallocatechin ((+)-GC), and (+)-catechin ((+)-C). In some embodiments, the catechin is (-)-epigallocatechin gallate.

[0103] In exemplary embodiments, the curcuminoid is curcumin, the catechin is (-)-epigallocatechin gallate, and the molar ratio of curcumin to (-)-epigallocatechin gallate to pterostilbene, or a pharmaceutically acceptable salt thereof, prodrug, and / or solvate is about 8:2:25. Accordingly, the present application relates to a method for treating or prophylacticizing resveratrol-resistant cancer in a subject requiring treatment or prophylactic treatment of resveratrol-resistant cancer, the method comprising the step of administering to the subject an effective amount of pterostilbene, or a pharmaceutically acceptable salt thereof, prodrug, and / or solvate, in combination with a curcuminoid and a catechin. The method comprises a curcuminoid being curcumin, a catechin being (-)-epigallocatechin gallate, and a molar ratio of curcumin to (-)-epigallocatechin gallate to pterostilbene, or a pharmaceutically acceptable salt thereof, prodrug, and / or solvate, being approximately 8:2:25. iii) Method and use of combinations of compound I and pterostilbene

[0104] The applicants have shown that combinations of one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, with pterostilbene, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof exhibit improved activity and synergistic effects against various cancer cell lines.

[0105] Therefore, this application also relates to a method for treating or preventing papillomavirus infection in a subject requiring treatment or prevention of papillomavirus infection, comprising delivering to the subject an effective amount of one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof [ka] (In the formula, X 1 ~X 4 (This is defined above with respect to Equation I.) The method also includes the step of administering pterostilbene, or a pharmaceutically acceptable salt thereof, prodrug, and / or solvate thereof, in combination with the pterostilbene.

[0106] The application also includes the use of one or more compounds of Formula I in combination with pterostilbene or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof for treating or prophylactic papillomavirus infection in subjects; the use of one or more compounds of Formula I in combination with pterostilbene or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof for preparing a medicament for treating or prophylactic papillomavirus infection in subjects; and the use of one or more compounds of Formula I in combination with pterostilbene or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof for use for treating or prophylactic papillomavirus infection in subjects.

[0107] In some embodiments, a papillomavirus infection is an infection with at least one papillomavirus. In some embodiments, a papillomavirus infection is a human papillomavirus (HPV) infection. In some embodiments, HPV infections are 1 (HPV-1), 2 (HPV-2), 3 (HPV-3), 4 (HPV-4), 5 (HPV-5), 6 (HPV-6), 8 (HPV-8), 11 (HPV-11), 16 (HPV-16), 18 (HPV-18), 21 (HPV-21), 22 (HPV-22), 23 (HPV-23), 27 (HPV-27), 29 (HPV-29), 31 (HPV-31), 33 (HPV-33), 35 (HPV-35), 39 (HPV-39), 45 (HPV-45), 51 (HPV-51), 52 (HPV-52), 56 (HPV-56), 57 (HPV-57) HPV infection is an infection of one or more HPV genotypes selected from 58 (HPV-58), 59 (HPV-59), and 68 (HPV-68). In some embodiments, HPV infection is an infection of one or more HPV genotypes selected from 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. In some embodiments, HPV genotypes selected from 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68 cause cancer. In some embodiments, HPV infection is an infection of one or more HPV genotypes selected from HPV genotypes 16 and 18. In some embodiments, HPV infection is an infection of HPV genotype 16. In some embodiments, HPV infection is an infection of HPV genotype 18. In some embodiments, HPV infection is an infection with one or more HPV genotypes selected from 1, 3, 27, 29, and 57. In some embodiments, HPV genotypes selected from 1, 3, 27, 29, or 57 cause common warts. In some embodiments, HPV infection is an infection with one or more HPV genotypes selected from 1, 2, 3, 4, 27, 29, and 57. In some embodiments, HPV genotypes selected from 1, 2, 3, 4, 27, 29, and 57 cause plantar warts, for example, deep palmoplantar warts.

[0108] The application also includes a method for treating or preventing a disease, disorder, or condition caused by a papillomavirus infection, comprising the step of administering a therapeutically effective amount of one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, in combination with pterostilbene, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, to a subject in need.

[0109] This application also includes the use of one or more compounds of Formula I in combination with pterostilbene or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof for the treatment or prevention of diseases, disorders, or conditions caused by papillomavirus infection, and the use of one or more compounds of Formula I in combination with pterostilbene or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof for the preparation of pharmaceuticals for the treatment or prevention of diseases, disorders, or conditions caused by papillomavirus infection. This application further includes one or more compounds of Formula I in combination with pterostilbene or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof for use in the treatment or prevention of diseases, disorders, or conditions caused by papillomavirus infection.

[0110] In some embodiments, the disease, disorder, or condition caused by papillomavirus infection is papillomavirus-associated cancer or precancerous (dysplasia). In some embodiments, the disease, disorder, or condition caused by papillomavirus infection is papillomavirus-associated cancer. In some embodiments, papillomavirus-associated cancer is selected from cervical cancer, anal cancer, oropharyngeal cancer, penile cancer, vaginal cancer, vulvar cancer, oral cancer, and skin cancer, and combinations thereof. In some embodiments, papillomavirus-associated cancer is cervical cancer.

[0111] In some embodiments, papillomavirus-associated cancer is cancer caused by one or more HPV genotypes selected from 16(HPV-16), 18(HPV-18), 31(HPV-31), 33(HPV-33), 35(HPV-35), 39(HPV-39), 45(HPV-45), 51(HPV-51), 52(HPV-52), 56(HPV-56), 58(HPV-58), 59(HPV-59), and 68(HPV-68). In some embodiments, papillomavirus-associated cancer is cancer caused by one or more HPV genotypes selected from 16(HPV-16) and 18(HPV-18). In some embodiments, papillomavirus-associated cancer is cancer caused by one or both of HPV genotypes 16(HPV-16) and 18(HPV-18). In some embodiments, papillomavirus-associated cancer is cancer caused by HPV genotype 16 (HPV-16). In some embodiments, papillomavirus-associated cancer is cancer caused by HPV genotype 18 (HPV-18).

[0112] In some embodiments, papillomavirus-associated cancer is a resveratrol-resistant papillomavirus-associated cancer as defined above. Therefore, in some embodiments, papillomavirus-associated cancer is a resveratrol-resistant cancer. Therefore, in some embodiments, a disease, disorder, or condition caused by a papillomavirus infection is a resveratrol-resistant cancer.

[0113] In some embodiments, the disease, disorder, or condition caused by papillomavirus infection is selected from warts and laryngeal papillomas, and combinations thereof. In some embodiments, the disease, disorder, or condition caused by papillomavirus infection is warts. In some embodiments, warts are caused by one or more of HPV-2, HPV-3, HPV-4, HPV-27, HPV-29, and HPV-57. In some embodiments, warts are selected from common warts, flat warts, filiform warts, mosaic warts, plantar warts, perinatal warts, and genital warts, and combinations thereof. In some embodiments, genital warts are selected from vaginal and anal warts, and combinations thereof. In some embodiments, warts are plantar warts.

[0114] In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, is combined with pterostilbene, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, to treat or prevent papillomavirus infection or treat or prevent disease, disorder, or condition caused by papillomavirus infection by inhibiting papillomavirus replication.

[0115] In some embodiments, one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, as well as pterostilbene, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, are administered or used in molar ratios of about 8:1 to about 1:10, about 4:1 to about 1:10, about 2:1 to about 1:10, about 8:1 to about 1:5, about 4:1 to about 1:5, about 2:1 to about 1:5, about 0.5:1 to about 1:10, about 0.5:1 to about 1:8, about 0.5:1 to about 1:5, about 0.5:1 to about 1:4, about 0.5:1 to about 1:3.75, about 0.5:1 to about 1:4, about 1:1 to about 1:4, about 1:1 to about 1:3.75, about 1:1 to about 1:3, and about 1:1 to about 1:2. In some embodiments, one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, as well as pterostilbene, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, are administered or used in molar ratios of about 0.5:1 to about 1:3.75, about 0.5:1 to about 1:4, about 1:1 to about 1:4, about 1:1 to about 1:3.75, about 1:1 to about 1:3, and about 1:1 to about 1:2. In some embodiments, one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, as well as pterostilbene, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, are administered or used in molar ratios of about 1:8, about 1:5, about 1:4, about 1:3.75, about 1:3, about 1:2, or about 1:1. In some embodiments, one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, as well as pterostilbene, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, are administered or used in molar ratios of about 1:5, about 1:4, about 1:3.75, about 1:3, about 1:2, or about 1:1. In some embodiments, one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, as well as pterostilbene, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, are administered or used in molar ratios of about 1:5 to about 1:1.In some embodiments, one or more compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, and pterostilbene, or its pharmaceutically acceptable salts, prodrugs, and / or solvates, are administered or used in a molar ratio of about 1:5. In some embodiments, one or more compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, and pterostilbene, or its pharmaceutically acceptable salts, prodrugs, and / or solvates, are administered or used in a molar ratio of about 1:3.75. In some embodiments, one or more compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, and pterostilbene, or its pharmaceutically acceptable salts, prodrugs, and / or solvates, are administered or used in a molar ratio of about 1:1.

[0116] The applicants have further demonstrated that combinations of one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, with pterostilbene, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, when further combined with curcumin and catechin, exhibit improved activity and synergistic effects against various cancer cell lines. Accordingly, in some embodiments, the above methods and uses involve administering to a subject an effective amount of one or more compounds of formula I, or pharmaceutically acceptable salts thereof, in combination with pterostilbene, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, or in combination with pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, and further in combination with curcuminoids and catechins.

[0117] In some embodiments, curcuminoids, catechins, and one or more compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, and pterostilbene, or its pharmaceutically acceptable salts, prodrugs, and / or solvates, are administered or used in molar ratios of curcuminoids to catechins to one or more compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, and pterostilbene, or its pharmaceutically acceptable salts, prodrugs, and / or solvates of about 1-16:0.25-4:1-40, about 1-16:1-4:10-40, about 1-10:1-3:1-30, about 4-12:1-3:15-35, or about 6-8:2-3:20-30. In some embodiments, curcuminoids, catechins, and one or more compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, and pterostilbene, or its pharmaceutically acceptable salts, prodrugs, and / or solvates, are administered or used in molar ratios of curcuminoids to catechins to one or more compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, and pterostilbene, or its pharmaceutically acceptable salts, prodrugs, and / or solvates of about 16:1 to 4:10 to 40, about 1 to 10:1 to 3:1 to 30, about 4 to 12:1 to 3:15 to 35, or about 6 to 8:2 to 3:20 to 30. In some embodiments, curcuminoids, catechins, and one or more compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, and pterostilbene, or its pharmaceutically acceptable salts, prodrugs, and / or solvates, are administered or used in molar ratios of curcuminoids to catechins to one or more compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, and pterostilbene, or its pharmaceutically acceptable salts, prodrugs, and / or solvates of about 16:2:25, about 8:4:25, about 4:1:20, about 4:2:25, about 8:1:25, about 4:1:6, or about 8:2:25.

[0118] In some embodiments, curcuminoids, catechins, and one or more compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, and pterostilbene, or its pharmaceutically acceptable salts, prodrugs, and / or solvates, are administered or used in a molar ratio of curcuminoids to catechins to one or more compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, and pterostilbene, or its pharmaceutically acceptable salts, prodrugs, and / or solvates of about 8:2:25.

[0119] In some embodiments, the curcuminoid is selected from curcumin (diferuloylmethane), tetrahydrocurcumin, demethoxycurcumin, tetrahydrodemethoxycurcumin, bisdemethoxycurcumin, tetrahydrobisdemethoxycurcumin, curcumin esters, and combinations thereof. In some embodiments, the curcuminoid is curcumin.

[0120] In some embodiments, the catechin is selected from epicatechin gallate (ECG), epigallocatechin gallate (EGCG or EGCg), epicatechin (EC), and epigallocatechin (EGC). (-)-Epigallocatechin gallate ((-)-EGCG), (-)-Epicatechin gallate ((-)-ECG), (-)-Epigallocatechin ((-)-EGC), (+)-Gallogallate ((+)-GCG), (-)-Epicatechin ((-)-EC), (+)Gallocatechin ((+)-GC), and (+)-Catechin ((+)-C). In some embodiments, the catechin is (-)-Epigallocatechin gallate.

[0121] In exemplary embodiments, one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, is I-1(isorapontigenin), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof; the curcuminoid is curcumin; the catechin is (-)-epigallocatechin gallate; and the molar ratio of I-1(isorapontigenin), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, to pterostilbene, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof is approximately 3.75:1. In some embodiments, the molar ratio of curcumin to (-)-epigallocatechin gallate to I-1 (isorapontigenin), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, and pterostilbene, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, is approximately 8:2:25.

[0122] In another exemplary embodiment, one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, is I-3(piceatannol), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, the curcuminoid is curcumin, the catechin is (-)-epigallocatechin gallate, and the molar ratio of I-3(piceatannol), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof to pterostilbene, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof is about 1:5 to about 1:1. In another exemplary embodiment, one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, is I-3(piceatannol), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, the curcuminoid is curcumin, the catechin is (-)-epigallocatechin gallate, and the molar ratio of I-3(piceatannol), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof to pterostilbene, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof is about 1:5. In some embodiments, the molar ratio of I-3(piceatannol), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof to pterostilbene, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof is about 1:1. In some embodiments, one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, is I-3(piceatannol), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof; the curcuminoid is curcumin; the catechin is (-)-epigallocatechin gallate; and the molar ratio of curcumin to (-)-epigallocatechin gallate to I-3(piceatannol), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, and pterostilbene, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, is approximately 8:2:25.Accordingly, in exemplary embodiments, the present application relates to a method for treating or preventing a papillomavirus infection in a subject requiring treatment or prevention of a papillomavirus infection, the method comprising the step of administering to the subject an effective amount of one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, in combination with pterostilbene, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, and further in combination with curcuminoids and catechins. One or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, are I-3 (piceatannol), or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, the curcuminoid is curcumin, and the catechin is (-)-epigallocatechin gallate. The method comprises a molar ratio of I-3 (piceatannol), or a pharmaceutically acceptable salt thereof, prodrug, and / or solvate, to pterostilbene, or a pharmaceutically acceptable salt thereof, prodrug, and / or solvate, being about 1:5 or about 1:1, and a molar ratio of curcumin to (-)-epigallocatechin gallate to I-3 (piceatannol), or a pharmaceutically acceptable salt thereof, prodrug, and / or solvate, and pterostilbene, or a pharmaceutically acceptable salt thereof, prodrug, and / or solvate, being about 8:2:25.

[0123] In the context of treating or preventing papillomavirus infection or diseases caused by papillomavirus infection as described above, an effective amount of one or more compounds of formula I, or their salts, prodrugs, and / or solvates, pterostilbene, or its salts, prodrugs, and / or solvates, or combinations thereof, is, for example, an amount that reduces papillomavirus infection compared to papillomavirus infection without administration of the compound, or its salts, prodrugs, and / or solvates. "Reducing papillomavirus infection" means, for example, a reduction in the amount of viral load in the subject and / or a reduction in the symptoms of infection. "Reduce" means any detectable decrease or reduction in the amount of papillomavirus in the presence of one or more compounds of formula I, or their salts, prodrugs, and / or solvates, pterostilbene, or its salts, prodrugs, and / or solvates, or combinations thereof, compared to conditions that are otherwise the same except for the absence of one or more compounds of formula I, or their salts, prodrugs, and / or solvates, or combinations thereof.

[0124] The effective dose may vary depending on factors such as the subject's disease state, age, sex, and / or weight. The amount of one or more given compounds corresponding to such a dose will vary depending on various factors such as the given drug or compound, pharmaceutical formulation, route of administration, and type of papillomavirus infection in the treated subject, but in any case, it can be conventionally determined by those skilled in the art. The effective dose is the amount that manifests as improvement or reduction of any disease symptoms after treatment with it.

[0125] In some embodiments, one or more compounds of formula I, or their salts, prodrugs, and / or solvates, pterostilbene, or its salts, prodrugs, and / or solvates, or combinations thereof, are administered or used as quickly as possible after exposure to or potential exposure to papillomavirus. In some embodiments, one or more compounds of formula I, or their salts, prodrugs, and / or solvates, pterostilbene, or its salts, prodrugs, and / or solvates, or combinations thereof, are administered or used until treatment of the papillomavirus infection is achieved. For example, until complete elimination of the papillomavirus is achieved, or until the number of papillomaviruses is reduced to the point where the subject's defense mechanisms are no longer overwhelmed and any remaining viruses can be killed.

[0126] In one embodiment, one or more compounds of formula I, or their salts, prodrugs, and / or solvates, pterostilbene, or its salts, prodrugs, and / or solvates, or combinations thereof, are administered or used as quickly as possible before anticipated exposure to papillomavirus.

[0127] In one embodiment, one or more compounds of formula I, or their salts, prodrugs, and / or solvates, pterostilbene, or its salts, prodrugs, and / or solvates, or combinations thereof, are administered at least once a week. However, in another embodiment, one or more compounds of formula I, or their salts, prodrugs, and / or solvates, pterostilbene, or its salts, prodrugs, and / or solvates, or combinations thereof, are administered to the subject once every two weeks, three weeks, or one month. In yet another embodiment, one or more compounds of formula I, or their salts, prodrugs, and / or solvates, pterostilbene, or its salts, prodrugs, and / or solvates, or combinations thereof, are administered from about once a week to about once a day. In another embodiment, one or more compounds of formula I, or their salts, prodrugs, and / or solvates, pterostilbene, or its salts, prodrugs, and / or solvates, or combinations thereof, are administered two, three, four, five, or six times daily. The length of treatment depends on various factors, including the severity of the disease, disorder, or condition caused by the papillomavirus infection or papillomavirus infection genotype, the age of the subject, and the concentration and / or activity of one or more compounds of formula I, or their salts, prodrugs, and / or solvates, pterostilbene, or its salts, prodrugs, and / or solvates, or combinations thereof. It is also understood that the effective dose of one or more compounds used in treatment may increase or decrease over the course of a particular treatment regimen. Changes in dosage may be elicited and revealed by standard diagnostic assays known in the art. In some cases, chronic administration is required. For example, one or more compounds of formula I, or their salts, prodrugs, and / or solvates, pterostilbene, or its salts, prodrugs, and / or solvates, or combinations thereof, are administered to the subject in an amount and duration sufficient to treat the subject.

[0128] In one embodiment, the subject is a mammal. In another embodiment, the subject is a human. In another embodiment, the subject is a non-human animal. Therefore, the compounds, methods, and uses of this application are intended for both human and veterinary papillomavirus infections or diseases, disorders, or conditions caused by papillomavirus infections.

[0129] One or more compounds of formula I, or their salts, prodrugs, and / or solvates, pterostilbene, or its salts, prodrugs, and / or solvates, or combinations thereof, may be used or administered alone or in combination with other known agents useful for treating one or more diseases, disorders, or conditions caused by papillomavirus infection as described herein.

[0130] When used or administered in combination with other drugs or treatments, it is one embodiment that one or more compounds of Formula I, or their salts, prodrugs, and / or solvates, pterostilbene, or its salts, prodrugs, and / or solvates, or combinations thereof, are used or administered simultaneously with the drug or treatment. As used herein, “concurrent administration” or “concurrent use” of compounds, drugs, or treatments to a subject means providing them such that at least two of the compounds, drugs, and treatments become simultaneously biologically active in the individual. The exact details of administration or use will depend on the pharmacokinetics of the compounds, drugs, or treatments in the presence of each other, and the exact details of administration or use may include administering or using the compounds, drugs, or treatments within a few hours of each other, or even administering or using one compound, drug, or treatment within 24 hours of the other (other) administration or use, where the pharmacokinetics are favorable. Designing a suitable dosing regimen is customary to those skilled in the art. In specific embodiments, compounds, drugs, or treatments are administered or used substantially simultaneously, i.e., within minutes of each other, or, in the case of two or more compounds or drugs being administered or used, in a single composition. A further embodiment of this application is that combinations of compounds, drugs, or treatments are administered or used on a subject in a non-simultaneous manner.

[0131] In the methods and embodiments of use of this application, one or more compounds of formula I, or their salts, prodrugs, and / or solvates, pterostilbene, or its salts, prodrugs, and / or solvates, or combinations thereof, are administered or used orally. In some embodiments, one or more compounds of formula I, or their salts, prodrugs, and / or solvates, pterostilbene, or its salts, prodrugs, and / or solvates, or combinations thereof, are administered or used parenterally. In some embodiments, parenteral administration is topical administration.

[0132] The dosage of one or more compounds of formula I, or their salts, prodrugs, and / or solvates, pterostilbene, or its salts, prodrugs, and / or solvates, or combinations thereof, may vary depending on numerous factors, including the pharmacodynamic properties of the compound, the mode of administration, the recipient's age, health status, and weight, the nature and severity of symptoms, the frequency of treatment, and, if present, the type of parallel treatment, as well as the clearance rate of the compound in the subject to be treated. A person skilled in the art can determine the appropriate dosage based on the factors described above. One or more compounds of formula I, or their salts, prodrugs, and / or solvates, pterostilbene, or its salts, prodrugs, and / or solvates, or combinations thereof, may first be administered in a suitable dosage that can be adjusted as needed in response to the clinical response. The dosage is generally selected to maintain serum compound levels of about 0.01 μg / cc to about 1000 μg / cc or about 0.1 μg / cc to about 100 μg / cc. Typical oral doses of one or more compounds of formula I, or their salts, prodrugs, and / or solvates, pterostilbene, or its salts, prodrugs, and / or solvates, or combinations thereof, for adults range from approximately 1 mg to approximately 1000 mg per day, preferably in the range of approximately 50 mg, approximately 100 mg, approximately 150 mg, approximately 200 mg, approximately 250 mg, approximately 300 mg, approximately 350 mg, approximately 400 mg, approximately 450 mg, or approximately 500 mg per day. For parenteral administration or use, typical doses are approximately 0.001 mg / kg to approximately 10 mg / kg, approximately 0.01 mg / kg to approximately 10 mg / kg, approximately 0.01 mg / kg to approximately 1 mg / kg, or approximately 0.1 mg / kg to approximately 1 mg / kg, and these are administered or used. For oral administration or use, typical doses are approximately 0.001 mg / kg to 10 mg / kg or approximately 0.1 mg / kg to 10 mg / kg. For administration or use in suppository form, typical doses are approximately 0.1 mg / kg to 10 mg / kg.In some embodiments of this application, the composition is formulated for oral administration or use, and the compound is preferably in the form of tablets containing 0.25, 0.5, 0.75, 1.0, 5.0, 10.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 75.0, 80.0, 90.0, 100.0, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of the active ingredient per tablet. One or more compounds of formula I, or their salts, prodrugs, and / or solvates, pterostilbene, or its salts, prodrugs, and / or solvates, or combinations thereof may be administered or used in a single dose once daily, once weekly, or once monthly, or the total daily dose may be divided into two, three, four, five, or six daily doses.

[0133] In some embodiments, the pharmaceutically acceptable salts are acid addition salts or base addition salts. The selection of a suitable salt can be made by those skilled in the art (see, for example, S.M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19).

[0134] Suitable or compatible acid addition salts for the treatment of a subject are any non-toxic organic or inorganic acid addition salts of any basic compound. Examples of basic compounds that form acid addition salts include compounds containing an amine group. Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, as well as acidic metal salts, such as sodium monohydrogen orthophosphate and potassium bisulfate. Exemplary organic acids that form suitable salts include monocarboxylic acids, dicarboxylic acids, and tricarboxylic acids. Examples of such organic acids include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, mandelic acid, salicylic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid, and other sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, and 2-hydroxyethanesulfonic acid. In some embodiments, monosulfonic or disulfonic acid salts are formed, and such salts exist in either a hydrated form, a solvated form, or a substantially anhydrous form. Generally, acid addition salts are more soluble in water and various hydrophilic organic solvents and generally exhibit higher melting points compared to their free base forms. The criteria for selecting a suitable salt are known to those skilled in the art. Other pharmaceutically unacceptable salts (e.g., oxalates, but not limited to these) may be used, for example, in the isolation of the compounds of this application for laboratory use, or for subsequent conversion to pharmaceutically acceptable acid addition salts.

[0135] Suitable or compatible base addition salts for the treatment of a subject are any non-toxic organic or inorganic base addition salts of any acidic compound. Examples of acidic compounds that form base addition salts include compounds containing a carboxylic acid group. Exemplary inorganic bases that form suitable salts include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or barium hydroxide, as well as ammonia. Exemplary organic bases that form suitable salts include aliphatic, alicyclic, or aromatic organic amines, such as isopropylamine, methylamine, trimethylamine, picoline, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydravamin, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins. Exemplary organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. A suitable salt selection may be useful, for example, one that prevents hydrolysis of other ester functional groups (if present) in the compound. Criteria for selecting a suitable salt are known to those skilled in the art.

[0136] One or more compounds of formula I, or their salts, prodrugs, and / or solvates, or pterostilbene, or its salts, prodrugs, and / or solvates, may be prepared using, for example, a pharmaceutically acceptable solvent. Examples of such solvents include water (the resulting solvate is called a hydrate) and ethanol. A preferred solvent is physiologically tolerable at the administered dose.

[0137] One or more compounds of formula I, or salts, prodrugs, and / or solvates thereof, or pterostilbene, or salts, prodrugs, and / or solvates thereof, may further exist in various polymorphic forms, and any polymorphs or mixtures thereof formed are intended to be within the scope of this application.

[0138] One or more compounds of formula I, or their salts, prodrugs, and / or solvates, or pterostilbene, or its salts, prodrugs, and / or solvates, may also be radiolabeled, and therefore all radiolabeled versions of the compounds of this application are included within the scope of this application. The compounds of this application also include those in which one or more radioactive atoms are incorporated into their structure.

[0139] In some embodiments, one or more compounds of formula I, or their salts, prodrugs, and / or solvates, and / or pterostilbene, or its salts, prodrugs, and / or solvates, are in pharmaceutically acceptable solvate form. In some embodiments, one or more compounds of formula I, or their salts, prodrugs, and / or solvates, and / or pterostilbene, or its salts, prodrugs, and / or solvate compounds, are in a neutral form (i.e., not salts). III. Compositions of this Application i) Composition containing a compound of formula I

[0140] The compound of formula I is preferably formulated into a composition by conventional methods, using one or more carriers as needed.

[0141] Therefore, this application also relates to compositions comprising one or more compounds of formula I, or pharmaceutically acceptable salts thereof, prodrugs, and / or solvates, curcuminoids, and catechins, [ka] During the ceremony, X 1 ~X 4 However, this also includes compositions as defined above with respect to Formula I in "Method and Use of this Application."

[0142] In some embodiments, the composition further includes a carrier.

[0143] Compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, are preferably formulated into pharmaceutical compositions for administration to a subject in a biocompatible form suitable for in vivo administration. Accordingly, this application further relates to pharmaceutical compositions comprising one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, curcuminoids, and catechins, [ka] During the ceremony, X 1 ~X 4 The invention includes a pharmaceutical composition which is defined above with respect to Formula I in "Method and Use of this Application".

[0144] In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0145] In some embodiments, the composition comprises two or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof. In exemplary embodiments, the composition comprises two compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof.

[0146] In some embodiments, if the composition contains two compounds, the two compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, are present in the composition in molar ratios of about 0.5:1 to about 1:10, about 0.5:1 to about 1:8, about 0.5:1 to about 1:5, about 0.5:1 to about 1:4, about 0.5:1 to about 1:3.75, about 0.5:1 to about 1:4, about 1:1 to about 1:4, about 1:1 to about 1:3.75, about 1:1 to about 1:3, or about 1:1 to about 1:2. In some embodiments, two compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, are present in the composition in molar ratios of about 0.5:1 to about 1:3.75, about 0.5:1 to about 1:4, about 1:1 to about 1:4, about 1:1 to about 1:3.75, about 1:1 to about 1:3, and about 1:1 to about 1:2. In some embodiments, two compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, are present in the composition in molar ratios of about 1:8, about 1:5, about 1:4, about 1:3.75, about 1:3, about 1:2, or about 1:1. In some embodiments, two compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, are present in the composition in molar ratios of about 1:4, about 1:3.75, about 1:3, about 1:2, or about 1:1. In some embodiments, two compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, are present in the composition in a molar ratio of about 1:1.

[0147] In some embodiments, curcuminoids, catechins, and one or more, preferably two or more, compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates are present in the composition in a molar ratio of curcuminoids to catechins to one or more, preferably two or more, compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates of about 1-16:0.25-4:1-40, about 1-16:1-4:10-40, about 1-10:1-3:1-30, about 4-12:1-3:15-35, or about 6-8:2-3:20-30. In some embodiments, curcuminoids, catechins, and one or more compounds of formula I, preferably two or more, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof are present in the composition in a molar ratio of curcuminoids to catechins to one or more compounds of formula I, preferably two or more, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof of about 16:1 to 4:10 to 40, about 1 to 10:1 to 3:1 to 30, about 4 to 12:1 to 3:15 to 35, or about 6 to 8:2 to 3:20 to 30. In some embodiments, curcuminoids, catechins, and one or more, preferably two or more, compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates are present in the composition in a molar ratio of curcuminoids to catechins to one or more, preferably two or more, compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates of about 16:2:25, about 8:4:25, about 4:1:20, about 4:2:25, about 8:1:25, about 4:1:6, or about 8:2:25. In some embodiments, curcuminoids, catechins, and one or more compounds of formula I, preferably two or more, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof are present in the composition in a molar ratio of curcuminoids to catechins to one or more compounds of formula I, preferably two or more, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof of about 8:2:25.

[0148] In some embodiments, the curcuminoid is selected from curcumin (diferuloylmethane), tetrahydrocurcumin, demethoxycurcumin, tetrahydrodemethoxycurcumin, bisdemethoxycurcumin, tetrahydrobisdemethoxycurcumin, or curcumin esters, and combinations thereof. In some embodiments, the curcuminoid is curcumin.

[0149] In some embodiments, the catechin is selected from epicatechin gallate (ECG), epigallocatechin gallate (EGCG or EGCg), epicatechin (EC), epigallocatechin (EGC), (-)-epigallocatechin gallate ((-)-EGCG), (-)-epikecatechin gallate ((-)-ECG), (-)-epigallocatechin ((-)-EGC), (+)-gallogallate ((+)-GCG), (-)-epicatechin ((-)-EC), (+)gallocatechin ((+)-GC), and (+)-catechin ((+)-C). In some embodiments, the catechin is (-)-epigallocatechin gallate.

[0150] In exemplary embodiments, one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, are selected from I-1 (isorapontigenin), or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, and I-3 (piceatannol), or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof.

[0151] In some embodiments, one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, is I-3(piceatannol), or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, the curcuminoid is curcumin, the catechin is (-)-epigallocatechin gallate, and the molar ratio of curcumin to (-)-epigallocatechin gallate to I-3(piceatannol), or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof is about 8:2:25. Therefore, in exemplary embodiments, the present application relates to a pharmaceutical composition comprising one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, curcuminoids, and catechins. The present invention comprises a pharmaceutical composition in which one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, are I-3(piceatannol) or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, the curcuminoid is curcumin, the catechin is (-)-epigallocatechin gallate, and the molar ratio of curcumin to (-)-epigallocatechin gallate to I-3(piceatannol) or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof is approximately 8:2:25.

[0152] In some embodiments, the two compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, are I-1 (isorapontigenin), or its pharmaceutically acceptable salt, prodrug, and / or solvate, and I-3 (piceatannol), or its pharmaceutically acceptable salt, prodrug, and / or solvate, the curcuminoid is curcumin, the catechin is (-)-epigallocatechin gallate, and the I-3 (piceatannol), or its pharmaceutically acceptable salt, prodrug, and / or solvate, and the I-1 (isorapontigenin), or its pharmaceutically acceptable salt, prodrug, and / or solvate, are present in the composition in a molar ratio of I-3, or its pharmaceutically acceptable salt, prodrug, and / or solvate to I-1, or its pharmaceutically acceptable salt, prodrug, and / or solvate of about 1:3.75. In some embodiments, two or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, are I-1 (isorapontigenin), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, and I-3 (piceatannol), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, the curcuminoid is curcumin, the catechin is (-)-epigallocatechin gallate, and the I-3 (piceatannol), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, and I-1 (isorapontigenin), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, are present in the composition in a molar ratio of I-3, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof to I-1, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof of about 1:3.75. In some embodiments, the molar ratio of curcumin to (-)-epigallocatechin gallate to I-3 (piceatannol) or its pharmaceutically acceptable salt, prodrug, and / or solvate and I-1 (isorapontigenin) or its pharmaceutically acceptable salt, prodrug, and / or solvate is approximately 8:2:25.

[0153] One or more compounds of formula I, preferably two or more, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, are preferably used on their own, but are generally administered in the form of a composition in combination with an acceptable carrier. Depending on the method of administration, the composition comprises about 0.05% to about 99% by weight or about 0.10% to about 70% by weight of one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, as well as curcuminoids and catechins as needed, and about 1% to about 99.95% by weight or about 30% to about 99.90% by weight of an acceptable carrier, all weight percentages based on the composition as a whole. ii) Composition of pterostilbene compounds

[0154] Pterostilbene, or a pharmaceutically acceptable salt thereof, prodrug, and / or solvate thereof, is preferably formulated into a composition by conventional methods, using one or more carriers as needed. Pterostilbene, or a pharmaceutically acceptable salt thereof, prodrug, and / or solvate thereof, is preferably formulated into a pharmaceutical composition for administration to a subject in a biocompatible form suitable for in vivo administration.

[0155] Therefore, this application also relates to a pharmaceutical composition for treating or preventing resveratrol-resistant cancer in subjects requiring treatment or prevention of resveratrol-resistant cancer, comprising an effective amount of pterostilbene or a pharmaceutically acceptable salt thereof, a prodrug, and / or a solvate, curcuminoid, and catechin. [ka] This also includes pharmaceutical compositions.

[0156] In some embodiments, pterostilbene, or a pharmaceutically acceptable salt thereof, prodrug, and / or solvate thereof, is present in an amount effective in treating or preventing resveratrol-resistant cancer in the subject.

[0157] In some embodiments, the present application includes a method for treating or preventing resveratrol-resistant cancer in a subject requiring treatment or prevention of resveratrol-resistant cancer, the method comprising the step of administering to the subject one or more compositions comprising an effective amount of pterostilbene or a pharmaceutically acceptable salt thereof, a prodrug, and / or a solvate, a curcuminoid, and a catechin.

[0158] In some embodiments, the application also includes the use of one or more compositions comprising an effective amount of pterostilbene, or a pharmaceutically acceptable salt thereof, a prodrug, and / or solvate thereof, curcuminoids, and catechins, for the treatment or prevention of resveratrol-resistant cancer in subjects requiring treatment or prevention of resveratrol-resistant cancer. The application also includes the use of one or more compositions comprising an effective amount of pterostilbene, or a pharmaceutically acceptable salt thereof, a prodrug, and / or solvate thereof, curcuminoids, and catechins, for the preparation of a pharmacopoeia for the treatment or prevention of resveratrol-resistant cancer in subjects requiring treatment or prevention of resveratrol-resistant cancer. Furthermore, the application also includes one or more compositions comprising an effective amount of pterostilbene, or a pharmaceutically acceptable salt thereof, a prodrug, and / or solvate thereof, curcuminoids, and catechins, for use in the treatment or prevention of resveratrol-resistant cancer in subjects requiring treatment or prevention of resveratrol-resistant cancer.

[0159] In some embodiments, resveratrol-resistant cancer is defined as described in “Methods and Uses of Pterostilbene Compounds”.

[0160] In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0161] In some embodiments, curcuminoids, catechins, and pterostilbene, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, are present in the composition in molar ratios of curcuminoids to catechins to pterostilbene, or their pharmaceutically acceptable salts, prodrugs, and / or solvates of about 1-16:0.25-4:1-40, about 1-16:1-4:10-40, about 1-10:1-3:1-30, about 4-12:1-3:15-35, or about 6-8:2-3:20-3. In some embodiments, curcuminoids, catechins, and pterostilbene, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, are present in the composition in molar ratios of curcuminoids to catechins to pterostilbene, or their pharmaceutically acceptable salts, prodrugs, and / or solvates of about 1 to 16:1 to 4:10 to 40, about 1 to 10:1 to 3:1 to 30, about 4 to 12:1 to 3:15 to 35, or about 6 to 8:2 to 3:20 to 30. In some embodiments, curcuminoids, catechins, and pterostilbene, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, are present in the composition in molar ratios of curcuminoids to catechins to pterostilbene, or their pharmaceutically acceptable salts, prodrugs, and / or solvates of about 16:2:25, about 8:4:25, about 4:1:20, about 4:2:25, about 8:1:25, about 4:1:6, or about 8:2:25. In some embodiments, curcuminoids, catechins, and pterostilbene, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, are present in the composition in molar ratios of curcuminoids to catechins to pterostilbene, or their pharmaceutically acceptable salts, prodrugs, and / or solvates of about 8:2:25.

[0162] In some embodiments, the curcuminoid is selected from curcumin (diferuloylmethane), tetrahydrocurcumin, demethoxycurcumin, tetrahydrodemethoxycurcumin, bisdemethoxycurcumin, tetrahydrobisdemethoxycurcumin, or curcumin esters, and combinations thereof. In some embodiments, the curcuminoid is curcumin.

[0163] In some embodiments, the catechin is selected from epicatechin gallate (ECG), epigallocatechin gallate (EGCG or EGCg), epicatechin (EC), and epigallocatechin (EGC), (-)-epigallocatechin gallate ((-)-EGCG), (-)-epikecatechin gallate ((-)-ECG), (-)-epigallocatechin ((-)-EGC), (+)-gallogallate ((+)-GCG), (-)-epicatechin ((-)-EC), (+)gallocatechin ((+)-GC), and (+)-catechin ((+)-C). In some embodiments, the catechin is (-)-epigallocatechin gallate.

[0164] In exemplary embodiments, the curcuminoid is curcumin, the catechin is (-)-epigallocatechin gallate, and the molar ratio of curcumin to (-)-epigallocatechin gallate to pterostilbene or its pharmaceutically acceptable salt, prodrug, and / or solvate is about 8:2:25. Thus, in exemplary embodiments, the present application relates to a pharmaceutical composition for treating or prophylacticizing resveratrol-resistant cancer in a subject requiring treatment or prophylaxis of resveratrol-resistant cancer, the method comprising an effective amount of pterostilbene or its pharmaceutically acceptable salt, prodrug, and / or solvate, curcuminoid, and catechin. The pharmaceutical composition comprises curcumin as the curcuminoid, epigallocatechin gallate as the catechin, and a molar ratio of curcumin to epigallocatechin gallate to pterostilbene, or a pharmaceutically acceptable salt thereof, prodrug, and / or solvate, of approximately 8:2:25.

[0165] Pterostilbene, or its pharmaceutically acceptable salts, prodrugs, and / or solvates, are preferably used on their own, but are generally administered in the form of compositions combined with an acceptable carrier. Depending on the method of administration, the composition comprises about 0.05% to about 99% by weight or about 0.10% to about 70% by weight of pterostilbene, or its pharmaceutically acceptable salts, prodrugs, and / or solvates, curcuminoids, and optionally catechin, and about 1% to about 99.95% by weight or about 30% to about 99.90% by weight of an acceptable carrier, all weight percentages based on the composition as a whole. iii) Combination composition

[0166] This application also relates to one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof. [ka] (In the formula, X 1 ~X 4 (This is defined above with respect to Formula I in "Method and Use of this Application.") Pterostilbene, or its pharmaceutically acceptable salts, prodrugs, and / or solvates [ka] This also includes compositions that include the same thing in combination with the same thing.

[0167] In some embodiments, the composition further includes a carrier.

[0168] This application also relates to one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof. [ka] (In the formula, X 1 ~X 4(This is defined above with respect to Formula I in "Method and Use of this Application.") Pterostilbene, or its pharmaceutically acceptable salts, prodrugs, and / or solvates [ka] This also includes pharmaceutical compositions that contain them in combination.

[0169] In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0170] In some embodiments, one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, and pterostilbene, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, are present in the composition in molar ratios of about 8:1 to about 1:10, about 4:1 to about 1:10, about 2:1 to about 1:10, about 8:1 to about 1:5, about 4:1 to about 1:5, about 2:1 to about 1:5, about 0.5:1 to about 1:10, about 0.5:1 to about 1:8, about 0.5:1 to about 1:5, about 0.5:1 to about 1:4, about 0.5:1 to about 1:3.75, about 0.5:1 to about 1:4, about 1:1 to about 1:4, about 1:1 to about 1:3.75, about 1:1 to about 1:3, and about 1:1 to about 1:2. In some embodiments, one or more compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, and pterostilbene, or its pharmaceutically acceptable salts, prodrugs, and / or solvates, are present in the composition in molar ratios of about 0.5:1 to about 1:3.75, about 0.5:1 to about 1:4, about 1:1 to about 1:4, about 1:1 to about 1:3.75, about 1:1 to about 1:3, and about 1:1 to about 1:2. In some embodiments, one or more compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, and pterostilbene, or its pharmaceutically acceptable salts, prodrugs, and / or solvates, are present in the composition in molar ratios of about 1:8, about 1:5, about 1:4, about 1:3.75, about 1:3, about 1:2, or about 1:1. In some embodiments, one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, and pterostilbene, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, are present in the composition in molar ratios of about 1:5, about 1:4, about 1:3.75, about 1:3, about 1:2, or about 1:1. In some embodiments, pterostilbene, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, and one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, are present in the composition in molar ratios of about 1:5 to about 1:1.In some embodiments, pterostilbene, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, and one or more compounds of formula I, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, are present in the composition in a molar ratio of about 1:5. In some embodiments, one or more compounds of formula I, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, and pterostilbene, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, are present in the composition in a molar ratio of about 1:3.75. In some embodiments, one or more compounds of formula I, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, and pterostilbene, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, are present in the composition in a molar ratio of about 1:1.

[0171] In some embodiments, the composition further comprises curcuminoids and catechins.

[0172] In some embodiments, curcuminoids, catechins, and one or more compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, as well as pterostilbene, or its pharmaceutically acceptable salts, prodrugs, and / or solvates, are present in the composition in molar ratios of curcuminoids to catechins to one or more compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, as well as pterostilbene, or its pharmaceutically acceptable salts, prodrugs, and / or solvates, of about 1-16:0.25-4:1-40, about 1-16:1-4:10-40, about 1-10:1-3:1-30, about 4-12:1-3:15-35, or about 6-8:2-3:20-30. In some embodiments, curcuminoids, catechins, and one or more compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, as well as pterostilbene, or its pharmaceutically acceptable salts, prodrugs, and / or solvates, are present in the composition in molar ratios of curcuminoids to catechins to one or more compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, as well as pterostilbene, or its pharmaceutically acceptable salts, prodrugs, and / or solvates, of about 1-16:1-4:10-40, about 1-10:1-3:1-30, about 4-12:1-3:15-35, or about 6-8:2-3:20-30. In some embodiments, curcuminoids, catechins, and one or more compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, as well as pterostilbene, or its pharmaceutically acceptable salts, prodrugs, and / or solvates, are present in the composition in molar ratios of curcuminoids to catechins to one or more compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, as well as pterostilbene, or its pharmaceutically acceptable salts, prodrugs, and / or solvates, of about 6:2:25, about 8:4:25, about 4:1:20, about 4:2:25, about 8:1:25, about 4:1:6, or about 8:2:25.In some embodiments, curcuminoids, catechins, and one or more compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, and pterostilbene, or its pharmaceutically acceptable salts, prodrugs, and / or solvates, are present in the composition in a molar ratio of curcuminoids to catechins to one or more compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, and pterostilbene, or its pharmaceutically acceptable salts, prodrugs, and / or solvates of about 8:2:25.

[0173] In some embodiments, the curcuminoid is selected from curcumin (diferuloylmethane), tetrahydrocurcumin, demethoxycurcumin, tetrahydrodemethoxycurcumin, bisdemethoxycurcumin, tetrahydrobisdemethoxycurcumin, or curcumin esters, and combinations thereof. In some embodiments, the curcuminoid is curcumin.

[0174] In some embodiments, the catechin is selected from epicatechin gallate (ECG), epigallocatechin gallate (EGCG or EGCg), epicatechin (EC), and epigallocatechin (EGC), (-)-epigallocatechin gallate ((-)-EGCG), (-)-epikecatechin gallate ((-)-ECG), (-)-epigallocatechin ((-)-EGC), (+)-gallogallate ((+)-GCG), (-)-epicatechin ((-)-EC), (+)gallocatechin ((+)-GC), and (+)-catechin ((+)-C). In some embodiments, the catechin is (-)-epigallocatechin gallate.

[0175] In exemplary embodiments, one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, are selected from I-1 (isorapontigenin), or pharmaceutically acceptable salts, prodrugs, and / or solvates, and I-3 (piceatannol), or pharmaceutically acceptable salts, prodrugs, and / or solvates. In exemplary embodiments, one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, are I-3 (piceatannol), or pharmaceutically acceptable salts, prodrugs, and / or solvates.

[0176] In another exemplary embodiment, one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, is I-1(isorapontigenin), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, the curcuminoid is curcumin, the catechin is (-)-epigallocatechin gallate, and the molar ratio of I-1(isorapontigenin), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof to pterostilbene, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, is about 3.75:1. In some embodiments, one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, is I-1(isorapontigenin), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof; the curcuminoid is curcumin; and the catechin is (-)-epigallocatechin gallate. In some embodiments, the molar ratio of curcumin to (-)-epigallocatechin gallate to I-1(isorapontigenin), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, and pterostilbene, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, is about 8:2:25.

[0177] In another exemplary embodiment, one or more compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, are I-3(piceatannol), or its pharmaceutically acceptable salts, prodrugs, and / or solvates. In some embodiments, the curcuminoid is curcumin, and the catechin is (-)-epigallocatechin gallate. In some embodiments, the molar ratio of I-3(piceatannol), or its pharmaceutically acceptable salts, prodrugs, and / or solvates, to pterostilbene, or its pharmaceutically acceptable salts, prodrugs, and / or solvates is about 1:5 to about 1:1. In another exemplary embodiment, one or more compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, are I-3(piceatannol), or its pharmaceutically acceptable salts, prodrugs, and / or solvates. In some embodiments, the curcuminoid is curcumin, and the catechin is (-)-epigallocatechin gallate. In some embodiments, the molar ratio of I-3 (piceatannol), or a pharmaceutically acceptable salt, prodrug, and / or solvate to pterostilbene, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof is about 1:5. In some embodiments, the molar ratio of I-3 (piceatannol) to pterostilbene, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof is about 1:1. In some embodiments, the molar ratio of curcumin to (-)-epigallocatechin gallate to I-3 (piceatannol), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, and pterostilbene, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof is about 8:2:25.Therefore, in some embodiments, one or more compounds of formula I, or their pharmaceutically acceptable salts, prodrugs, and / or solvates, is I-3(piceatannol), or its pharmaceutically acceptable salts, prodrugs, and / or solvates; curcuminoid is curcumin; catechin is (-)-epigallocatechin gallate; the molar ratio of I-3(piceatannol), or its pharmaceutically acceptable salts, prodrugs, and / or solvates to pterostilbene, or its pharmaceutically acceptable salts, prodrugs, and / or solvates is about 1:5 to about 1:1; and the molar ratio of curcumin to (-)-epigallocatechin gallate to I-3(piceatannol), or its pharmaceutically acceptable salts, prodrugs, and / or solvates, and pterostilbene, or its pharmaceutically acceptable salts, prodrugs, and / or solvates is about 8:2:25. In some embodiments, one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, is I-3(piceatannol), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, the curcuminoid is curcumin, the catechin is (-)-epigallocatechin gallate, the molar ratio of I-3(piceatannol), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof to pterostilbene, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof is about 1:5, and the molar ratio of curcumin to (-)-epigallocatechin gallate to I-3(piceatannol), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof and pterostilbene, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof is about 8:2:25.In some embodiments, one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, is I-3(piceatannol), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, the curcuminoid is curcumin, the catechin is (-)-epigallocatechin gallate, the molar ratio of I-3(piceatannol), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof to pterostilbene, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof is about 1:1, and the molar ratio of curcumin to (-)-epigallocatechin gallate to I-3(piceatannol), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof and pterostilbene, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof is about 8:2:25. Accordingly, in exemplary embodiments, the present application relates to a pharmaceutical composition comprising one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, in combination with pterostilbene, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, and further in combination with curcuminoids and catechins, wherein one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, is I-3 (piceatannol), or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, the curcuminoid is curcumin, and the catechin is (-)-epigallocatechin gallate. The molar ratio of I-3 (piceatannol), or its pharmaceutically acceptable salt, prodrug, and / or solvate, to pterostilbene, or its pharmaceutically acceptable salt, prodrug, and / or solvate is approximately 1:1 or approximately 1:5. The pharmaceutical composition comprises curcumin to (-)-epigallocatechin gallate to I-3 (piceatannol), or a pharmaceutically acceptable salt thereof, prodrug, and / or solvate, and pterostilbene, or a pharmaceutically acceptable salt thereof, prodrug, and / or solvate, in a molar ratio of approximately 8:2:25.

[0178] One or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, and / or pterostilbene, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, are preferably used on their own, but are generally administered in the form of compositions combined with acceptable carriers. Depending on the method of administration, the composition comprises about 0.05% to about 99% by weight or about 0.10% to about 70% by weight of one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, and / or pterostilbene, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, as well as curcuminoids and catechins as needed, and about 1% to about 99.95% by weight or about 30% to about 99.90% by weight of an acceptable carrier, all weight percentages based on the whole composition.

[0179] In some embodiments of this application, the pharmaceutical compositions of this application are used in the treatment of any of the diseases, disorders, or conditions described herein.

[0180] Accordingly, this application further includes methods or uses of administering or using the compositions of this application for treating or preventing papillomavirus infections, or for treating or preventing diseases, disorders, or conditions caused by papillomavirus infections, including resveratrol-resistant cancer.

[0181] One or more compounds of formula I, or their salts, prodrugs, and / or solvates, pterostilbene, or its salts, prodrugs, and / or solvates, or combinations thereof, optionally curcuminoids and catechins, are administered to or used in a variety of forms depending on the chosen route of administration, as will be understood by those skilled in the art. For example, administration may be by oral, inhalation, parenteral, buccal, sublingual, intranasal, rectal, intravaginal, patch, pump, minipump, topical, or transdermal administration, and the pharmaceutical composition is formulated accordingly. In some embodiments, administration is by pump for periodic or continuous delivery. Conventional techniques and ingredients for the selection and preparation of suitable compositions are described, for example, in Remington's Pharmaceutical Sciences (2000-20th edition) and The United States Pharmacopeia: The National Formulary (USP 24 NF19), published in 1999.

[0182] Parenteral administration includes systemic delivery routes other than the gastrointestinal tract (GI), such as intravenous, intra-arterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, intranasal, intrapulmonary (e.g., by aerosol), intrathecal, rectal, and topical (including the use of patches or other transdermal delivery devices). Parenteral administration may also be by continuous infusion over a selected period.

[0183] In some embodiments, the composition is administered orally, for example, using an inert diluent or an absorbable food carrier, or it is encapsulated in a hard or soft-shell gelatin capsule, or it is compressed into a tablet, or it is directly incorporated into a meal. In some embodiments, excipients are incorporated, and the composition is in the form of ingestible tablets, buccal tablets, lozenges, capsules, caplets, pellets, granules, mouthwash, lozenges, chewing gum, powders, syrups, elixirs, wafers, aqueous solutions, and suspensions. In the case of tablets, carriers used include salts of lactose, corn starch, sodium citrate, and phosphoric acid. Pharmaceutically acceptable excipients include binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose), fillers (e.g., lactose, microcrystalline cellulose, or calcium phosphate), lubricants (e.g., magnesium stearate, talc, or silica), disintegrants (e.g., potato starch or sodium starch glycolate), or wetting agents (e.g., sodium lauryl sulfate). In several embodiments, the tablets are coated by methods well known in the art. For tablets, capsules, caplets, pellets, or granules for oral administration, pH-sensitive enteric coatings designed to control the release of the active ingredient, such as Eudragits, are used. TMHowever, these are used as needed. Oral dosage forms also include modified release formulations, such as immediate-release and sustained-release formulations. Examples of modified release formulations include sustained-release (SR), long-release (ER, XR, or XL), time-release or timed-release, controlled-release (CR), or continuous-release (CR or Contin), which are used, for example, in the form of coated tablets, osmotic delivery devices, coated capsules, microencapsulated microspheres, aggregated particles such as those found in molecular sieve particles, or hollow permeable fine fiber bundles or hollow permeable chopped fibers held in aggregated or fibrous packets. Sustained-release compositions are formulated, for example, as liposomes, or with the active compound protected by a differentially disintegrating coating, such as microcapsule encapsulation or multiple coating. Examples of liposome delivery systems include small single-lamellar vesicles, large single-lamellar vesicles, and multi-lamellar vesicles. In some embodiments, liposomes are formed from various phospholipids, such as cholesterol, stearylamine, or phosphatidylcholine. For oral administration in capsule form, lactose and dried corn starch are useful carriers or diluents.

[0184] In some embodiments, liquid preparations for oral administration may take the form of solutions, syrups, or suspensions, or they may be presented as dry products to be mixed with water or other suitable vehicles before use. When aqueous suspensions and / or emulsions are administered orally, the compounds of this application may be suspended or dissolved in an oily phase mixed with emulsifiers and / or suspending agents. Certain sweeteners and / or flavoring agents and / or coloring agents may be added, if desired. Such liquid preparations for oral administration may be prepared by conventional means using pharmaceutically acceptable additives, such as suspending agents (e.g., sorbitol syrup, methylcellulose, or hydrogenated edible lipids), emulsifiers (e.g., lecithin or acacia), non-aqueous vehicles (e.g., almond oil, oily esters, or ethyl alcohol), and preservatives (e.g., methyl p-hydroxybenzoate or propyl p-hydroxybenzoate, or sorbic acid). Useful diluents include lactose and high molecular weight polyethylene glycol.

[0185] The composition can also be freeze-dried, and the resulting freeze-dried product can be used, for example, in the preparation of injectable products.

[0186] In some embodiments, administration is parenteral. For example, solutions are prepared with water preferably mixed with surfactants, such as PEGylated oils, polysorbates, and sorbitan esters. In some embodiments, dispersions are prepared with glycerol, liquid polyethylene glycol, DMSO, and mixtures thereof with or without alcohol, as well as oils. Under normal storage and use conditions, these preparations contain preservatives to prevent microbial growth. Those skilled in the art will know how to prepare suitable formulations. For parenteral administration, sterile solutions are usually prepared, and the pH of this solution is preferably adjusted and buffered. For intravenous use, the total concentration of the solute should be controlled to make the preparation isotonic. For intraocular administration, ointments or droppable liquids are delivered, for example, by intraocular delivery systems known in the art, such as applicators or ophthalmic drops. In some embodiments, such compositions include a mucus mimic, such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose, or polyvinyl alcohol; a preservative, such as sorbic acid, EDTA, or benzyl chromium chloride; and a typical amount of diluent or carrier. For intrapulmonary administration, the diluent or carrier is selected to be suitable for enabling aerosol formation.

[0187] In some embodiments, the composition is formulated for parenteral administration by injection, including the use of conventional catheterization techniques or infusions. The injectable formulation is presented in unit dosage forms, for example, in ampoules or multi-dose containers, with or without the addition of preservatives. In some embodiments, the composition takes the form of a sterile suspension, solution, or emulsion in an oily or aqueous vehicle and comprises formulation agents, such as suspending agents, stabilizers, and / or dispersants. In all cases, the form must be sterile and fluid enough to allow for easy syringability. Alternatively, the composition is preferably in a sterile powder form for reconstitution with a suitable vehicle, such as a sterile pyrogen-free water, before use.

[0188] Sterilization methods are well known in the art, and include, for example, terminal sterilization by autoclaving or irradiation, or sterilization by filtration, such as sterile filtration.

[0189] In some embodiments, compositions for intranasal administration are conveniently formulated as aerosols, droplets, gels, and powders. For administration into the nasal cavity, compositions are conveniently delivered by irrigation, for example, using an intranasal irrigation device. For administration by intranasal or inhalation, compositions are conveniently delivered in the form of a solution, dry powder formulation, or suspension from a pump spray container pushed out or pumped by the patient, or as an aerosol spray from a pressurized container or nebulizer. Aerosol formulations typically contain a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in sterile single-dose or multiple-dose form in a sealed container, which takes the form of, for example, a cartridge or refill for use in a spray device. Alternatively, the sealed container is a uniform-volume dispensing device equipped with a metering valve, such as a single-dose intranasal inhaler or aerosol dispenser, which is intended to be discarded after use. If the dosage form includes an aerosol dispenser, it contains a propellant, which is, for example, a compressed gas (e.g., compressed air) or an organic propellant (e.g., fluorochlorohydrocarbon). Suitable propellants include, but are not limited to, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkane, carbon dioxide, or other suitable gases. In the case of pressurized aerosols, the dosage unit is preferably determined by providing a valve for delivering a fixed amount. In some embodiments, the pressurized container or nebulizer contains a solution or suspension of the active compound. Capsules and cartridges for use in inhalers or blowers (e.g., made from gelatin) are formulated to contain, for example, a powder mixture of the active compound and a suitable powder base, such as lactose or starch. Aerosol dosage forms can also take the form of pump-type spray devices.

[0190] Suitable compositions for buccal or sublingual administration include tablets, lozenges, and pastilles, using a carrier such as sugar, acacia, tragacanth, or gelatin, and glycerin. Suitable compositions for buccal or sublingual administration include sublingual solutions or suspensions, using a carrier such as water. For rectal administration, the composition is conveniently in the form of a suppository containing a conventional suppository base, such as cocoa butter.

[0191] Suppository forms are useful for vaginal, urethral, ​​and rectal administration. Such suppositories generally consist of a mixture of substances that are solid at room temperature but melt at body temperature. Substances widely used to construct such vehicles include, but are not limited to, theobroma oil (also known as cocoa butter), glycerin-containing gelatin, other glycers including stearoyl polyoxyl-32 glyceride and glyceryl dibehenate, hydrogenated vegetable oils, mixtures of polyethylene glycol and fatty acid esters of polyethylene glycol of various molecular weights including PEG-8 distearate, and phosphatidylcholine. For further consideration of suppository dosage forms, see, for example, Remington's Pharmaceutical Sciences, 16th Ed., Mack Publishing, Easton, PA, 1980, pp. 1530–1533.

[0192] In some embodiments, one or more compounds of formula I, or their salts, prodrugs, and / or solvates, pterostilbene, or its salts, prodrugs, and / or solvates, or combinations thereof, optionally curcuminoids and catechins, are linked to a soluble polymer as a targetable drug carrier. Such polymers include, for example, polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide-phenol, polyhydroxyethyl aspartamide-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Furthermore, in some embodiments, the polymer belongs to a class of biodegradable polymers useful for achieving controlled release of the compound, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyran, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.

[0193] Administration may also be achieved using nanocarrier systems, such as liposomes, micelles, nanoparticles, nanoemulsions, and lipid nanosystems (see, for example, Bhat, M. et al. Chem. and Phys. of Lipids, 2021, 236, 105053).

[0194] In some embodiments, one or more compounds of formula I, or their salts, prodrugs, and / or solvates, pterostilbene, or its salts, prodrugs, and / or solvates, optionally curcuminoids, and catechins are ligated to a viral vector, a non-viral vector, or other vector. Examples of viral vectors include retroviruses, lentiviruses, adenoviruses, herpesviruses, poxviruses, alphaviruses, vaccinia viruses, or adeno-associated viruses. Examples of non-viral vectors include nanoparticles, cationic lipids, cationic polymers, metal nanoparticles, nanorods, liposomes, micelles, microbubbles, cell-permeable peptides, or lipospheres. Examples of nanoparticles include silica, lipids, carbohydrates, or other pharmaceutically acceptable polymers.

[0195] In some embodiments, the compositions of this application are formulated as suppositories, creams, gels, foams, sprays, films, sponges, tablets, capsules, emulsions, solutions, lotions, nanofibers, suspensions, particles, nanoparticles, bioadhesives, or mouthwashes.

[0196] In some embodiments, the composition of this application is formulated as a cream.

[0197] In some embodiments, the cream comprises about 10% to about 30% by weight, about 15% to about 25% by weight, about 15% to about 20% by weight, or about 20% by weight of one or more compounds of Formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, as well as curcuminoids and catechins, and about 90% to about 70% by weight, about 85% to about 75% by weight, about 85% to about 80% by weight, or about 80% by weight of an acceptable carrier, all weight percentages based on the whole composition. In some embodiments, the cream comprises about 15% to about 20% by weight of one or more compounds of Formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, as well as curcuminoids and catechins.

[0198] In some embodiments, the cream comprises about 10% to about 30% by weight, about 15% to about 25% by weight, about 15% to about 20% by weight, or about 20% by weight of pterostilbene or its pharmaceutically acceptable salts, prodrugs, and / or solvates, curcuminoids, and optionally catechin, and about 90% to about 70% by weight, about 85% to about 75% by weight, about 85% to about 80% by weight, or about 80% by weight of an acceptable carrier, all weight percentages based on the whole composition. In some embodiments, the cream comprises about 15% to about 20% by weight of one or more pterostilbene compounds or their pharmaceutically acceptable salts, prodrugs, and / or solvates, and optionally curcuminoids and catechin.

[0199] In some embodiments, the cream comprises about 10% to about 30% by weight, about 15% to about 25% by weight, about 15% to about 20% by weight, or about 20% by weight of one or more compounds of Formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, and / or pterostilbene, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, and optionally curcuminoids and catechins, and about 90% to about 70% by weight, about 85% to about 75% by weight, about 85% to about 80% by weight, or about 80% by weight of an acceptable carrier, all weight percentages based on the whole composition. In some embodiments, the cream comprises about 15% to about 20% by weight of one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, and / or pterostilbene, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, and optionally curcuminoids and catechins.

[0200] In some embodiments, acceptable carriers are selected from Pluronic®, lecithin, organogel, Lipoderm®, Vanpen®, Aladerm®, Perme8, Ellage®, VersaBase® cream, VersaBase® lotion, VersaBase® gel, VersaBase® anhydrous HRT, XemaTop®, Mucolo, and anhydrous gel. In some embodiments, the acceptable carrier is Ellage®.

[0201] In some embodiments, a device comprising the composition of this application is placed in the oral cavity or anal cavity as a pellet, tablet, capsule, foam, or film.

[0202] In some embodiments, the compositions of this application are formulated to be attached to, incorporated into, or cover an intravaginal device or a device inserted into the oral or anal cavity, or to be positioned in contact with the skin. In some embodiments, the intravaginal device is a tampon, a tampon-like device, a ring, a pessary, a tablet, a capsule or pellet, a sponge, a foam, or a female condom.

[0203] In some embodiments, the compositions of this application are formulated to be attached to, incorporated into, coated on, or embedded in a condom.

[0204] In some embodiments, one or more compounds of formula I, or their salts, prodrugs, and / or solvates, as well as / or pterostilbene, or its salts, prodrugs, and / or solvates, and optionally curcuminoids and catechins, are administered together with another therapeutic agent, either simultaneously or sequentially in separate unit dosage forms, or together in a single unit dosage form. Accordingly, this application provides a single unit dosage form comprising one or more compounds of formula I, or their salts, prodrugs, and / or solvates, as well as / or pterostilbene, or its salts, prodrugs, and / or solvates, and optionally curcuminoids and catechins, along with a pharmaceutically acceptable carrier, together with an additional therapeutic agent.

[0205] One or more compounds of formula I, or salts, prodrugs, and / or solvates thereof, pterostilbene, or salts, prodrugs, and / or solvates thereof, curcuminoids and catechins as may be used alone to treat or prevent diseases, disorders, or conditions caused by papillomavirus infection, including resveratrol-resistant cancer, or in combination with other known agents useful for treating or preventing diseases, disorders, or conditions caused by papillomavirus infection, including resveratrol-resistant cancer.

[0206] One embodiment is that another known agent useful for treating or preventing a disease, disorder, or condition caused by a papillomavirus infection, including papillomavirus infection or resveratrol-resistant cancer, is administered or used in accordance with a known treatment protocol of the other known agent.

[0207] In some embodiments, the compounds of formula I and pterostilbene are available from commercial sources. For example, isolariciresinol, lariciresinol, piceatannol, pterostilbene, laricirescin, and astragalin are available from Millipore Sigma Aldrich (Burlington, Massachusetts, United States, USA).

[0208] In one embodiment, 8 μM of curcumin, 2 μM of (−)-epigallocatechin gallate, and 25 μM of piceatannol, 8 μM of curcumin, 2 μM of (−)-epigallocatechin gallate, and 25 μM of pterostilbene, 8 μM of curcumin, 2 μM of (−)-epigallocatechin gallate, 12.5 μM of piceatannol, and 12.5 μM of pterostilbene, and 8 μM of curcumin, 2 μM of (−)-epigallocatechin gallate, 4.2 μM of piceatannol, and 20.8 μM of pterostilbene A pharmaceutical composition selected from the group consisting of is provided.

[0209] In another embodiment, Tetrahydrocurcumin, (−)-epigallocatechin gallate, and pinosylvin in a molar ratio of 4:1:12.5, Tetrahydrocurcumin, (−)-epigallocatechin gallate, and pterostilbene in a molar ratio of 4:1:12.5, Tetrahydrocurcumin, (−)-epigallocatechin gallate, piceatannol, and pterostilbene in a molar ratio of 4:1:6.25:6.25, Tetrahydrocurcumin, (−)-epigallocatechin gallate, piceatannol, and pterostilbene in a molar ratio of 4:1:2.1:10.4, [ Tetrahydrocurcumin, (−)-epigallocatechin gallate, and pterostilbene in a molar ratio of 1:1:1, and A pharmaceutical composition selected from the group consisting of curcumin, (-)-epigallocatechin gallate, and pterostilbene in a molar ratio of 1:1:1 is provided.

Example

[0210] The following non-limiting examples are illustrative of the present application. Representative commercially available sources of the components of the formulations of the present invention are as follows.

Table 27-1

Table 27-2

[0211] In the following examples, all test compounds or combinations thereof were incubated with HPV(+) cancer cells for 72 hours and a 3-(4,5-dimethylthiazol-2-yl)- 50 2,5-diphenyltetrazolium bromide (MTT) assay was performed to determine the half-maximal inhibitory concentration (IC 50 ). All experiments had six biological replicates at each drug dose, and the values listed represent the mean. The IC TM values were determined using a parametric logistic regression model by Quest Graph 50 IC

[0212] Cell culture and MTT assay: 1. Hela cells were cultured in a T75 flask in DMEM medium containing 10% FBS, 100 U / ml penicillin, and 100 μg / ml streptomycin in a humidified incubator at 37°C and an atmosphere of 5% CO2 (volume / volume). Semi-confluent cells were trypsinized, pelleted, and resuspended in DMEM medium. After cell counting, approximately 4000 cells were seeded into each well of a 96-well plate and cultured overnight under the above conditions. 2. 1% ITS in DMEM was added to each well. The culture medium in each well was replaced with 200 μL of the corresponding drug solution. Each dilution was tested in 6 wells. Cells were treated with the drug in a cell culture incubator for 72 hours. 3. After 72 hours, the drug's effect was measured by an MTT assay. After washing the cells with PBS, 1% ITS and 50 μL of MTT reagent in 100 μL of DMEM were added to each well. The cells were incubated at 37°C for 4 hours. The reaction was terminated with stop solution. The plate was incubated overnight in a humidified incubator at 37°C in a sealed plastic bag, and absorbance was recorded at 570 nm using an absorbance plate reader. Background correction was achieved using a separate well containing all other reagents but without cells. 4. IC50 was calculated. Example 1 Identification of exemplary compounds derived from Rheum L. in this application

[0213] Chemical drug screening of diphenylethylene compounds derived from the plant genus Rheum L. (rhubarb), and especially from the species Rheum rhaponticum L. and Rheum rhabarbarum, was first performed using primordial HPV-18 positive HeLa cells.

[0214] Highly active compounds were identified, and they were found to have slight modifications in the number and type of functional groups compared to resveratrol. Table 1 shows six naturally occurring diphenylethylene compounds derived from the tested rhubarb species that were identified as having the most potent cytotoxic effect against HPV-18 Hela cells. [Table 1]

[0215] Table 2 shows the dose-response effects obtained from MTT assays for each of the identified native diphenylethylene compounds in certified HPV-18(+) HeLa cells. [Table 2]

[0216] As can be seen from Table 2, all identified compounds have an IC50 below 30 μM. 50 The compounds possessed the following properties. The most active compounds were found to be piceatannol, pterostilbene, rapontigenin, and resveratrol, all of which produced approximately 10 μM IC2 in HeLa cells. 50 The following were found (pterostilbene = 7.55 μM, resveratrol = 7.92 μM, rapontigenin = 8.0 μM, piceatannol = 8.0 μM). Isolapontigenin was effective, but IC 50 It was found to have an IC50 concentration of approximately 27.07 μM, which is about one-third the potency of the other four compounds. The next most potent naturally occurring diphenylethylene compound identified in drug screening of Rheum rhaponticum L. and Rheum rhabarbarum species was desoxyrapontigenin (also known as 4'-O-methylresveratrol). This compound had an IC50 concentration of approximately 38.32 μM. 50 It was found that it possesses this characteristic. Example 2 Evaluation of exemplary compounds in the resveratrol-resistant cell line HeLa-GS1

[0217] The polyphenol trans-3,5,4'-trihydroxystilbene (resveratrol) is known to have anti-human papillomavirus (HPV) activity. However, cancer cells develop resistance to resveratrol, which is one of the main reasons why the clinical efficacy of resveratrol-based drugs is limited (Colin DJ et al., Cell Death Dis. 2014 Nov 20;5(11):e1533).

[0218] To overcome the limitations in the prior art, a resveratrol-resistant cell line was developed from the HPV-18(+) cervical cancer cell line HeLa. This mutant cell line, named HeLa-GS1, was found to exhibit significant resistance to resveratrol. Certified original HeLa cells were obtained from the American Type Culture Collection (Manassas, Virginia, USA), and the results in Table 1 were obtained using these. The HeLa-GS1 cells were developed by serially passaging the parental cell line over a long period in cells incubated in the presence of resveratrol. In repeated experiments, the IC 50 of resveratrol in the original HeLa cells was in the range of 7 - 11 μM, and the average IC 50 value was 7.9189 μM. On the other hand, in repeated experiments, the IC 50 of resveratrol in the HeLa-GS1 cells ranged from 80 μM or higher to complete resistance, and the average IC 50 was 111.251 μM.

[0219] The four most active identified compounds obtained in Example 1 and resveratrol were evaluated in the resveratrol-resistant cell line HeLa-GS1. Table 3 shows the dose-response results of the identified diphenyl ethylene compounds obtained using the MTT assay in the resveratrol-resistant cell line HeLa-GS1.

Table 3

[0220] As can be understood from Table 3, the IC 50The values ​​were as follows, with the most potent compound being pterostilbene = 8.34 μM, rapontigenin = 11.47 μM, piceatannol = 28.99 μM, and isolapontigenin = 41.18 μM. This data indicates variability in the efficacy of the compounds. For example, pterostilbene was found to be five times more potent than isolapontigenin and approximately three times more potent than piceatannol. On the other hand, cells treated with resveratrol showed clear resistance, with over 90% of HeLa-GS1 cells remaining viable at the highest dose tested (50 μM), confirming the unique properties of the identified compounds that had not been reported in any conventional techniques for HPV-infected cells.

[0221] Like many plant polyphenols, resveratrol modulates a diverse number of cellular pathways. Previous studies have shown that resveratrol eliminates several HPV(+) cell lines in cancerous and precancerous tissues (Einbond et al. 2021, Br J Cancer. 2021 Mar;124(5):901-913). Prior to cell death, resveratrol upregulated pro-apoptotic genes and affected cell cycle regulators such as p53. Furthermore, the compound suppressed HPV virus transcripts E6 and E7, which induce malignant transformation and maintain cancer cell growth. On the other hand, trans-stilbene, which is identical to resveratrol except for the absence of certain functional groups, was not cytotoxic to HPV(+) cancer cells, even at very high doses. Example 3 Evaluation of exemplary compounds in the HPV-16-positive cervical cancer cell line CaSki

[0222] Resveratrol and four diphenylethylene compounds identified in the initial screening (see Example 1) were further tested against CaSki, an HPV-16 positive cervical cancer cell line. It is known that 50% of cervical cancers worldwide are HPV-16 positive, and Tables 4 and 5 show the MTT assay data for each of these compounds in CaSki cells. [Table 4] [Table 5] As can be seen from Tables 4 and 5, the IC of the identified compounds 50 The values ​​were as follows, from the most potent compound: resveratrol = 5.96 μM, isolapontigenin = 8.48 μM, pterostilbene = 11.25 μM, piceatannol = 16.55 μM, and lapontigenin = 173.07 μM. Example 4 Evaluation of exemplary compounds in HPV-16-positive cervical cancer cell lines (SiHa).

[0223] Further dose-response analyses were performed using the HPV-16(+) cervical cancer cell line, SiHa, to confirm the results observed in the HPV-16-positive cervical cancer CaSki cell line. Table 6 shows the MTT survival data and IC for trans-resveratrol, isolapontigenin, piceatannol, pterostilbene, and rapontigenin in the HPV-16(+) cancer cell line, SiHa. 50 Show the value. [Table 6]

[0224] As can be seen from the data in Table 6, the cytotoxic results of the identified compounds in the HPV-16(+) cancer cell line SiHa are consistent with the values ​​observed in CaSki cells. For example, IC 50The values ​​were as follows: resveratrol = 12.4347 μM, isolapontigenin = 8.9131 μM, pterostilbene = 8.7824 μM, and piceatannol = 21.9006 μM. All of these compounds were shown to have potent efficacy against SiHa cells. On the other hand, the IC of rapontigenin... 50 The concentration was 130.39 μM, and this compound was not effective in another HPV-16 positive cell line, exhibiting approximately one-tenth the potency of resveratrol. Examples 1-4 above demonstrate that different diphenylethylene compounds can induce different anti-papillomavirus (e.g., anti-HPV) effects.

[0225] Table 7 provides a summary of the test results for Examples 1 to 3. [Table 7] Example 5 Combinations containing exemplary compounds of formula I and / or pterostilbene

[0226] Cancer and HPV(+) cells develop resistance to resveratrol, limiting its use. Another significant limitation of resveratrol-based drugs, as seen in the clinical trial data presented, is that resveratrol and resveratrol derivatives have significant bioavailability issues. They are poorly absorbed, leading to systemic circulation, due to low solubility and rapid degradation. Consequently, target tissue concentrations achieved are low, and the resulting biological efficacy is either nonexistent or limited. To attempt to overcome these limitations, combinations of two or more exemplary diphenylethylene compounds of formula I or combinations of pterostilbene were tested. These compound combinations were observed to act synergistically against HPV(+) cells. Data showed lower IC50 when using combinations of diphenylethylene compounds of formula I (compared to administration alone). 50The level was demonstrated to be achieved. Synergistic combinations of compounds may help reduce the cytotoxic dose required in target tissues and overcome the inherent problems in achieving appropriate drug concentrations of resveratrol-based drugs.

[0227] Furthermore, resveratrol and some of the natural diphenylethylene compounds are phytoalexin compounds, used by plants in a polyclonal manner (by multiple compounds) to combat microbial diseases. Therefore, drug combinations were tested.

[0228] Isolapontigenin and piceatannol, the most potent exemplary diphenylethylene compounds of formula I, were tested in combination with each other and in double drug combinations with pterostilbene. For the first combination drug test, the two compounds were used in a 1:1 molar ratio. The concentrations were measured using the IC50 of each compound. 50 Starting with a dose of 1, the dose was doubled or halved to obtain the full range of dose-response effects. To illustrate how to derive the combined dose for the study, Table 8 lists the concentrations of a 1:1 molar mixture of the exemplary compounds isolapontigenin and piceatannol. As shown in the examples above, the IC of the compounds 50 The values ​​were as follows: pterostilbene (8 μM), isolapontigenin (30 μM), and piceatannol (8 μM). Table 9 shows the IC50 of these first paired mixtures in HeLa cells. [Table 8] [Table 9]

[0229] *Note: Paired studies were initiated with IC50 values ​​for each compound in a 1:1 molar ratio: Iso IC50 = 30 μM, Pice IC50 = 8 μM, and Ptero IC50 = 8 μM. The paired doses were then doubled or halved to obtain the dose-response range.

[0230] Table 9 shows that the strongest pairing was piceatannol with pterostilbene in a 1:1 molar ratio, with an IC50 of 4.308. 50 This indicates that it has been shown. Example 6 Evaluation of the molar ratio of exemplary compounds

[0231] After identifying the pair of piceatannol and pterostilbene using Example 5, further drug combination tests were conducted to determine the optimal molar ratio of the piceatannol and pterostilbene combination.

[0232] Since the initial molar ratio was piceatannol to pterostilbene at 1:1, the following additional ratios of 8:1, 4:1, 2:1, 1:2, 1:3, 1:4, and 1:5 were considered, and the following molar ratios of piceatannol to pterostilbene at 8:1, 1:1, 1:3, and 1:5 were selected for further testing.

[0233] Table 10 shows the IC values ​​of piceatannol and pterostilbene as individual drugs against Hele cells. 50 Table 11 shows the IC values ​​for piceatannol and pterostilbene combinations in various ratios in HeLa cells. 50 Show the value. [Table 10] [Table 11]

[0234] Table 11 IC 50The data again showed that the 1:1 molar ratio of piceatannol to pterostilbene was highly synergistic and demonstrated remarkable efficacy. This pice:ptero(1:1) pair increased cytotoxicity by 600% compared to piceatannol alone and by 800% compared to pterostilbene alone. The 8:1 ratio of piceatannol to pterostilbene showed good IC50. 5O Although this was shown, combinations of piceatannol and pterostilbene in molar ratios of 1:3 and 1:5 also showed good efficacy. The data in Tables 10 and 11 show that the effects at these ratios are merely additive (e.g., IC2 of piceatannol). 50 It is 7.3388uM, and is the IC of pterostilbene. 50 (This is 9.2021 μM). However, the combination of piceatannol and pterostilbene in a 1:1 molar ratio yields 1.0373 μM IC. 50 It possessed this property and showed a strong synergistic effect between these two compounds at this molar ratio. Example 7 A combination composition comprising exemplary compounds of formula I and / or pterostilbene, curcumin, and catechin.

[0235] Plant-derived polyphenols, such as resveratrol, modulate a wide range of cellular pathways. As mentioned above, the polyphenol trans-3,5,4'-trihydroxystilbene (resveratrol) is known to have anti-human papillomavirus (HPV) activity. Furthermore, a pharmaceutical mixture of curcumin (32 μM), epicatechin gallate (8 μM), and resveratrol (100 μM) has been found to be synergistic in eliminating HPV(+) cancer cell lines (Mukherjee et al., 2017 Oncotarget. 2017 Mar 29;8(37), International Publication No. 2015 / 081319, U.S. Patent Application Publication No. 2016 / 0287533, Einbond et al. 2021, Br J Cancer. 2021 Mar;124(5):901-913). Therefore, we investigated whether piceatannol or a combination of piceatannol and pterostilbene, in further combinations with curcumin and (-)-epigallocatechin gallate (EGCg), exhibit superior cytotoxicity. The data in Examples 1-4 demonstrate that pterostilbene overcomes resistance to resveratrol in HeLa-GS1 cells. Examples 5 and 6 further demonstrate that the exemplary compound combination of formula I, or the combination thereof with pterostilbene, is potent compared to the individual formula I diphenylethylene compounds or pterostilbene. For example, the exemplary compound piceatannol combined with pterostilbene in a 1:1 molar ratio yielded 1.0373 μM IC2. 50 It was found to have the properties of piceatannol or pterostilbene individually, which were 7 to 9 times more potent.

[0236] Table 12 shows the IC25 of exemplary compounds piceatannol or pterostilbene in combination with curcumin and (-)-EGCG, respectively, referred to as T-Pice and T-Ptero. 50The values ​​are shown. The IC50 is obtained by combining the exemplary compound piceatannol with the exemplary compound pterostilbene in a 1:1 molar ratio and a 1:5 molar ratio, and further combining it with curcumin and (-)-EGCG, respectively, in the T-Pice:Ptero(1:1) and T-Pice:Ptero(1:5) IC50 ratios. 50 The values ​​are also shown. The combination of piceatannol and pterostilbene was found to act synergistically in Example 4. Table 12 shows all four tested combinations and the doses they were tested at. All combinations had equal amounts of curcumin, EGCG, and diphenylethylene components. These four combinations were tested in the HPV-positive cell lines CasKi, HeLa, and the resveratrol-resistant cell line HeLa-GS1. The data in Table 12 show that all four mixtures had potent efficacy against these HPV cell lines. [Table 12]

[0237] All formulations contain curcumin and (-)-EGCg ((-)-epigallocatechin gallate) in a molar ratio of 8:2.

[0238] By adding a diphenylethylene compound, drug combinations were prepared in the following ratios: T-Pice = Curcumin (8 μM) + (-)-EGCg (2 μM) + Pice (25 μM) T-Ptero = Curcumin (8 μM) + (-)-EGCg (2 μM) + ptero (25 μM) T-Pice:Ptero(1:1) = Curcumin (8μM) + (-)-EGCg (2μM) + Pice (12.5μM) + Ptero (12.5μM) T-Pice:Ptero(1:5) = Curcumin (8 μM) + (-)EGCg (2 μM) + Pice (4.2 μM) + Ptero (20.8 μM)

[0239] For all mixture ratios, an equal amount of diphenylethylene compound was used for comparison. As a control, curcumin and (-)-EGCg were evaluated individually in HPV-18 positive HeLa cells (Table 13) and HeLa-GS1 cell lines (Table 13). [Table 13] Example 8 Investigation of combination indexes

[0240] To quantify synergy when observed IC50s are close, the inventors determined the combination index using the well-established method by Chow-Talallay (Chou TC, Cancer Res. (2010) 70(2):440-6), which defines the median dose-action and combination index (CI) using the chemosmotic mass action equation, which is defined as follows: CI > 1 drug antagonistism, CI = 1 additive action, CI < 1 drug synergy.

[0241] Table 14 shows the drug IC for each of the four mixtures. 50 ,I C 75 ,I C 90 , and IC 95 The combination index is shown. [Table 14]

[0242] Drug abbreviations: Curcumin (Curc), (-)-EGCG (Epi), Piceatannol (Pice), Pterostilbene (Ptero)

[0243] Drug combinations (molar ratio): T-Pic:(Curc+Epi+Pice[32:8:100]) T-Pte:(Curc+Epi+Ptero[32:8:100]) T-1:1:(Curc+Epi+Pice+Ptero[32:8:50:50]) T-1:5:(Curc+Epi+Pice+Ptero[32:8:16.67:83.33]) The data in Table 14 show that not all mixtures are optimal across the entire dose range tested. Some mixtures have a CI value greater than 1, indicating that the mixture is not effective as a drug combination in terms of its ratio and dose action. However, the data above shows that mixture T-1:1, with piceatannol and pterostilbene in a 1:1 molar ratio, plus curcumin and (-)-EGCg, is the most synergistic and IC at the highest dose. 50 This demonstrates an additive, highly potent combination. The mixtures in Table 14 are derived through combinatorial testing, and their effects are verified experimentally.

[0244] Tables 15 and 16 show the complete statistical output of the data in Table 14, which is an overview of the CI values ​​for each mixture. [Table 15] [Table 16] Example 9 Evaluation of exemplary combination compositions comprising the compound of formula I and / or pterostilbene, as well as curcuminoids and catechins.

[0245] The compounds of Formula I exhibit potent anti-HPV activity, either alone or in combination with pterostilbene, and further in combination with curcumin and (-)-epigallocatechin gallate (EGCg), as shown in Examples 6-8 above. It was also unexpectedly discovered that certain curcuminoid compounds increase the activity of the disclosed diphenylethylene mixtures.

[0246] Curcumin (or diferuloylmethane) is a yellow crystalline compound isolated from turmeric (Curcuma longa L., Zingiberaceae) and is the major curcuminoid present in turmeric. In addition, this medicinal root contains demethoxycurcumin and bisdemethoxycurcumin. Curcuminoids are naturally occurring phenols that can exist in at least two tautomer forms: keto and enol. Tetrahydrocurcumin, a metabolite of curcumin, is a reduced form of the compound. Curcumin contains an α,β-unsaturated carbonyl group, while tetrahydrocurcumin lacks an α,β-diene. Similarly, demethoxycurcumin and bisdemethoxycurcumin can be reduced to form tetrahydrodemethoxycurcumin and tetrahydrobisdemethoxycurcumin, respectively.

[0247] To develop additional embodiments of the diphenylethylene mixture, the inventors individually tested the effects of curcumin and tetrahydrocurcumin on HPV(+) CaSki cell lines. The IC50 of curcumin was 4.9722 μM, and the IC50 of tetrahydrocurcumin was 30.2386 μM, indicating that curcumin was six times more potent than its reduced form (Table 17). Similarly, in SiHa cells, tetrahydrocurcumin had an IC50 of 87.7979 μM compared to curcumin, which had an IC50 of 14.0525 μM, showing significantly weaker efficacy (Table 18). This demonstrates that curcumin is 500% more potent than reduced curcumin (tetrahydrocurcumin) against these HPV(+) cancer cells. Similarly, in resveratrol-resistant Hela-GS1 cells, curcumin was 200% more effective than tetrahydrocurcumin (Table 18). Unexpectedly, when used in the diphenylethylene mixture derived by the inventors, the combination with tetrahydrocurcumin proved superior and more effective compared to a mixture with natural curcumin.

[0248] The inventors tested the mixture T-1:5 described in Example 7 above, which contains: curcumin (32 μM), EGCG (8 μM), piceatannol (16.67 μM), and pterostilbene (83.33 μM). This was compared to an equal volume of a mixture containing the reduced form of curcumin: tetrahydrocurcumin (32 μM), EGCG (8 μM), piceatannol (16.67 μM), and pterostilbene (83.33 μM). This combination was denoted as TW-1:5. In vitro tests were performed in HeLa cells at various concentrations listed in Table 19. The IC50 of TW-1:5 was observed to be 1.2395 μM, while the curcumin-containing mixture T-1:5 had an IC50 of 2.4196 μM. In contrast to a comparison of curcumin and tetrahydrocurcumin (when used individually), in which tetrahydrocurcumin was found to be weaker with a 500% reduction, the diphenylethylene mixture (TW-1:5) of the present invention using tetrahydrocurcumin showed a 100% increase in potency. [Table 17] [Table 18] [Table 19] Example 10 Exemplary in vivo antiviral efficacy of diphenylethylene mixture using an MmuPV-1 vaginal papilloma mouse model

[0249] The Mus musculus papillomavirus 1 (MmuPV1) mouse model is known in the art to be an important tool in papillomavirus research. MmuPV1 infects laboratory mice, making it the first rodent papillomavirus capable of such infection, thus providing an opportunity to study papillomavirus biology and pathogenesis. MmuPV1 can infect both the skin and mucosal (oral and genital) tissues of mice, closely mimicking human papillomavirus (HPV) infections. This model is unique and enables viral-host studies as well as preclinical evaluation of drugs for antiviral efficacy. The MmPV / mouse model was used to examine diphenyl ethylene mixtures to evaluate whether they have in vivo activity against murine vaginal papillomas. This study aimed to evaluate the ability to deliver the drug intravaginally and determine whether an antiviral effect was seen against MmuPV-1. Parameters used to evaluate the antiviral effect included: 1) the MmuPV1 viral DNA copy number in vaginal and anal swabs, 2) histological evaluation of papillomas for virological assessment at the end of the study. The experimental method has been previously described in detail. Briefly, NU / J heterozygous mice with the Foxn1 nu / + genotype were used. These mice were injected subcutaneously with 3 mg of progesterone in the form of Depo-Provera diluted in 100 microliters of PBS. Three days after the injection, the mice were sedated and Doctors’ Brush Picks were gently rotated 15 times in the vaginal canal to create slight friction. Twenty-four hours later, the mice were anesthetized again and 25 μl of a sterile virus suspension was pipetted into the vaginal canal. A study involving 25 adult female heterozygous Nu / J mice (purchased from Jackson Labs) followed this protocol. After a 7-day isolation period, on day 0, mice in groups A–E were inoculated with MmuPV-1 at the vaginal and anal sites. On day 7, all mice were administered 25 μl of the formulated compound via the vaginal canal using a soft plastic pipette tip. Treatment was administered 5 times per week for up to 5 weeks. The study included five groups (A–E) and one placebo group as a control to evaluate the effect of the topical treatment. Vaginal lavage was performed every Monday to determine the viral copy number (weeks 3 and 4), which was then analyzed to calculate the viral DNA titer. At the end of the study, histological evaluation of the vaginal canal was performed, and MmuPV1 was identified using immunohistochemistry and an anti-E4 protein probe. The tested mixtures are shown in Table 20. To determine whether tetrahydrocurcumin is superior to curcumin when tested in a mixture that is identical except for the curcuminoids (labeled TW-pinostilbene and T-pinostilbene), T-pterostilbene and a positive control were also tested. [Table 20] [Table 21]

[0250] During weeks 3 and 4 of the study, the viral load of vaginal douche was measured to evaluate the acute effects of the drug and the feasibility of vaginal delivery. A positive effect on changes in viral load was observed during weeks 3–4 (Table 20). Short-term drug exposure reduced viral replication rates in groups A, C, and the positive control group compared to vehicle-treated mice.

[0251] Group A, containing a mixture of tetrahydrocurcumin (32 μM), EGCG (8 μM), and pinostylbene (100 μM), showed statistically significant inhibition of viral replication (p=0.0244). In contrast, the mixture containing curcumin (32 μM), EGCG (8 μM), and pinostylbene (100 μM) was not effective in reducing viral replication (p=0.1508). The mixture T-pterostilbene (p=0.0397) and the positive control (p=0.0317) certainly showed a significant response in suppressing MmuPV1 compared to vehicle-treated mice.

[0252] This study lasted a total of five weeks, at which point the animals were autopsied and the lower reproductive tract was histopathologically evaluated. Histopathology using an anti-MmuPV1 E4 protein probe for immunohistochemistry showed MmuPV1 infection along the vaginal epithelium, indicated by brown-stained cells. Groups A and C showed a strong immune response around the MmuPV1-positive areas.

[0253] In conclusion, vaginal delivery was feasible and effective in attenuating viral growth. The mixture containing T-pterostilbene was particularly potent in inhibiting viral replication, while the mixture using tetrahydrocurcumin also demonstrated enhanced antiviral activity in vivo. Example 11 Exemplary in vivo antiviral efficacy of diphenylethylene mixture using a cottontail rabbit papillomavirus / rabbit model

[0254] The cottontail rabbit papillomavirus (CRPV) model, established in the 1930s, is considered the optimal standard for studying the pathogenesis of human papillomavirus (HPV) and testing anti-HPV treatments. This model remarkably mimics human HPV infection and disease progression, including the development of papillomas and cancer. It is central to the development and testing of both prophylactic and therapeutic HPV vaccines by providing insights into immune responses and vaccine efficacy. CRPV infection in rabbits replicates human HPV infection, enabling research into viral pathogenesis and therapeutic interventions.

[0255] Initial in vivo studies of diphenylethylene mixtures in the MmuPV1 / mouse model showed significant antiviral activity. To further evaluate these mixtures, we developed novel self-emulsifying ointment formulations of the mixtures and evaluated their delivery and administration strategies using the CRV / rabbit preclinical in vivo model. This study focused on the number of papillomas that developed at the infection site, as well as the growth rate and size of the papillomas, over a 6-week treatment period.

[0256] The experimental design was based on previously published protocols. Twenty-five adult New Zealand White rabbits of both sexes were purchased from Inotiv and isolated for 14 days. On day 0, each rabbit was inoculated with 5 μg / site of wild-type (wt-CRPV) DNA at two sites and 25 μl / site of mutant virus (mE8-CRPV) at two other sites. From day 10, L1 and L2 rabbits were treated with drugs, while the R sites (R1 and R2) were left untreated as an internal control for papilloma growth. Local treatment was initiated on day 10 and applied five times a week (twice daily, Monday through Friday) only to the left-sided papilloma. The papilloma was measured weekly in millimeters along three axes (length × width × height). The data was entered into a spreadsheet, and calculations were performed to determine the geometric mean diameter of each papilloma, the mean ± SEM for each group, and the corresponding Student's t-test between the groups. Plots were created as papilloma size over time, and changes in body weight were also plotted. Skin / papilloma sites were monitored photographically, and summaries of the mixtures and treatment groups are shown in Tables 22 and 23. The compositions are as follows:

[0257] Group A: TW-SD1 = Tetrahydrocurcumin (32 μM) + EGCG (8 μM) + Pinostilbene (100 μM)

[0258] Group B: TW-SD2 = Tetrahydrocurcumin (32 μM) + EGCG (8 μM) + Pterostilbene (100 μM)

[0259] Group C, TW-1:1 = Tetrahydrocurcumin (32 μM) + EGCG (8 μM) + Piceatannol (50 μM) + Pterostilbene (50 μM)

[0260] Group D:TW-1:5 = Tetrahydrocurcumin (32 μM) + EGCG (8 μM) + Piceatannol (16.67 μM) + Pterostilbene (83.33 μM)

[0261] Group E: T-SD1 (positive control) = curcumin (32 μM) + EGCG (8 μM) + pterostilbene (100 μM) [Table 22]

[0262] Summary of findings. As a class, combinations of curcuminoids, catechins, and diphenylethylene were found to exhibit potent activity in the CRPV / rabbit model. Complete suppression of wild-type CRPV and mutant m8CRPV was observed during 5 weeks of treatment in all treatment groups except A[TW-SD1=tetrahydrocurcumin (32 μM) + EGCG (8 μM) + pinostilbene (100 μM)]. This mixture did not contain the diphenylethylene compounds derived from medicinal rhubarb that were screened and discussed in Examples 1 and 2 of the above section. This mixture contained a resveratrol derivative called transinostylbene (3,4'-dihydroxy-5-methoxystilbene), a monomethoxy derivative of resveratrol that showed activity during standardization. This compound did not completely suppress papillomas during treatment, as in groups B-E, confirming that not all resveratrol derivatives have equivalent efficacy. On the other hand, group B (TW-pterostilbene), which contains one of the identified potent diphenylethylene compounds, performed better than TW-pinostilbene in suppressing the size of wild-type and mutant CRPV papillomas at the end of 11 weeks post-study when used in equal amounts in our cream.

[0263] The inventors conducted further comparisons among all groups. The highest efficacy was observed in groups B, C, and D. For all three treatments, a steady increase in papilloma size was observed in the untreated groups (R1, R2). In the positive control group, T-SD1 (containing pinostylbene) showed a slower growth rate in the treated groups (L1, L2) compared to the untreated group, resulting in a drug-induced reduction of 30.6% for wild-type CRPV and 36.4% for mutant CRPV at 10 weeks. Two lead mixtures were identified as highly effective. Group D (TW-1:5) showed a significant reduction in papilloma size in the treated group, with drug-induced reductions of 82% for wild-type CRPV and 81.9% for mutant CRPV at the end of 10 weeks. Lead number 2 (TW-1:1) showed the most substantial reduction, with drug-induced reductions of 92% in wild-type CRPV and 85.7% in mutant CRPV at 10 weeks. Overall, lead number 2 (TW-1:1) proved to be the most effective treatment for reducing papilloma size, followed by lead number 1 (TW-1:5), with the positive control (T-SD1) being the least effective of the three. In the positive control group (Group E) treated with T-SD1 (pinostylbene), there was no cure for either wild-type or mutant CRPV warts (Table 23), with 0 out of 5 rabbits cured in each category (0%). In contrast, Group D, treated with TW-1:5 (containing piceatannol and pterostilbene in a 1:5 molar ratio), showed a 40% cure rate for wild-type CRPV warts, with 2 out of 5 rabbits cured, and a 60% cure rate for mutant CRPV warts, with 3 out of 5 rabbits cured. Group C, treated with TW-1:1(5 (containing piceatannol and pterostilbene in a 1:1 molar ratio)), showed the highest efficacy, with 3 out of 4 rabbits cured of wild-type CRPV warts (75%) and 2 out of 4 rabbits cured of mutant CRPV warts (50%) (Tables 23 and 24). [Table 23] [Table 24] Example 12 A specific formulation embodiment In one embodiment of the present invention, the formulation comprises, by weight percentage, the following: Tetrahydrocurcumin: 6% EGCg: 2% Piceatannol: 2% Pterostilbene: 10.86% Propylene glycol: 8% Diethylene glycol monoethyl ether NF 8% Pharmacologically acceptable carriers: 63.14% In one embodiment, pharmaceutically acceptable carriers are as follows: [Table 28] The pharmaceutically acceptable carrier described above is an anhydrous, self-emulsifying ointment composition that enhances the delivery and stability of the active pharmaceutical ingredient. The formulation improves contact time and adhesion within the vaginal environment, forms micelles upon contact with vaginal moisture, reduces the risk of hydrolysis and oxidation of the active pharmaceutical ingredient, and thereby enhances the stability and efficacy of the drug. Example 13 Embodiments of certain other pharmaceutically acceptable carriers

[0264] The following pharmaceutically acceptable carriers can also be used in the formulations of the present invention.

[0265] Carrier A: Active pharmaceutical ingredient. An aqueous penetration-enhancing gel-cream composition that enhances the transdermal and transmucosal delivery of active pharmaceutical ingredients. This composition contains lecithin, poloxamer 407, isopropyl myristate, and propylene glycol. This formulation has good adhesion to mucosal surfaces, has a gel- and cream-like aesthetic appearance, and improves the delivery of various APIs.

[0266] Carrier B: A topical, cosmetically pleasing, penetration-enhancing oil-in-water (O / W) emulsion that improves the delivery of active pharmaceutical ingredients through undamaged human and animal skin. This composition contains phosphatidylcholine, isopropyl myristate, cetearyl alcohol, and ceteareth-20 as key components to enhance penetration, as well as polyacrylamide and dimethicone to improve cosmetic quality.

[0267] Carrier C: A topical or vaginal penetration-enhancing O / W emulsion (cream) that improves the delivery of active pharmaceutical ingredients to and through human and animal skin or vaginal tissue. This composition contains lecithin, urea, isopropyl palmitate, isopropyl myristate, glyceryl stearate, and PEG-40 stearate as key components for improving the penetration of the API.

[0268] Carrier D: Active pharmaceutical ingredient. A topical water-in-oil (W / O) emulsion (cream) with high moisturizing properties for surface delivery of the active pharmaceutical ingredient. This heavier cream forms a moisturizing barrier on the skin and releases the active substance to the skin surface. This composition contains petrolatum, urea, stearyl alcohol, lanolin alcohol, PEG-40 stearate, and mineral oil as key components for forming a high-viscosity emulsion with good barrier formation.

[0269] Carrier E: An anhydrous (low water activity) penetration-promoting topical ointment having excellent cosmetic elegance (silky feel) and excellent spreadability. This composition contains phosphatidylcholine, PEG-16 macadamia glyceride, and PEG-8 caprylic / capric acid glyceride as key components for delivery in the carrier of dimethicone and caprylyl methicone, and has polysilicone-11 and PEG-12 dimethicone / PPG-20 crosspolymer to provide viscosity and cosmetic elegance.

[0270] Carrier F: An anhydrous (low water activity) self-emulsifying vaginal cream with good mucosal adhesion, designed to deposit active pharmaceutical ingredients onto the surface of the vaginal mucosa. This composition contains PEG-32 stearate, glyceryl stearate, poloxamer 407, and glyceryl ricinoleate as key components in the medium-chain triglyceride oil carrier. The formulation has a gel-cream-like aesthetic appearance and is less likely to leak from the vagina after injection.

[0271] Carrier G: A topical oil-in-water (O / W) nonionic lamellar emulsion (cream) for surface delivery of active pharmaceutical ingredients, having a soft / smooth and aesthetically pleasing feel. This composition contains emulsifying wax, ethylhexyl stearate, and cyclopentasiloxane as key components, and includes a natural preservative system free of parabens and formaldehyde donors.

[0272] Carrier H: A topical oil-in-water (O / W) emulsion having a lotion-like consistency that is highly moisturizing for surface delivery of active pharmaceutical ingredients. This composition contains ethylhexyl stearate, cyclopentasiloxane, PEG-100 stearate, glyceryl stearate, PEG / PPG-18 / 18 dimethicone, and sorbitol as key components for the physicochemical properties of lotion and API release.

[0273] Carrier I: An aqueous topical gel for surface delivery of an active pharmaceutical ingredient, having a soft, "velvety" feel after drying on the skin surface. This composition contains ammonium acryloyldimethyltaurate / VP copolymer in a water-based carrier as a key component responsible for the gel's physicochemical characteristics (drug release and cosmetic elegance).

[0274] Carrier J: An oil-in-water (O / W) emulsion (cream) for topical delivery of active pharmaceutical ingredients to patients with sensitive skin or atopic dermatitis (eczema) or psoriasis. This composition contains polyglyceryl-3 cetearyl ether olive, carapa guaianesis seed oil, theanine, Vitis vinifera (grape) seed extract, xylityl glucoside, Boswelia serrata resin extract, phosphatidylcholine, phosphatidylglycerol, and Brassica campestris sterols as key components for API delivery and skin soothing, and has dimethicone and cyclopentasiloxane for film formation and cosmetic elegance. Example 14 Evaluation of exemplary combination compositions containing pterostilbene, as well as curcuminoids and catechins.

[0275] The mixture T-pterostilbene, containing curcumin (8 μM) + EGCG (2 μM) + pterostilbene (25 μM), was further tested, and two additional mixtures were prepared as follows:

[0276] T-Ptero(1:1:1) equimolar:curcumin (10 μM) + EGCG (10 μM) + pterostilbene (10 μM)

[0277] T-Ptero(25:2:8): Curcumin (10 μM) + EGCG (10 μM) + Pterostilbene (10 μM)

[0278] These mixtures were tested in HeLa cells (Table 25). The data showed that the T-Ptero mixture in an 8:2:25 ratio was the most potent, with an IC50 of 2.433 μM. This ratio is the molar concentration exemplified in Examples 6-8. Reversing the molar ratio of the compounds to 25:2:8 resulted in antagonistism, yielding an IC50 of 14.535 μM. The equimolar mixture T-Ptero (1:1:1) also showed good efficacy, with an IC50 of 4.570 μM, demonstrating substantial inhibitory effect. This indicates that, for the diphenylethylene compound pterostilbene, mixtures with curcuminoids and catechins are effective in this equimolar ratio. [Table 25] In one embodiment of the present invention, the formulation comprises the following equimolar composition by weight percentage: Tetrahydrocurcumin: 6.8% EGCg: 8.4% Pterostilbene: 4.7% Propylene glycol: 8% Diethylene glycol monoethyl ether NF 8% Pharmacologically acceptable carriers: 63.14% Here, pharmaceutically acceptable carriers are illustrated in Examples 12 and 13. *** Although this application is described with reference to examples, it should be understood that the claims should not be limited by the embodiments described in the examples, but rather should be given the broadest possible interpretation consistent with the description as a whole.

Claims

1. A pharmaceutical composition, in an effective amount One or more compounds of formula I: 【Chemistry 19】 or its pharmaceutically acceptable salts, prodrugs, and / or solvates (In the formula, X １ and X ２ These are independently OH and OR １ Selected from, X ３ and X ４ These are independently OH and OCH ３ Selected from, R １ teeth, 【Chemistry 20】 (It is) Curcuminoids, Catechin, Pterostilbene or pinostilbene, if necessary. Each of them, Pharmacologically acceptable carriers and A pharmaceutical composition containing the following:

2. The pharmaceutical composition according to claim 1, wherein the curcuminoid is selected from curcumin (diferloylmethane), tetrahydrocurcumin, demethoxycurcumin, tetrahydrodemethoxycurcumin, bisdemethoxycurcumin, tetrahydrobisdemethoxycurcumin, curcumin esters, and combinations thereof.

3. The pharmaceutical composition according to claim 1, wherein the curcuminoid is tetrahydrocurcumin.

4. The pharmaceutical composition according to claim 1, wherein the catechin is selected from epicatechin gallate (ECG), epigallocatechin gallate (EGCG or EGCg), epicatechin (EC), epigallocatechin (EGC), (-)-epigallocatechin gallate ((-)-EGCG), (-)-epicatechin gallate ((-)-ECG), (-)-epigallocatechin ((-)-EGC), (+)-gallogallate ((+)-GCG), (-)-epicatechin ((-)-EC), (+)gallocatechin ((+)-GC), and (+)-catechin ((+)-C).

5. The pharmaceutical composition according to claim 1, wherein the catechin is (-)-epigallocatechin gallate.

6. The pharmaceutical composition according to claim 1, wherein the composition comprises two or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof.

7. The pharmaceutical composition according to claim 1, wherein the composition comprises two compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, the two compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, present in the composition in molar ratios of about 0.5:1 to about 1:10, about 0.5:1 to about 1:8, about 0.5:1 to about 1:5, about 0.5:1 to about 1:4, about 0.5:1 to about 1:3.75, about 0.5:1 to about 1:4, about 1:1 to about 1:4, about 1:1 to about 1:3.75, about 1:1 to about 1:3, or about 1:1 to about 1:2.

2.

8. The pharmaceutical composition according to claim 7, wherein the two compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, are present in the composition in a molar ratio of about 1:4, about 1:3.75, about 1:3, about 1:2, or about 1:

1.

9. The pharmaceutical composition according to claim 1, wherein the curcuminoid, the catechin, and the one or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof are present in the composition in a molar ratio of the curcuminoid to the catechin to the one or more compounds of formula I, or two or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof of about 1 to 16:0.25 to 4:1 to 40, about 1 to 16:1 to 4:10 to 40, about 1 to 10:1 to 3:1 to 30, about 4 to 12:1 to 3:15 to 35, or about 6 to 8:2 to 3:20 to 30.

10. The pharmaceutical composition according to claim 9, wherein the one or more or two or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, the curcuminoids, and the catechins are present in the composition in a molar ratio of the one or more or two or more compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof to the curcuminoids to the catechins of about 8:2:

25.

11. The pharmaceutical composition according to claim 1, wherein the one or more compounds of formula I, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, is I-3 (piceatannol), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, the curcuminoid is curcumin, the catechin is (-)-epigallocatechin gallate, and the molar ratio of curcumin to (-)-epigallocatechin gallate to I-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof is about 8:2:

25.

12. The pharmaceutical composition according to claim 11, wherein the composition comprises two compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, the two compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof being I-1 (isorapontigenin), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof, and I-3 (piceatannol), or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

13. The pharmaceutical composition according to claim 12, wherein the two compounds of formula I, or pharmaceutically acceptable salts, prodrugs, and / or solvates thereof, are I-1 (isorapontigenin) and I-3 (piceatannol), the curcuminoid is curcumin, the catechin is (-)-epigallocatechin gallate, and I-3 (piceatannol) and I-1 (isorapontigenin) are present in the composition in a molar ratio of I-3 to I-1 of about 1:3.

75.

14. A pharmaceutical composition for treating or prophylactically treating resveratrol-resistant cancer or HPV-induced cancer or HPV-infected cells in subjects requiring treatment or prophylactic treatment of resveratrol-resistant cancer or HPV-induced cancer or HPV-infected cells, comprising an effective amount of pterostilbene or pinostylbene, or their individual pharmaceutically acceptable salts, prodrugs, and / or solvates, curcuminoids, and catechins.

15. The pharmaceutical composition according to claim 14, wherein the curcuminoid, the catechin, and pterostilbene, or a pharmaceutically acceptable salt thereof, prodrug, and / or solvate thereof are present in the composition in a molar ratio of the curcuminoid to the catechin to the pterostilbene, or a pharmaceutically acceptable salt thereof, prodrug, and / or solvate of about 1 to 16:1 to 4:10 to 40, about 1 to 10:1 to 3:1 to 30, about 4 to 12:1 to 3:15 to 35, or about 6 to 8:2 to 3:20 to 30.

16. The pharmaceutical composition according to claim 14, wherein the curcuminoid, the catechin, and pterostilbene, or a pharmaceutically acceptable salt thereof, prodrug, and / or solvate thereof are present in the composition in a molar ratio of the curcuminoid to the catechin to the pterostilbene, or a pharmaceutically acceptable salt thereof, prodrug, and / or solvate of about 8:2:

25.

17. The pharmaceutical composition according to claim 14, wherein the curcuminoid is selected from curcumin (diferloylmethane), tetrahydrocurcumin, demethoxycurcumin, bisdemethoxycurcumin, tetrahydrodemethoxycurcumin, tetrahydrobisdemethoxycurcumin, curcumin esters, and combinations thereof.

18. The pharmaceutical composition according to claim 14, wherein the curcuminoid is curcumin.

19. The pharmaceutical composition according to claim 14, wherein the catechin is selected from epicatechin gallate (ECG), epigallocatechin gallate (EGCG or EGCg), epicatechin (EC), epigallocatechin (EGC), (-)-epigallocatechin gallate ((-)-EGCG), (-)-epicatechin gallate ((-)-ECG), (-)-epigallocatechin ((-)-EGC), (+)-gallogallate ((+)-GCG), (-)-epicatechin ((-)-EC), (+)gallocatechin ((+)-GC), and (+)-catechin ((+)-C).

20. The pharmaceutical composition according to claim 14, wherein the catechin is (-)-epigallocatechin gallate.

21. The pharmaceutical composition according to claim 14, wherein the curcuminoid is curcumin, the catechin is (-)-epigallocatechin gallate, and the molar ratio of curcumin to (-)-epigallocatechin gallate to pterostilbene, or a pharmaceutically acceptable salt thereof, prodrug, and / or solvate is about 8:2:

25.

22. The pharmaceutical composition according to claim 1 or 14, wherein the pharmaceutical composition is formulated as a cream or a self-emulsifying ointment.

23. The pharmaceutical composition according to claim 22, wherein curcuminoids are present in an amount of 1 to 10%, catechins in an amount of 0.33 to 4%, and diphenylethylene compounds in an amount of 2 to 16%.

24. 8 μM curcumin, 2 μM (-)-epigallocatechin gallate, and 25 μM piceatannol, 8 μM curcumin, 2 μM (-)-epigallocatechin gallate, and 25 μM pterostilbene, 8 μM curcumin, 2 μM (-)-epigallocatechin gallate, 12.5 μM piceatannol, and 12.5 μM pterostilbene, 8 μM curcumin, 2 μM (-)-epigallocatechin gallate, 4.2 μM piceatannol, and 20.8 μM pterostilbene A pharmaceutical composition selected from the group consisting of the following.

25. Tetrahydrocurcumin, (-)-epigallocatechin gallate, and pinostylbene in a molar ratio of 4:1:12.5 Tetrahydrocurcumin, (-)-epigallocatechin gallate, pterostilbene in a molar ratio of 4:1:12.5 Tetrahydrocurcumin, (-)-epigallocatechin gallate, piceatannol, and pterostilbene in a molar ratio of 4:1:6.25:6.25, Tetrahydrocurcumin, (-)-epigallocatechin gallate, piceatannol, and pterostilbene in a molar ratio of 4:1:2.1:10.4 Tetrahydrocurcumin, (-)-epigallocatechin gallate, and pterostilbene in a molar ratio of 1:1:1, and Curcumin, (-)-epigallocatechin gallate, and pterostilbene in a molar ratio of 1:1:1 A pharmaceutical composition selected from the group consisting of the following.

26. A method for treating or preventing a papillomavirus infection in a subject requiring treatment or prevention of a papillomavirus infection, comprising the step of administering to the subject an effective amount of the pharmaceutical composition according to claim 1 or claim 14.

27. The method according to claim 26, wherein the papillomavirus infection is human papillomavirus (HPV) infection.

28. The HPV infection is 1 (HPV-1), 2 (HPV-2), 3 (HPV-3), 4 (HPV-4), 5 (HPV-5), 6 (HPV-6), 8 (HPV-8), 11 (HPV-11), 16 (HPV-16), 18 (HPV-18), 21 (HPV-21), 22 (HPV-22), 2 3 (HPV-23), 27 (HPV-27), 29 (HPV-29), 31 (HPV-31), 33 (HPV-33), 35 (HPV-35), 39 (HPV-39), 45 (HPV-45), 51 (HPV-51), 52 (HPV-52), 56 (HPV-56), 57 (HPV-57) The method according to claim 27, wherein the infection is one or more HPV genotypes selected from 58 (HPV-58), 59 (HPV-59), and 68 (HPV-68).

29. The method according to claim 28, wherein the HPV infection is an infection of one or more HPV genotypes selected from HPV genotypes 16 (HPV-16) and 18 (HPV-18).

30. A method for treating or preventing a disease, disorder, or condition caused by a papillomavirus infection, comprising the step of administering a therapeutically effective amount of the pharmaceutical composition according to claim 1 or 14 to a subject in need thereof.

31. The method according to claim 30, wherein the disease, disorder, or condition caused by a papillomavirus infection is a papillomavirus-associated cancer or precancerous condition.

32. The method according to claim 31, wherein the papillomavirus-related cancer is selected from cervical cancer, anal cancer, oropharyngeal cancer, penile cancer, vaginal cancer, vulvar cancer, oral cancer, and skin cancer, and combinations thereof.

33. The method according to claim 31, wherein the papillomavirus-related cancer is resistant to resveratrol.

34. The method according to claim 31, wherein the disease, disorder, or condition caused by papillomavirus infection is selected from warts and laryngeal papillomas, and combinations thereof.

35. The method according to claim 34, wherein the wart is selected from common warts, flat warts, filiform warts, mosaic warts, plantar warts, perineal warts, and genital warts, and combinations thereof.

36. The method according to claim 35, wherein the wart is a plantar wart.

37. The method according to claim 36, wherein the warts are caused by one or more of HPV-1, HPV-2, HPV-3, HPV-4, HPV-5, HPV-6, HPV-11, HPV-27, HPV-29, and HPV-57.

38. A method for treating resveratrol-resistant cancer or HPV-induced cancer or HPV-infected cells in a subject requiring treatment of such cancer, comprising the step of administering to the subject a therapeutically effective amount of the pharmaceutical composition according to claim 14.

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