Compositions comprising FAD, L-GSH, ATP and myristic acid for use alone or with medicaments

Abstract

The present invention relates to a pharmaceutical or nutraceutical composition comprising a salt of flavin adenine dinucleotide (FAD) in combination with ATP or a salt thereof, reduced L-GSH and optionally myristic acid or a salt thereof for use in the treatment of a disease and / or as a supplement for reducing the side effects caused by a drug, in particular an anti-cancer drug.

Description

Technical Field

[0001] The present invention generally relates to the fields of pharmacy and / or nutrition. Background Art

[0002] "Drug" is a general term for a compound or combination of compounds that, when administered to a patient, can at least partially prevent or treat a disease. Depending on the dosage used and the sensitivity of the patient, a drug may have adverse side effects or even cause death.

[0003] For example, due to the increasing incidence of cancer, anticancer drugs are used more and more frequently, but it is well known that these drugs can cause very serious side effects that affect patients' compliance with treatment.

[0004] "Cancer" is a general term for diseases in which certain cells in the body divide in an uncontrolled manner and are thought to lose the ability to differentiate. These cells all come from the same clone, the cancer-inducing cell, which has special characteristics that allow it to divide indefinitely. As the disease progresses, some cells may migrate from their primary site and form metastases. The resulting new cells may form malignant tumors (neoplasms) and / or spread throughout the body. With an aging population and advances in diagnostic technology, the incidence of cancer is increasing. Cancer has thus become a public health problem.

[0005] An effective treatment must be able to effectively destroy cancer cells while sparing the body's healthy cells as much as possible. However, most existing treatments are increasingly aggressive not only to cancer cells but also to healthy cells, leading to some adverse effects, especially disability.

[0006] Therefore, there is still a need to develop new treatments, especially for cancers with a very poor prognosis or metastatic cancers.

[0007] Furthermore, a solution is needed to mitigate the adverse side effects caused by drugs or pharmaceuticals, especially anti-cancer drugs, as these drugs can produce very severe and disabling side effects.

[0008] Liver cancer is the fifth most common cancer and the third most common cause of cancer-related death in the world. Llovet et al., 2003, "Hepatocellular carcinoma," Lancet 362: 1907-17. The most common liver cancer is hepatocellular carcinoma, also known as HCC, which often occurs at the same time as other common liver injuries such as hepatitis or cirrhosis. Thorgeirsson et al., 2002, "Molecular pathogenesis of human hepatocellular carcinoma," Nature Genetics 31: 339-346. Other forms of liver cancer are less common and include hepatoblastoma and cholangiocarcinoma.

[0009] The standard treatment for liver cancer is surgical resection when possible, or chemotherapy, chemoembolization, or radiation therapy when surgery is not an option. Surgery is not always an option due to tumor size or location and advanced cirrhosis, and even when surgery is performed, tumor recurrence / relapse occurs 5 years after resection in 70% of cases (see Llovet et al. (supra)). Chemotherapy also appears to be less effective in liver cancer, possibly due to the enhanced ability of liver cancer cells to excrete chemotherapy drugs. Therefore, more effective treatments are urgently needed for liver cancer.

[0010] Similarly, in France, pancreatic cancer is the sixth most common cause of cancer death (7,181 deaths in 2000), in some industrialized countries it is the fifth most common cause of cancer death, and in the United States it has become the fourth most common cause of death. In France, its incidence is 5 to 10 / 100,000 people per year, and it increases slightly every year (1% to 2%). It accounts for 7% of digestive system cancers and is more common in men (60%) than in women (40%). Since it is often diagnosed in an advanced stage, metastasis is found in half of the cases, resulting in an average survival time of only a few months for this cancer, with a 5-year survival rate of 4% to 6%. The median survival of patients of all stages is 4 to 7 months, and the median survival of patients who have undergone resection surgery increases by 15 to 18 months.

[0011] If pancreatic tumors are inoperable or metastatic, chemotherapy can be considered for informed patients who are in good general condition. The response rate is about 15% to 30%. The drugs used are gemcitabine (Burris et al., European Journal of Cancer, 1997, 33: 18-22), gemcitabine and oxaliplatin combination therapy (Zhao et al., Chinese-German Journal of Clinical Oncology, 2007, 6 (5): 461-463), and 5-fluorouracil (5-FU) combined with platinum derivatives. These chemotherapy methods can modestly improve the median survival of patients with metastatic tumors (4-6 months without treatment), but the side effects are also significant, especially weight loss.

[0012] Despite the progress of new chemotherapy, the prognosis of pancreatic cancer remains poor. Even for patients who have undergone radical surgery, the 5-year survival rate is only about 20% due to local recurrence and metastatic recurrence.

[0013] Given the severity and poor prognosis of pancreatic cancer, there is a real need to propose an alternative treatment option that is more effective than current treatments.

[0014] Document WO2020089310A1 discloses a composition comprising only FAD for treating cancer. Summary of the invention

[0015] One object of the present invention is to provide a new anti-cancer treatment method that is effective for cancer cells, especially for aggressive cancers (rapid progression and / or no or little treatment), such as pancreatic cancer or liver cancer cells, which acts on the initial tumor or metastatic cancer spread cells while having as little toxicity as possible to healthy tissues.

[0016] Another object is to provide an anticancer treatment method in combination with the composition of the present invention to solve the toxicity or side effects associated with the anticancer drugs.

[0017] In addition, the researchers also found that the novel composition of the present invention can reduce the adverse side effects of drug or pharmaceutical treatment, and ultimately can not only improve compliance with the above-mentioned drug treatment. Better yet, during treatment, whether the composition of the present invention is used alone or in combination with other treatment methods, the survival rate of the disease can be improved. In some embodiments, the present invention provides a composition comprising flavin adenine dinucleotide (FAD) or a salt thereof, reduced glutathione (GSH), adenosine triphosphate (ATP) or a salt thereof, optional myristic acid or a salt thereof, and a carrier. In some embodiments, the present invention provides a composition according to the above embodiments, wherein the salt of FAD is flavin adenine dinucleotide disodium salt hydrate, the salt of ATP is adenosine triphosphate disodium salt hydrate, and GSH is reduced L-glutathione.

[0018] In some embodiments, the present invention provides a composition according to the above embodiments, wherein the carrier is selected from metal salts, polymers, liposomes, excipients and combinations thereof.

[0019] In some embodiments, the present invention provides a composition according to the above embodiments, wherein the carrier comprises a polymer selected from polyethylene glycol (PEG), chitosan, collagen, starch, and hyaluronic acid, preferably PEG or chitosan or hyaluronic acid, more preferably PEG 600; more preferably PEG-600-diacid; more preferably hyaluronic acid.

[0020] In some embodiments, the present invention provides a composition according to the above embodiments, wherein the carrier comprises a metal salt, preferably a gold salt, more preferably HAuCl 4 6H 2 O.

[0021] In some embodiments, the present invention provides a composition according to the above embodiments, which is in a form suitable for intravenous injection (iv), oral administration including sublingual administration (po), rectal administration, intratumoral administration, intraocular administration, intramucosal administration, intravesical administration or intraurethral administration, advantageously iv or po administration.

[0022] In some embodiments, the present invention provides a composition according to the above embodiments, wherein the composition is administered to an individual at a dose of 0.1 mg to 10 g of FAD or a salt thereof, a dose of 0.1 mg to 10 g of GSH, a dose of 0.1 mg to 10 g of ATP or a salt thereof, and a dose of 0.1 mg to 10 g of myristic acid or a salt thereof.

[0023] In some embodiments, the present invention provides a composition according to the above embodiments, which is a therapeutically effective amount of the composition and a pharmaceutically acceptable carrier or a nutritionally acceptable carrier.

[0024] In some embodiments, the present invention provides a composition and a medicament for use according to the above embodiments.

[0025] In some embodiments, the present invention provides a composition for use according to the above embodiments for preventing and / or treating a disease.

[0026] In some embodiments, the present invention provides a composition for use according to the above embodiments, wherein the disease is cancer.

[0027] In some embodiments, the present invention provides a composition for use according to the above embodiments, as an adjuvant (supplement) or neoadjuvant (scavenger) for cancer treatment.

[0028] In some embodiments, the present invention provides a composition according to the above embodiments, wherein the disease is selected from the group consisting of brain cancer, breast cancer, prostate cancer, lung cancer, tracheal cancer, upper digestive tract and / or lower digestive tract cancer, gastric cancer, kidney cancer, pancreatic cancer, liver cancer, urethral cancer, reproductive organ cancer, skin cancer, ear, nose and throat (ENT) cancer and lymphatic organ cancer, preferably pancreatic cancer or liver cancer, more preferably invasive metastatic tumor cancer.

[0029] The composition according to the above-mentioned embodiment is used for preventing and / or treating side effects caused by drugs or diseases.

[0030] In some embodiments, the present invention provides a composition according to the above embodiments for use in preventing and / or treating side effects caused by 5-FU.

[0031] In some embodiments, the present invention provides a composition according to the above embodiments for preventing and / or treating side effects selected from weight loss, nausea, vomiting, headache, bleeding, alopecia, neutropenia, pain, thrombosis, lymphedema and combinations thereof, advantageously weight loss.

[0032] The main object of the present invention is to provide a composition comprising flavin adenine dinucleotide (FAD) or a salt thereof, reduced glutathione (GSH) or a salt thereof, adenosine triphosphate (ATP) or a salt thereof, optional myristic acid or a salt thereof and a carrier. More specifically, the present invention relates to the use of the composition, i.e., as a composition or in combination with another drug that may exhibit side effects. In the composition provided by the present invention, the salt of FAD is flavin adenine dinucleotide disodium salt hydrate, the salt of ATP is adenosine triphosphate disodium salt hydrate, and GSH is reduced L-glutathione.

[0033] In the composition provided by the present invention, the carrier is selected from metal salts, polymers, liposomes, excipients and combinations thereof.

[0034] In the composition provided by the present invention, the carrier comprises a polymer selected from polyethylene glycol (PEG), chitosan, collagen, starch, and hyaluronic acid, preferably PEG or chitosan or hyaluronic acid, more preferably PEG 600; more preferably PEG-600-diacid, more preferably hyaluronic acid.

[0035] The composition of the present invention is provided in a form suitable for intravenous injection (iv), oral administration including sublingual administration (po), rectal administration, intratumoral administration, intraocular administration, intramucosal administration, intravesical administration or intraurethral administration, advantageously iv or po administration.

[0036] The dosage of the composition provided to an individual is: 0.1 mg to 10 g of FAD or its salt, 0.1 mg to 10 g of GSH, 0.1 mg to 10 g of ATP or its salt, and 0.1 mg to 10 g of myristic acid or its salt.

[0037] The composition provided by the present invention is a therapeutically effective amount of the composition and a pharmaceutically acceptable carrier or a nutritionally acceptable carrier.

[0038] The invention provides a composition and a medicine.

[0039] The composition provided by the present invention is used for preventing and / or treating diseases.

[0040] The composition provided by the present invention is used for preventing and / or treating cancer.

[0041] The compositions provided by the present invention can be used as adjuvants (supplements) or neoadjuvants (scavengers) for cancer treatment.

[0042] The composition provided by the present invention is used for preventing and / or treating a disease, wherein the disease is selected from the group consisting of brain cancer, breast cancer, prostate cancer, lung cancer, tracheal cancer, upper digestive tract and / or lower digestive tract cancer, gastric cancer, kidney cancer, pancreatic cancer, liver cancer, urethral cancer, reproductive organ cancer, skin cancer, ear, nose and throat (ENT) cancer and lymphatic organ cancer, preferably pancreatic cancer or liver cancer, more preferably invasive metastatic tumor cancer.

[0043] The composition provided by the present invention can be used to prevent and / or treat side effects caused by drugs or diseases.

[0044] The composition provided by the present invention is used for preventing and / or treating the side effects caused by 5-FU.

[0045] The composition provided by the present invention is used for preventing and / or treating side effects, wherein the side effects are selected from weight loss, nausea, vomiting, headache, bleeding, alopecia, neutropenia, pain, thrombosis, lymphedema and combinations thereof, especially weight loss.

[0046] Other implementations include:

[0047] A composition comprising flavin adenine dinucleotide (FAD) or a salt thereof and a carrier, characterized in that the composition further comprises adenosine triphosphate (ATP) or a salt thereof; glutathione (GSH), preferably reduced L-glutathione (L-GSH).

[0048] In a specific embodiment, the composition of the present invention comprises flavin adenine dinucleotide (FAD) or a salt thereof, reduced glutathione (L-GSH), adenosine triphosphate (ATP) or a salt thereof, and may optionally include myristic acid or a salt thereof.

[0049] According to a preferred embodiment, the composition of the present invention comprises flavin adenine dinucleotide disodium salt hydrate, reduced L-glutathione (L-GSH), adenosine triphosphate disodium salt hydrate (ATP) and myristic acid or a salt thereof.

[0050] In certain embodiments, the carrier may be selected from the group consisting of metal salts, polymers, liposomes, lipids, excipients, and combinations thereof.

[0051] In the composition of the present invention, the carrier can be any polymer selected from polyethylene glycol (PEG), chitosan, collagen, starch, alginic acid, hyaluronic acid and combinations thereof, preferably PEG, hyaluronic acid or chitosan, more preferably PEG-600; more preferably PEG-600-diacid.

[0052] The composition of the present invention may comprise a metal salt in the form of nanoparticles, preferably a gold salt, more preferably HAuCl 4 6H 2 O.

[0053] The composition of the present invention is provided in a form suitable for intravenous injection, oral administration, sublingual administration, rectal administration, intratumor administration, intraperitoneal administration, intraocular administration, intramucosal administration, intravesical administration or intraurethral administration.

[0054] In the composition of the present invention, the dosage range of FAD is 0.01 mg to 80 g, the dosage range of GSH is 0.1 to 70 g, the dosage range of ATP is 0.1 mg to 80 g, and the dosage range of myristic acid is 0.1 mg to 10 g. The dosage can be given once or several times a day.

[0055] The composition of the present invention is provided in the form of a therapeutically effective amount and combined with a pharmaceutically acceptable carrier.

[0056] The composition of the present invention can also be used as a nutritional composition, provided in combination with an effective amount of the composition and a nutritionally acceptable carrier. In a specific embodiment, the composition of the present invention can be administered to patients or individuals in need, especially patients suffering from side effects caused by drugs or symptoms caused by diseases, in order to achieve the desired effect.

[0057] The composition of the present invention is particularly suitable for alleviating the side effects of drugs.

[0058] Another object of the invention is a composition and a drug or a medicament according to the invention in any of the embodiments described herein.

[0059] Since the therapeutic effect of the composition of the present invention itself has been confirmed, the composition of the present invention can be used alone for the prevention and / or treatment of diseases.

[0060] When the composition of the present invention is used in combination with another drug, it can also be used to prevent and / or treat diseases.

[0061] In certain embodiments, the composition of the present invention is used in combination with another drug to prevent and / or treat the side effects of the drug.

[0062] In certain embodiments, the compositions of the present invention are combined with another drug to prevent and / or treat a side effect of the drug, and the side effect of the drug is weight loss.

[0063] In particular, the composition of the present invention can be used alone or in combination with a drug to prevent and / or treat a certain disease, which can be cancer.

[0064] The composition of the present invention can be used alone or in combination with drugs as an adjuvant (supplement) or neoadjuvant (scavenger) for cancer treatment.

[0065] In other embodiments, the compositions of the present invention can be used alone or in combination with drugs as an adjuvant or neoadjuvant for cancer treatment.

[0066] In a specific embodiment, the composition of the present invention can be used alone or in combination with a drug to prevent and / or treat cancer, wherein the cancer is selected from the group consisting of brain cancer, breast cancer, prostate cancer, lung cancer, tracheal cancer, upper digestive tract cancer / or lower digestive tract cancer, gastric cancer, kidney cancer, pancreatic cancer, liver cancer, pancreatic cancer, urethral cancer, reproductive organ cancer, skin cancer, ear, nose and throat (ENT) cancer and lymphatic organ cancer, preferably pancreatic cancer or liver cancer, more preferably metastatic pancreatic cancer or metastatic liver cancer.

[0067] In a specific embodiment, the composition of the present invention, used alone or in combination with a drug, can be used to prevent and / or treat pancreatic cancer or liver cancer, especially to prevent and / or treat invasive pancreatic cancer or liver cancer.

[0068] In certain aspects, the invention relates to a nutritional or pharmaceutical composition, nutritional set or pharmaceutical set.

[0069] The composition prepared according to any one of the compositions described herein can be used to prevent and / or treat side effects caused by drugs, preferably side effects include weight loss, nausea, vomiting, headache, bleeding, hair loss, rash, eye irritation, neutropenia, pain, thrombosis, lymphedema and combinations thereof, preferably weight loss. BRIEF DESCRIPTION OF THE DRAWINGS

[0070] Figure 1 The figure shows the effect of composition A (Group A) or composition B (Group B) alone or in combination with 5-fluorouracil (5-FU) on tumor volume on days 30 and 82 after cancer cell transplantation in a pancreatic metastatic cancer model, compared with the control group (MODEL) or 5-FU alone (mean + SEM). *P<0.05, **P<0.01 Tukey test.

[0071] Figure 2 It shows the effect of composition A (Group A) or composition B (right Group B) alone or in combination with 5-FU on the survival rate of mice in a pancreatic metastatic cancer model, compared with a control group (MODEL) or 5-FU alone.

[0072] Figure 3 The graph shows the effect of composition A (Group A) or composition B (Group B) on the side effect (weight loss) caused by 5-FU in a pancreatic metastatic cancer model, compared with a control group (MODEL) or 5-FU alone.

[0073] Figure 4 The figure shows the effect of composition A (Group A) or composition B (Group B) alone or in combination with 5-FU on tumor volume at different times and on day 19 after cancer cell injection in a liver metastatic cancer model, compared with a control group (MODEL) or 5-FU alone.

[0074] Figure 5 The graph shows the effects of composition A (Group A) or composition B (Group B) alone or in combination with 5-FU on the survival rate of mice in a liver metastasis cancer model, compared with a control group (MODEL) or 5-FU alone.

[0075] Figure 6The graph shows the effect of composition A (Group A) or composition B (Group B) on the side effect (weight loss) caused by 5-FU in the liver metastasis cancer model, compared with the control group (MODEL) or 5-FU alone. DETAILED DESCRIPTION

[0076] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.

[0077] Unless otherwise stated, all amounts in the compositions are expressed as weight percent of the material described.

[0078] The expression "effective amount" when used to describe the treatment of a patient with a disease refers to the amount of the drug, medicament or active ingredient of the present invention that will cause a biological or medical response in a cell, tissue, system, animal or human, such as those responses being sought by a researcher or clinician. Such responses include, but are not limited to, the improvement, inhibition or other effect on a disorder, adverse condition, disease, infection or other problem with or in an individual tissue, wherein the disorder, adverse condition, disease or other problem is active, and wherein such inhibition or other effect occurs to an extent sufficient to produce a beneficial therapeutic effect. In addition, the term "therapeutically effective amount" means any amount that can significantly treat, heal, prevent or improve a disease, disorder or side effect, or reduce the rate of progression of a disease or disorder, as compared to a corresponding subject not receiving the amount. The term also includes amounts that are effective within its scope to enhance normal physiological function.

[0079] As used herein, "treating" or "treatment" refers to alleviating the symptoms associated with a disorder or disease, or inhibiting the further development or worsening of these symptoms, or preventing the disease or disorder, or curing the disease or disorder.

[0080] Likewise, as used herein, an "effective amount" or "therapeutically effective amount" of a compound of the invention refers to an amount of the compound that can fully or partially alleviate the symptoms associated with a disorder or disease, or prevent or slow the further development or exacerbation of such symptoms, or prevent or provide relief from the disorder or disease. In particular, a "therapeutically effective amount" refers to an effective amount that achieves the desired therapeutic effect at the necessary dosage and time period. A therapeutically effective amount is also an amount in which any toxic or deleterious effects of a compound of the invention outweigh the therapeutically beneficial effects.

[0081] Implementation

[0082] Before describing the products and manufacturing methods of the present invention in detail, the following lists additional features that can be used in the composition or kit according to the present invention, or in the combination of the composition or kit according to the present invention with another drug. Various embodiments are as follows:

[0083] A composition (hereinafter referred to as "the composition of the present invention") may include:

[0084] FAD, ATP and GSH;

[0085] FAD, ATP, GSH, and myristic acid;

[0086] FAD, ATP, GSH and carriers;

[0087] FAD, ATP, GSH, myristic acid, and carriers;

[0088] (FAD, carrier), ATP;

[0089] (FAD, carrier), GSH;

[0090] (FAD, vehicle), myristic acid;

[0091] (FAD, carrier), ATP; GSH;

[0092] (FAD, carrier), ATP; myristic acid;

[0093] (FAD, carrier), ATP; GSH, myristic acid;

[0094] "Vector" or "carrier" refers to a substance, a vehicle or an excipient; a carrier can be part of a galenic form of the active ingredient (AP).

[0095] Active ingredient (AP) refers to the substance on which the drug depends for certain properties.

[0096] In a specific embodiment, the carrier includes a metal salt, which allows the composition to participate in the destruction of the tumor once it enters the active tumor cells in the tumor (to be irradiated later). The active ingredients according to the present invention include but are not limited to: FAD, ATP, GSH and myristic acid and combinations thereof.

[0097] The active ingredients may be combined as a composition or as part of a kit of parts. The dose of each active ingredient is selected so as to determine its activity alone and / or in combination with the other or all active ingredients.

[0098] In another embodiment, the active ingredient is in a composition with a drug, or as part of a kit of parts. The dose of the active ingredient is selected so that it is effective against the side effects of the drug or the activity against the side effects of the drug.

[0099] According to certain embodiments, the carrier can be a polymer, including, for example, a biopolymer, a metal salt, such as a gold salt nanoparticle (e.g., HAuCl4 6H 2 O), a lipid, a liposome, a carrier or a combination of carriers.

[0100] In certain embodiments, the polymer can be chitosan, starch, polyethylene glycol (PEG), hyaluronic acid, or a combination of polymers.

[0101] The following ingredients were found to be active against the following substances.

[0102] FAD, chitosan, ATP;

[0103] FAD, chitosan, GSH;

[0104] FAD, chitosan, ATP, GSH;

[0105] FAD, chitosan, myristic acid;

[0106] FAD, chitosan, GSH, myristic acid;

[0107] FAD, chitosan, ATP, myristic acid;

[0108] FAD, chitosan, ATP, GSH, myristic acid;

[0109] FAD, PEG600, ATP;

[0110] FAD, PEG600, GSH;

[0111] FAD, PEG600, myristic acid;

[0112] FAD, PEG600, GSH, myristic acid;

[0113] FAD, PEG600, ATP, myristic acid;

[0114] FAD, PEG600, ATP, GSH;

[0115] FAD, PEG600, ATP, GSH, myristic acid;

[0116] FAD, hyaluronic acid, ATP;

[0117] FAD, hyaluronic acid, GSH;

[0118] FAD, hyaluronic acid, myristic acid;

[0119] FAD, hyaluronic acid, GSH, myristic acid;

[0120] FAD, hyaluronic acid, ATP, myristic acid;

[0121] FAD, hyaluronic acid, ATP, GSH;

[0122] FAD, hyaluronic acid, ATP, GSH, myristic acid;

[0123] FAD, gold nanoparticles, ATP;

[0124] FAD, gold nanoparticles, GSH;

[0125] FAD, gold nanoparticles, ATP; myristic acid;

[0126] FAD, gold nanoparticles, GSH; myristic acid;

[0127] FAD, gold nanoparticles, ATP, GSH;

[0128] FAD, gold nanoparticles, ATP, GSH, myristic acid;

[0129] FAD, gold nanoparticles, PEG600;

[0130] FAD, gold nanoparticles, PEG600, myristic acid;

[0131] FAD, gold nanoparticles, PEG600, ATP;

[0132] FAD, gold nanoparticles, PEG600, GSH;

[0133] FAD, gold nanoparticles, PEG600, ATP, GSH;

[0134] FAD, gold nanoparticles, PEG600, ATP, GSH, myristic acid;

[0135] FAD, HAuCl 4 6H 2 O, PEG600;

[0136] FAD, HAuCl 4 6H 2 O, PEG600, myristic acid;

[0137] FAD, HAuCl 4 6H 2 O, PEG600, ATP;

[0138] FAD, HAuCl 4 6H 2 O, PEG600, GSH;

[0139] FAD, HAuCl 4 6H 2O, PEG600, ATP, GSH;

[0140] FAD, HAuCl 4 6H 2 O, PEG600, ATP, GSH, myristic acid;

[0141] FAD, HAuCl 4 6H 2 O, hyaluronic acid;

[0142] FAD, HAuCl 4 6H 2 O, hyaluronic acid, myristic acid;

[0143] FAD, HAuCl 4 6H 2 O, hyaluronic acid, ATP;

[0144] FAD, HAuCl 4 6H 2 O, hyaluronic acid, GSH;

[0145] FAD, HAuCl 4 6H 2 O, hyaluronic acid, ATP, GSH;

[0146] FAD, HAuCl 4 6H 2 O, hyaluronic acid, ATP, GSH, myristic acid.

[0147] In any specific embodiment of the above or following embodiments, FAD can be flavin adenine dinucleotide disodium salt hydrate, the polymer can be PEG600-diacid or hyaluronic acid; the salt metal can be gold nanoparticles, in particular gold nanoparticles of the following formula: HAuCl 4 6H 2 O.

[0148] According to another aspect, the present invention relates to a composition, in particular a pharmaceutical composition or a nutritional composition.

[0149] According to another aspect, the invention relates to a set (set of parts).

[0150] In another embodiment, the present invention relates to a composition, in particular a pharmaceutical composition or a nutritional composition for preventing and / or treating a disease.

[0151] In another embodiment, the present invention relates to a composition, in particular a pharmaceutical composition or a nutritional composition and a medicine for preventing and / or treating a disease.

[0152] In another embodiment, the present invention relates to a composition, in particular a pharmaceutical composition or a nutritional composition for preventing and / or treating side effects of drugs.

[0153] In another embodiment, the present invention relates to a composition, in particular a pharmaceutical composition or a nutritional composition and a medicament for preventing and / or treating side effects of a drug.

[0154] A drug is a medicine or other substance that has a physiological effect when ingested or otherwise introduced into the human body.

[0155] Drugs are medicines or chemical compounds used to treat or cure disease.

[0156] In a preferred embodiment, the disease is cancer.

[0157] The composition of the present invention may contain a carrier which has a protective effect on FAD and can limit its degradation by enzymes.

[0158] The galenic form makes it possible to improve the absorption and distribution of the composition comprising FAD, GSH, ATP and myristic acid in the body while limiting its degradation, in particular by blood hydrolytic enzymes.

[0159] According to another aspect, the present invention relates to a composition, advantageously a pharmaceutical composition, comprising FAD in an amount therapeutically effective against cancer in the presence of ATP and GSH, more particularly consisting of FAD in an amount therapeutically effective against cancer in the presence of ATP and GSH and myristic acid.

[0160] According to another aspect, the invention relates to a composition according to the invention in which FAD is associated with a biopolymer and / or a metal salt, in the form of particles, advantageously nanoparticles, and an excipient.

[0161] According to another aspect, the present invention relates to a nutritional composition comprising an amount of FAD in the presence of ATP and GSH that is therapeutically effective against cancer, more particularly comprising an amount of FAD in the presence of ATP and GSH and myristic acid that is therapeutically effective against cancer.

[0162] According to another aspect, the present invention relates to a nutritional composition comprising an amount of FAD that is therapeutically effective against cancer in the presence of ATP and GSH, more specifically an amount of FAD that is therapeutically effective against cancer in the presence of ATP and GSH and myristic acid, wherein the FAD is combined with a biopolymer and / or a metal salt, in the form of particles, advantageously nanoparticles, and an excipient.

[0163] In one aspect of the present invention, the composition of the present invention may be provided alone or in combination with a drug.

[0164] The drug combined with the composition or kit of the present invention can be any known drug or medicine, and in particular can be a drug that affects food intake, affects appetite, causes nausea, vomiting, headache, bleeding, hair loss, rash, eye irritation, neutropenia, pain, blood clots, lymphedema, or a combination of the side effects.

[0165] Depending on the disease to be treated and / or the side effects of the drug associated with the composition of the invention to be alleviated, the composition or kit of the invention provides an appropriate galenic form for a particular route of administration.

[0166] The composition can be administered orally, intravenously, intramuscularly, intraperitoneally, sublingually, intraocularly, intranasally, intraurethrally, intrarectally, or intertumorally.

[0167] In a particular embodiment, each active ingredient of the composition or kit according to the invention is provided in galenic form for a specific route of administration, which may be the same or different from the route of administration of the other active ingredients.

[0168] Flavin adenine dinucleotide (FAD)

[0169] Flavin adenine dinucleotide (FAD) is a redox coenzyme that participates in a variety of enzymatic reactions in metabolism.

[0170] FAD involved in this article can exist in four redox states, which are flavin-N (5) -oxide, quinone, semiquinone and hydroquinone. FAD can be converted between these states by accepting or providing electrons. The fully oxidized or quinone state of FAD accepts two electrons and two protons to become FADH2 (hydroquinone state). Semiquinone (FADH ·) can be formed by FAD reduction or FADH2 oxidation by accepting or providing an electron and a proton, respectively.

[0171] In the composition according to the invention, the active ingredients include FAD, ATP, GSH and especially myristic acid.

[0172] Compositions or suits according to the present invention include FAD.FAD may be present in the form of salts in compositions or suits according to the present invention.According to the present invention, FAD refers to, for example, FAD or a salt, hydrate or solvate of FAD obtained by any method described in this specification or in WO2020089310A1, and WO2020089310A1 is incorporated herein by reference in its entirety. In the composition of the present invention, FAD may be protected by natural protection or in combination with a polymer. In other embodiments, FAD may be a FAD combined with an enzyme, and the enzyme may be modified to be more stable (such as in JP2015084676A or EP2844747B1), and JP2015084676A, EP2844747B1 are incorporated herein by reference in their entirety. In a preferred embodiment, FAD may be a flavin adenine dinucleotide disodium salt hydrate, such as disclosed in CN103826642B, which is incorporated herein by reference in its entirety. The salt of flavin adenine dinucleotide is not particularly limited as long as it is a pharmaceutically acceptable salt or a nutritionally acceptable salt.

[0173] Examples of suitable salts for any of the ingredients or AP (i.e., FAD, ATP, myristic acid, hyaluronic acid) in the compositions of the present invention include salts of inorganic acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, or phosphoric acid); salts of organic acids (e.g., acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptonic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isothioic acid, lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfide); ester, methyl sulfate, naphthalenesulfonic acid or sulfosalicylic acid); quaternary ammonium salts of methyl bromide, methyl iodide or the like; salts of halogen ions such as bromide, chloride or iodide; salts of alkali metals such as lithium, sodium or potassium; salts of alkaline earth metals such as calcium or magnesium; metal salts of iron, zinc or the like; salts of ammonia; and salts of organic amines such as triethylenediamine, 2-aminoethanol, 2,2-iminobis(ethanol), 1-deoxy-1-(methylamino)-2-D-sorbitol, 2-amino-2-(hydroxymethyl)-1,3-propanediol, procaine or N,N-bis(phenylmethyl)-1,2-ethylenediamine.

[0174] Preferably, the salt of FAD is an alkali metal salt, more preferably, the alkali metal is sodium.

[0175] In the present invention, as the "salt of FAD" or "salt of ATP", a sodium salt is preferred, and flavin adenine dinucleotide disodium salt hydrate is particularly preferred. Adenosine triphosphate disodium salt hydrate is particularly suitable as the salt of ATP.

[0176] Therefore, flavin adenine dinucleotide disodium salt hydrate can be used in combination with reduced L-glutathione (L-GSH) and salts of ATP (such as adenosine triphosphate disodium salt hydrate).

[0177] In the composition of the present invention, FAD or flavin adenine dinucleotide disodium salt hydrate may be in free form and / or combined with a carrier. Preferably, FAD or flavin adenine dinucleotide disodium salt hydrate may be combined with at least one carrier. More preferably, FAD may be combined with at least one carrier selected from metal salts, polymers, fatty acids, and carrier combinations.

[0178] In the composition of the present invention, FAD or flavin adenine dinucleotide disodium salt hydrate is combined with a carrier, more preferably, FAD or flavin adenine dinucleotide disodium salt hydrate can be combined with hyaluronic acid (such as hyaluronic acid in EP2762144) or polyethylene glycol.

[0179] In the compositions of the present invention, various metal salts are also suitable for combination with FAD or flavin adenine dinucleotide disodium salt hydrate alone or in combination with a polymer. In a preferred embodiment, FAD-HAuCl is provided in the compositions of the present invention. 4 6H 2 O, or more preferably a combination of flavin adenine dinucleotide disodium salt hydrate.

[0180] The composition or kit according to the invention comprises adenosine triphosphate (ATP).

[0181] Adenosine triphosphate (ATP) or adenosine-5'-(tetrahydrogen triphosphate) is a well-known compound used in various treatments and as a nutritional compound. Various forms and salts of ATP, such as those described in US7585850B2 (incorporated herein by reference in its entirety), can be used in combination with FAD and L-GSH (optionally, myristic acid) according to the present invention to prepare the composition or kit of the present invention.

[0182] According to the invention, the composition or kit comprises glutathione (GSH).

[0183] Reduced glutathione (GSH) or L-GSH is a tripeptide (glutamic acid-cysteine-glycine) with a chemical formula of 2-amino-5-acid-{[2-[(carboxymethyl)amino]-1-(mercaptomethyl)-2-oxoethyl]amino}-5-oxopentanoic acid. In its reduced form, GSH exhibits a very strong reducing ability. GSH can be produced by any known method or by a method disclosed in, for example, EP1391517B1 or EP2501823, which are incorporated herein by reference in their entirety.

[0184] The composition or kit according to the present invention may comprise myristic acid.Myristic acid may be synthesized or extracted by any method or by the method disclosed in, for example, EP3146059 or EP2689020 or Organic syntheses Coll. Vol.1 p.379 (1941) Vol.6, p.66 (1926).

[0185] Carrier or carrier

[0186] In the composition of the present invention, FAD is combined with a carrier. In a specific embodiment, the carrier can be a pharmaceutically acceptable carrier or a nutritionally acceptable carrier. In the composition of the present invention, the carrier combined with FAD may include at least one polymer, preferably at least one biopolymer, more specifically, at least one selected from polyethylene glycol (PEG), PEG-diacid, PEG-600, PEG600-diacid, alginic acid or alginate; poly-lactide; bisphosphonate; gelatin; maltodextrin; polyamino acids (poly-L-lysine, poly-L-ornithine, poly-L-arginine); lauryl glucoside; chitosan; elastin; hyaluronic acid; cellulose; glucose polymers; and biopolymers of biopolymer combinations; preferably PEG600, more preferably PEG600-diacid.

[0187] In a specific embodiment, the carrier conjugated to FAD includes alginate, collagen, chitosan, glucose polymer. In a specific embodiment, PEG600 or chitosan is conjugated to FAD in the composition of the present invention.

[0188] In a specific embodiment, the carrier combined with FAD includes hyaluronic acid in the composition or kit of the present invention. Hyaluronic acid suitable for nutritional or pharmaceutical compositions can be produced by any known method and, for example, by the method described in EP3294355 or in WO1992008799A1, which are incorporated herein by reference in their entirety.

[0189] In an advantageous embodiment of the composition of the invention, FAD is combined with PEG and myristic acid; ATP, GSH are combined with hyaluronic acid.

[0190] In an advantageous embodiment of the composition according to the invention, FAD is combined with hyaluronic acid and ATP, GSH and myristic acid are combined.

[0191] In certain embodiments, polymers or biopolymers, such as starch, hyaluronic acid, glycogen, sucrose, lactose, combinations of these polymers, may be combined with any of the PAs of the composition or kit according to the present invention.

[0192] Therefore, according to the present invention, in the composition of the present invention, FAD may be bound or combined with any one glucose polymer selected from starch, glycogen, sucrose, and lactose, or may be bound or combined with several of these glucose polymers.

[0193] Among the collagens that may bind to FAD in the composition of the present invention, collagen I or IV is preferred, human or rabbit collagen I or IV is more preferred, human collagen I or IV is more preferred, and human collagen I is more preferred.

[0194] In a preferred embodiment, the carrier comprises PEG-600-diacid.

[0195] In another preferred embodiment, the carrier comprises hyaluronic acid.

[0196] Metal Salts

[0197] In a specific embodiment, the present invention relates to a composition comprising FAD-HAuCl 4 6H 2 O, FAD-PEG600, FAD-HAuCl 4 6H 2 O-PEG600, FAD-chitosan, FAD-HAuCl 4 6H 2 O-chitosan, FAD-human collagen I, FAD-HAuCl 4 6H 2 O-human collagen I, FAD-arginine, FAD-HAuCl 4 6H 2 O-arginine, FAD-hyaluronic acid, FAD-HAuCl 4 6H 2 A combination of O-hyaluronic acid with ATP, GSH and myristic acid.

[0198] According to the present invention, a preferred example of FAD combined with ATP, GSH and myristic acid is FAD-HAuCl 4 6H 2 O, FAD-PEG600, FAD-HAuCl 4 6H 2 O-PEG600, FAD-chitosan, FAD-HAuCl 4 6H 2 O-chitosan. According to the present invention, a more preferred combination example in the composition is FAD-PEG600, FAD-HAuCl 4 6H 2 O-PEG600 or FAD-hyaluronic acid, FAD-HAuCl 4 6H2 O-Hyaluronic acid.

[0199] In certain embodiments, a polymer, preferably a biopolymer, is used to protect FAD from degradation.

[0200] Therefore, the pharmaceutical or nutritional composition according to the present invention comprises a FAD carrier compound, which may be present together with ATP, GSH, and optionally myristic acid, and the preferred FAD carrier is selected from FAD-polymers, FAD-fatty acids, FAD-biopolymers, FAD-metal salts, and combinations of these compounds (FAD-polymer-metal salts, FAD-fatty acids-metal salts, FAD-biopolymer-metal salts).

[0201] In other embodiments, such as in EP1034791 (incorporated herein by reference in its entirety), the FAD is protected from degradation.

[0202] One aspect of the present invention relates to a composition comprising a protected FAD-metal salt composition in combination with ATP, GSH and myristic acid in a composition according to the present invention, and a device for providing anti-cancer radiation.

[0203] An object of the present invention may be a FAD-gold salt (FAD-AU salt) or a FAD-gold particle composition in combination with ATP, GSH and myristic acid in a composition according to the present invention, and a device for providing infrared light, preferably near infrared light.

[0204] Another object of the present invention is a composition according to the invention and an infrared (IR) generating device, preferably a near infrared generating device.

[0205] Infrared is a type of electromagnetic radiation; the infrared range is divided into near infrared (0.5 micrometers to 5 micrometers, preferably 0.7 micrometers <λ < 3 micrometers), mid-infrared (3 micrometers <λ < 25 micrometers) and far infrared (above 25 micrometers). The object of the present invention is a near infrared (0.5 μm to 5 μm) generating device having the HAuCl 4 6H 2 Any composition of O. A solution containing FAD, ATP, L-GSH and myristic acid or a pharmacologically acceptable salt in the form of a free base can be prepared in water appropriately mixed with a surfactant (e.g., hydroxypropylcellulose). This dispersion according to the present invention can also be prepared in glycerol, liquid polyethylene glycol, mixtures thereof, and oils. Under normal storage and use conditions, these preparations contain preservatives to prevent microbial growth. The composition of the present invention can be formulated into a composition in a neutral form or a salt form.

[0206] "Pharmaceutically" or "pharmaceutically acceptable" refers to molecular entities and compositions that do not cause allergic or other adverse reactions when administered to mammals, especially humans.

[0207] A pharmaceutically acceptable "excipient" or carrier refers to any compound that helps to formulate a pharmaceutical composition and does not alter the biological activity of the active ingredient.

[0208] Pharmaceutically acceptable excipients may be solvents, plasticizers, lubricants, dispersion media, agents for retarding absorption, flow agents, etc. Preferably, the composition further comprises a plasticizer, a lubricant and / or a flow agent, a pharmaceutically acceptable excipient and an optional sustained release matrix, such as a biodegradable polymer, to form a therapeutic composition.

[0209] A pharmaceutically acceptable carrier or excipient refers to any type of filler, diluent, encapsulating material or solid, semisolid or liquid formulation auxiliary.

[0210] Pharmaceutically acceptable salts include acid addition salts (formed with free amino groups of proteins) and salts formed with inorganic acids (such as hydrochloric acid or phosphoric acid) or organic acids (such as acetic acid, oxalic acid, tartaric acid, mandelic acid, etc.).

[0211] Salts formed with the free carboxyl groups can also be derived from inorganic bases, such as sodium, potassium, ammonium, calcium or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.

[0212] In the pharmaceutical composition of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, topical or rectal administration, or intratumoral administration, the active ingredient can be alone or in combination with another active ingredient (another drug) that may exhibit side effects in a single form (or in a package form), mixed with conventional pharmaceutical carriers or excipients, for administration to animals and humans.

[0213] The content of pharmaceutical excipients in the final product ranges from 1-30%.

[0214] Suitable unit dosage forms include oral dosage forms such as tablets, capsules, powders, granules and suspensions or oral solutions, sublingual and oral dosage forms, aerosols, implants, subcutaneous injections, transdermal formulations, topical, intraperitoneal, intramuscular, intravenous, transdermal, intrathecal and intranasal, and rectal and intraurethral administration.

[0215] The pharmaceutical composition according to the present invention is a pharmaceutically acceptable preparation and can be administered orally, sublingually, parenterally, intratumorally, intraperitoneally, subcutaneously, intramuscularly, intravenously, intraorally (it, ip, sc, im, iv, po) or intraurethrally or intravenously.

[0216] In particular, these pharmaceutical compositions can be sterile isotonic saline solutions (monosodium phosphate or disodium phosphate, chlorides of sodium, potassium, calcium or magnesium or similar salts, or mixtures of these salts), or dry mixtures, in particular lyophilized mixtures, which can be sterile water or physiological saline, depending on the specific circumstances, to form injectable solutions.

[0217] The manufacturing support of the meta-salt particles containing the composition of the present invention can also be a solvent or dispersion medium such as water, ethanol, polyol (such as glycerol, propylene glycol and liquid polyethylene glycol, etc.) and a suitable mixture thereof, and vegetable oil. For example, suitable fluidity can be maintained by using coatings such as lecithin, maintaining required particle size in the case of dispersion, and by using a surfactant.

[0218] The prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents well known in the art. In most cases, it will be preferable to add isotonic agents, for example, sugars or sodium chloride.

[0219] Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0220] Sterile injectable solutions are prepared by combining the active ingredient in the composition or kit of the present invention in the required amount with several other ingredients listed herein (as required) in an appropriate solvent, followed by filtration and sterilization.

[0221] The dispersion prepared according to the present invention is prepared by adding the sterilizing agent of the present invention to a sterile carrier containing an alkaline dispersion medium and the other required ingredients listed above. For sterile powders for preparing sterile injections, typical preparation processes are vacuum drying and freeze drying techniques, which produce a combination of FAD, GSH, ATP and myristic acid (or each of FAD, GSH, ATP and myristic acid alone) and the composition of the present invention plus any other required ingredients from their sterile filtered solutions.

[0222] The dosage forms suitable for injection include sterile aqueous solutions or dispersions, which may include coconut oil, sesame oil, peanut oil, advantageously, coconut oil or propylene glycol in water, and sterile powders for the immediate preparation of sterile injectable solutions or dispersions. In any case, as long as there is a syringe, the medicament must be sterile and fluid. It must remain stable under the conditions of manufacture and storage, and must not be contaminated by microorganisms such as bacteria and fungi.

[0223] Nutritional composition

[0224] Another main aspect of the present invention relates to a nutritional composition of the present invention, comprising effective amounts of FAD, GSH and ATP, and optionally myristic acid and a nutritional excipient.

[0225] Another aspect of the present invention relates to a medicament, in particular a medicament used in a dosage that causes side effects, and a nutritional composition of the present invention.

[0226] Nutritional excipients are inactive ingredients used in the manufacturing process of nutritional supplements. Some of these ingredients include film coatings, thickeners, preservatives, lubricants, binders, and colors.

[0227] The content of nutritional supplements in the final product ranges from 0.1% to 30%.

[0228] Unless otherwise indicated, all percentages and amounts expressed herein and elsewhere in the specification are to be understood as percentages by weight.

[0229] As used herein, "effective amount" and similar terms refer to an amount of a compound, material, or composition described herein that is effective to achieve a particular effect. These results may include, but are not limited to, reduced inflammation, reduced tumor growth, increased survival, and reduced side effects of drugs. For example, such effective activity can be achieved by administering the composition of the present invention to an individual. The effective amount can be based on a variety of factors, including body weight and the frequency of treatment or administration of the composition of the present invention, for example, once, twice, or three times a day, as well as other drugs administered to the individual.

[0230] dose

[0231] According to the present invention, the dosage of AP (FAD, GSHATP, myristic acid) whether in a pharmaceutical or nutritional composition or set may be as follows.

[0232] Dosage of FAD

[0233] The amount of FAD in the composition or kit of the present invention can be between 0.1 mg and 50 g, in particular between 1 mg and 500 mg, and the composition can be taken once, twice or three times a day. In a particularly preferred embodiment, the dosage of FAD is 25 mg / kg. In a particularly preferred embodiment, the dosage of FAD is 25 mg / kg, taken once a day or every two days. In a particularly preferred embodiment, the dosage of FAD is taken once a day or every two days, for at least one month or at least two months, or at least three months or at least six months. According to the present invention, the dosage of ATP can be expressed in millimoles according to the amount of ATP in the composition or kit of the present invention, and the dosage can be between 0.1 millimoles and 10 millimoles, or between 0.5 millimoles and 1 millimoles.

[0234] According to the present invention, the amount of ATP in the composition or kit of the present invention may also be expressed in grams, milligrams or micrograms, and the dosage is by weight.

[0235] An effective amount of ATP may also be provided at a dosage level of 100 mg / dose. ATP may be used at a dose of 100 mg, with a local concentration of about 1 to 10 mmol / L or more.

[0236] Advantageously, according to the invention, the dosage of ATP may vary from 1 mg to 1000 mg / kg, preferably 10 mg to 100 mg / kg, such as 400 mg / kg or 100 mg / kg.

[0237] For example, individuals with an average body weight of 60 to 80 kg may use the sublingual ATP dosage form named ATEPADENE. According to the use of the present invention, ATEPADENE at a dose of 30 mg / capsule, or ATP Max(R) 400 mg or PEAK ATP(TM) are sources of ATP of interest.

[0238] An effective amount of ATP is provided at a dosage level ranging from 0.01 mg / kg to about 1 g / kg (body weight) per day, particularly from about 0.1 mg / kg to 100 mg / kg (body weight) per day; preferably 100 mg / kg, 3 times / day or 100 mg / kg, 5 times / day; 250 mg / kg, 2 times / day or 250 mg / kg, 3 times / day. In the active sublingual form, ATP is taken in doses of 30 mg three times.

[0239] In a particularly preferred embodiment, the dose of ATP is 25 mg / kg.

[0240] In particularly preferred embodiments, ATP is taken every day or every two days for at least one month, or at least 2 months, or at least 3 months, or at least 6 months.

[0241] Dosage of GSH

[0242] The dosage of GSH in the composition or kit of the present invention ranges from 0.01 mg to 5 g, and the dosage of GSH in the kit of the present invention is preferably 100 mg; or 500 mg can be used in the composition or kit of the present invention. GSH can be taken 1 to 3 times a day.

[0243] Advantageously, the GSH in the composition according to the invention may be administered in a dosage of from 0.01 mg to 10 g, from 0.1 mg to 1 g, from 1 mg to 1 g, from 10 mg to 900 mg, from 100 mg to 300 mg, in a dosage of 100 mg / dose or mg / kg or 200 mg / dose or mg / kg.

[0244] According to the composition of the present invention, for example, the dosage of reduced glutathione per administration is 100 mg, 200 mg, 300 mg or 40 mg (Sublinthion).

[0245] The amount of GSH used ranges from 0.01 mg to 10 g, 0.01 mg to 1 g, 0.1 mg to 1 g, 1 mg to 10 mg, 40 mg to 900 mg, 100 mg to 300 mg, 100 mg or 200 mg.

[0246] In a particularly preferred embodiment, the dosage of L-GSH is 25 mg / kg.

[0247] In particularly preferred embodiments, the dose of GSH administered is once a day or every two days for at least one month, or at least 2 months, or at least 3 months, or at least 6 months.

[0248] Myristic Acid Dosage

[0249] In general, a suitable dosage of myristic acid may be in the range of about 0.5 to about 100 mg / kg, for example, about 1 to about 75 mg / kg body weight per day, or 1.5 to about 50 mg per kg of subject body weight per day, or about 2 to about 30 mg / kg / day, or about 2.5 to about 15 mg / kg / day. Myristic acid may conveniently be administered in unit dosage form; for example, each unit dosage form contains 5 to 1000 mg of active ingredient, conveniently 10 to 750 mg, and most conveniently 50 to 500 mg.

[0250] Administration of myristic acid can achieve peak plasma concentrations of the active compound of about 0.5 to about 75 μM, preferably about 1 to 50 μM, and most preferably about 2 to about 30 μM, which can be achieved, for example, by intravenous injection of a 0.05 to 5% solution of the active ingredient (optionally in saline) or oral administration in the form of a bolus containing about 1 to 100 mg of the active ingredient.

[0251] Desired plasma concentrations may be maintained by continuous infusion providing about 0.01-5.0 mg / kg / hour or by intermittent infusion of about 0.4-15 mg / kg of active ingredient.

[0252] In a particularly preferred embodiment, the dosage of myristic acid is 10 mg / kg.

[0253] In particularly preferred embodiments, myristic acid is administered daily or every two days for at least one month or at least two months, or at least three months or at least six months.

[0254] The present invention provides a method for preparing a composition according to the present invention, the method comprising:

[0255] A polymer (preferably PEG 600 or hyaluronic acid) is conjugated to FAD (optionally, and a metal salt).

[0256] By adding a polymer, preferably PEG 600 or hyaluronic acid, to a FAD solution (5 mg / mL), the resulting FAD polymer (and / or metal salt) is then combined with L-GSH (5 mg / mL), ATP (5 mg / mL) and myristic acid (2 mg / mL).

[0257] Depending on the dosage and form of the molecules used, the ratio of FAD, ATP, GSH may be 1:1:1, which may be adjusted or varied, but the ratio cannot be lower than 1:50 or 50: 1. This is to ensure a synergistic effect of the molecules on cell proliferation and / or differentiation.

[0258] The composition or kit of the present invention can be used alone to prevent and / or treat a disease or side effect.

[0259] Based on the results obtained herein, the compositions of the present invention may also be provided for the prevention or treatment of any disease, in particular a disease or a symptom or a group of symptoms caused by a drug or pharmaceutical product.

[0260] A possible definition of "disease" is: a disorder of the structure or function of the human or animal body, especially one with a known cause and / or a distinct set of symptoms, signs, or anatomical changes.

[0261] The composition of the present invention can be used alone to prevent and / or treat diseases, especially diseases associated with inflammation, such as cancer or degenerative neurological diseases. In a preferred embodiment, the composition of the present invention is used alone to prevent and / or treat cancer.

[0262] The cancer can be any cancer, or a metastatic cancer, or a rapidly progressing (aggressive) cancer.

[0263] An aggressive cancer may be, for example, one that progresses rapidly due to overexpression of Aurora kinase A (AURKA) and / or B (AURKB) compared to healthy cells.

[0264] The composition of the present invention can be used as an adjuvant or neoadjuvant for cancer treatment and can be used for preventing and / or treating cancer.

[0265] Adjuvant chemotherapy is chemotherapy that people receive after they have had another cancer treatment, such as surgery. Neoadjuvant chemotherapy is chemotherapy that people receive as their primary treatment before they have other treatments. Both adjuvant and neoadjuvant therapy may include chemotherapy, radiation therapy, hormone therapy, and more. Neoadjuvant therapy is given before a person has their primary cancer treatment. Adjuvant therapy is given after that treatment. For example, a person might first have surgery to remove their tumor and then have adjuvant chemotherapy.

[0266] The composition of the present invention is used as an adjuvant and neoadjuvant for cancer treatment, for preventing and / or treating cancer. Whether the cancer treatment is used as an adjuvant or neoadjuvant therapy, the composition of the present invention can be used for combined treatment during, before and after cancer treatment.

[0267] Set

[0268] As another object of the present invention, the present invention also provides a kit comprising flavin adenine dinucleotide disodium salt hydrate bound to a polymer, or flavin adenine dinucleotide, adenosine triphosphate disodium salt hydrate (ATP), and L-GSH that are more resistant to degradation as described above.

[0269] Advantageously, the composition or kit of parts of the present invention may further contain a fatty acid, preferably a fatty acid selected from the group consisting of myristic acid, palmitic acid, oleic acid and combinations thereof, more preferably myristic acid.

[0270] As another object of the present invention, the present invention also provides a kit comprising flavin adenine dinucleotide disodium salt hydrate bound to a polymer, or FAD, adenosine triphosphate disodium salt hydrate (ATP), L-GSH and myristic acid as described above which are more resistant to degradation.

[0271] According to a preferred aspect, the present invention relates to a composition or kit of parts according to the present invention comprising fatty acids, wherein the specific fatty acids can form liposomes or capsules comprising the encapsulated composition according to the present invention comprising FAD, ATP, GSH and optionally myristic acid.

[0272] Myristic acid can be extracted from natural sources or synthesized as in EP2861059.

[0273] One aspect of the invention is that the composition according to the invention is formulated in a form suitable for parenteral administration, including intravenous, intramuscular and subcutaneous administration. Mucosal administration, such as oral, intranasal, vaginal or rectal administration, is one aspect of the invention.

[0274] A further aspect of the invention is a composition according to the invention in a form suitable for intravesical or intraurethral administration.

[0275] According to another aspect, the present invention relates to a pharmaceutical composition or kit, advantageously a medicament, comprising a therapeutically effective amount of a salt of FAD, a salt of AT, L-GSH and optionally myristic acid, and at least one other medicament.

[0276] According to another aspect, the present invention relates to a nutritional composition or set, advantageously a medicament, comprising a therapeutically effective amount of a salt of FAD, a salt of ATP, L-GSH and optionally myristic acid, and at least one other medicament.

[0277] According to another aspect, the present invention relates to a pharmaceutical composition or kit comprising a therapeutically effective amount of a salt of FAD, a salt of ATP, L-GSH and optionally myristic acid according to the present invention, for use in combination with surgery and / or radiotherapy, preferably in combination with radiotherapy and / or radiation, more preferably in combination with radiotherapy and / or near-infrared radiation.

[0278] According to another aspect, the present invention relates to a pharmaceutical composition or kit comprising a therapeutically effective amount of a salt of FAD, a salt of ATP, L-GSH and optionally myristic acid according to the present invention, and at least one other drug, for use in combination with surgery and / or radiotherapy, preferably in combination with radiotherapy and / or radiation, more preferably in combination with radiotherapy and / or near-infrared radiation.

[0279] According to another aspect, the present invention relates to a pharmaceutical composition or kit, and at least one drug or medicament for chemotherapy, preferably for anti-cancer chemotherapy.

[0280] One aspect of the present invention relates to the combination of a composition of the present invention and at least one anti-cancer chemotherapeutic agent.

[0281] The anti-cancer chemotherapy drugs used in conjunction with the composition of the present invention can be selected from chemotherapy drugs, hormone therapy drugs, immunotherapy drugs, and targeted immunotherapy drugs.

[0282] Among the anti-cancer chemotherapeutic drugs that can be used with the composition or kit according to the present invention, the anti-cancer chemotherapeutic drugs used in connection with the composition of the present invention can be:

[0283] i. Microtubule activating agents;

[0284] ii. Alkylating agents;

[0285] iii. antimetabolites;

[0286] iv. Insertion agent;

[0287] v. Topoisomerase I or II inhibitors, such as camptothecin and its derivatives;

[0288] vi. Compounds that target / reduce protein or lipid activity or protein or lipid phosphatase activity;

[0289] vii. proteasome inhibitors;

[0290] viii. Protein kinase inhibitors;

[0291] ix. Antibiotics;

[0292] x. Anti-inflammatory agents;

[0293] xi. Monoclonal antibodies.

[0294] According to another aspect, the present invention relates to a pharmaceutical composition or kit, and at least one drug for cancer chemotherapy, for treating cancer.

[0295] According to another aspect, the present invention relates to a pharmaceutical composition or kit, and at least one drug for cancer chemotherapy, for treating side effects caused by anti-cancer therapy.

[0296] Anticancer chemotherapy is a general drug-based treatment designed to destroy cancer cells or prevent them from multiplying throughout the body. There are many different chemotherapy drugs, which are often used in combination to increase their effectiveness.

[0297] According to one aspect, the composition of the present invention can be used for:

[0298] -In the adjuvant setting, once the tumor has been removed, ensuring that no cancer cells remain.

[0299] - In neoadjuvant therapy, used to reduce the size of the tumor before surgery: thus limiting the possible sequelae of surgery.

[0300] -In case of metastatic disease, systemic therapy.

[0301] -Prevents the development of cancer.

[0302] There are examples of chemotherapy being used based on the characteristics of the cancer.

[0303] According to one aspect, the present invention relates to a composition according to the invention for use before, during and / or after i) resection surgery, preferably tumor resection; ii) radiotherapy, preferably infrared; iii) chemotherapy, preferably anticancer chemotherapy, preferably classical (anticancer) chemotherapy, such as chemotherapy using synthetic or plant-derived products, hormone therapy, immunotherapy, targeted immunotherapy.

[0304] Resection is a surgical procedure to remove harmful or useless elements (organs, tumors, foreign bodies, etc.) from the body.

[0305] The goal of immunotherapy is to help or replace the immune system recognize and attack pathological cells, especially cancer cells; some immunotherapies try to bypass the mechanisms that prevent B lymphocytes from triggering an immune response, while others try to stimulate a specific immune response.

[0306] Immunotherapy involves treating a patient with an immune-derived compound (eg, an antibody, fusion protein, receptor, preferably an antibody, more preferably a monoclonal antibody).

[0307] Among the chemotherapeutic drugs or formulations that can be combined with the compositions according to the invention are synthetic or plant-derived products, hormone-based drugs (including hormone agonists or antagonists), drugs containing immune-derived proteins (such as therapeutic antibodies), or immune cells selected or modified to act specifically on cell or tissue targets.

[0308] According to another aspect, the present invention relates to a pharmaceutical composition or kit comprising an excipient and a therapeutically effective amount of a salt of FAD, a salt of ATP, L-GSH, optionally myristic acid, and at least one therapeutic antibody, preferably a monoclonal antibody.

[0309] The term "monoclonal antibody" as used herein includes, but is not limited to, bevacizumab, cetuximab, trastuzumab, ibrutinib, rituximab and tocilizumab, and iodine-131.

[0310] Bevacizumab can be administered in its commercial form (e.g., AVASTIN); cetuximab can be administered as ERBITUX; trastuzumab can be administered as HERCEPTIN; rituximab can be administered as MABTHERA; ibrutinib can be administered as ZEVULIN; and tocilizumab and iodine-131 can be administered as BEXXAR.

[0311] Monoclonal therapeutic antibodies that can be used in combination with the composition according to the present invention include Rituximab (ATC code L01XC02), Trastuzumab (Herceptin) (ATC code L01XC03), Gemtuzumab Ozogamicin, ATC code L01XC05, Alemtuzumab, ATC code L01XC04, Ibritumomab tiuxetan, ATC code V10XX02, Cetuximab, ATC code L01XC06, Bevacizumab, ATC code L01XC07, Nivolumab, Ipilimumab, which are particularly suitable for use.

[0312] These monoclonal antibodies are used to treat cancer and therefore may be used in combination with the compositions of the present invention at doses lower than those conventionally used.

[0313] Hormone therapy is understood to be a therapy based on the administration of drugs, such as hormones, steroid antagonists or agonists.

[0314] According to a preferred aspect, the present invention relates to a pharmaceutical composition or kit comprising (a) a therapeutically effective amount of a composition of the present invention, and (b) at least one drug for hormone therapy.

[0315] One aspect of the invention relates to a combination of a composition of the invention and at least one chemotherapeutic agent selected from antimetabolites, antibiotics, alkylating agents, intercalating agents (anthracyclines), microtubule inhibitors, topoisomerase I or II inhibitors, spindle poisons (taxoids, vinca glycosides, oxazolidinones), proteasome inhibitors, protein kinase or phosphatase inhibitors.

[0316] For example: i) topoisomerase I inhibitors, such as irinotecan, topotecan; ii) topoisomerase II inhibitors, such as anthracyclines or etoposide; iii) spindle toxins, such as Taxane, docetaxel, paclitaxel, vinca alkaloids, iv) antimetabolites, such as antifolates, such as methotrexate MTX, pemetrexed; purine analogs, fludarabine; pyrimidine analogs, such as 5-fluorouracil (5-FU), gemcitabine, cytarabine; v) alkylating agents, selected from nitrogen mustards, nitrosoureas, alkyl sulfonates and sulfates (such as methyl triflate and dimethyl sulfate); platinum salts, such as trimethyloxonium tetrafluoroborate, cystaplatin, carboplatin, oxaliplatin; oxazaphosphorines, such as cyclophosphamide, ifosfamide; fluorouracil or 5-fluorouracil (5-FU) can be used to treat cancer with the composition or kit of the present invention.

[0317] The term "antimetabolite" or "antineoplastic antimetabolite" includes, but is not limited to: 5-fluorouracil (5-FU); capecitabine; gemcitabine; DNA demethylating agents such as 5-azacytidine and decitabine; methotrexate; edatrexate; and folic acid antagonists such as, but not limited to, pemetrexed. For example, capecitabine can be administered in its marketed form (e.g., under the brand name XELODA); gemcitabine can be administered in the form of GEMZAR.

[0318] Antimetabolites interfere with the DNA synthesis of components; they are structural analogs of purine and pyrimidine bases (or the corresponding nucleosides) on the one hand and of the folinic coenzyme on the other hand, since the latter is involved in many stages of purine and pyrimidine biosynthesis. Their effect is to inhibit cell replication, for example by incorporation into nucleic acids, leading to cell death, including DNA fragmentation.

[0319] Antimetabolites that can be used in combination with the compositions of the present invention include:

[0320] i) pyrimidine analogs, such as 5-FU, tegafur, capecitabine, azacitidine, gemcitabine; ii) purine analogs, such as mercaptopurine, fludarabine, azathioprine, cladribine, pentostatin, cytarabine, nelarabine, clofarabine. iii) folic acid analogs, such as methotrexate, pemetrexed, pralatrexate, ralitrexed, trimetrexate, piritrexine; iv) decitabine, sapacitabine are particularly suitable.

[0321] The antimetabolite drug associated with the composition or kit of the present invention is selected from 5-FU, cytarabine, capecitabine (xeloda), fluoropyrimidine (Alimta), pemetrexed, gemcitabine (gemzar), Tomudex (raltitrexed), more preferably 5-FU.

[0322] The composition or kit according to the invention may be used in combination with an antifolate, methotrexate or pemetrexed and or with the purine analogue fludarabine or the pyrimidine analogue 5-FU.

[0323] 5-FU belongs to the class of antimetabolites, a subclass of pyrimidine analogs.

[0324] The present invention relates to the composition of the present invention and an antimetabolite, preferably an antimetabolite such as 5-fluorouracil (5-FU).

[0325] The present invention also relates to a pharmaceutical composition according to a preferred production method, comprising:

[0326] (a) a therapeutically effective amount of a composition according to the present invention;

[0327] (b) antimetabolites, preferably pyrimidine analogs, more preferably 5-FU;

[0328] (c) a pharmaceutically acceptable carrier.

[0329] Furthermore, the present invention relates to a kit or commercial product according to the preferred implementation method, comprising:

[0330] (a) a pharmaceutical preparation or a nutritional preparation of the composition of the present invention;

[0331] (b) pharmaceutical preparations of one or more chemotherapeutic drugs;

[0332] (a) and (b) may be used simultaneously, in parallel, separately or sequentially.

[0333] In a specific embodiment, the posology of combining the composition of the present invention with a drug or pharmaceutical product can be daily administration or once every two days administration of the composition of the present invention, regardless of the posology of the anticancer drug, preferably the administration is such that the levels of FAD, ATP, GSH are constant compared to the levels without administration of the composition of the present invention comprising FAD, ATP, GSH, myristic acid (i.e., based only on endogenous FAD, ATP, GSH). The duration of administration of the composition is at least the same as and / or longer than the duration of the other treatments to maintain the levels of FAD, ATP, GSH constant compared to the levels without administration of the composition of the present invention comprising FAD, ATP, GSH, myristic acid (i.e., based only on endogenous FAD, ATP, GSH).

[0334] Furthermore, the present invention relates to a kit or commercial product according to the preferred implementation method, comprising:

[0335] (a) Pharmaceutical formulations of FAD-PEG, ATP, GSH and myristic acid;

[0336] (b) a pharmaceutical preparation of one or more chemotherapeutic agents, including antimetabolites, preferably pyrimidine analogs, more preferably 5-FU;

[0337] (a) and (b) may be used simultaneously, in parallel, separately or sequentially.

[0338] An object of the present invention is the use of standard or conventional chemotherapeutic drugs in combination with the composition according to the present invention.

[0339] The term "conventional chemotherapeutic agent" has a broad meaning and includes many chemotherapeutic agents with different mechanisms of action. The combination of these drugs with the composition or kit of the present invention can improve the therapeutic effect of cancer. In general, chemotherapeutic drugs are classified according to their mechanism of action.

[0340] As used herein, the term "microtubule active agent" or "spindle poison" refers to agents that stabilize tubulin, microtubule stabilizers, and microtubule polymerization inhibitors, including but not limited to taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine, especially vinblastine sulfate; vincristine, especially vincristine sulfate and vinorelbine; discodermolide; colchicine and epothilones and their derivatives, such as epothilone B or its derivatives. As used herein, these "microtubule active agents" or "spindle poisons" are used in combination with the composition or kit of the present invention.

[0341] The trade name of paclitaxel is TAXOL; the trade name of docetaxel is TAXOTERE; the trade name of vinblastine sulfate is VINBLASTIN RP; and the trade name of vincristine sulfate is FARMISTIN. Also included are generic forms of paclitaxel and various galenic forms of paclitaxel that can be used with the composition or kit of the present invention. Generic dosage forms of paclitaxel include, but are not limited to, betaxolol hydrochloride. Various dosage forms of paclitaxel include, but are not limited to, albumin nanoparticle paclitaxel, trade names ABRAXANE, ONXOL, CYTOTAX. Discodermolide can be obtained as described in U.S. Patent No. 5,010,099.

[0342] In addition, epothilone derivatives described in U.S. Pat. No. 6.194.181, WO 98 / 10121, WO 98 / 25929, WO 98 / 08849, WO 99 / 43653, WO 98 / 22461 and WO 00 / 31247; in particular, epothilone A and / or B, can be used in combination with the composition or kit of the present invention.

[0343] Among the preferred spindle poisons to be combined with the composition or kit of the invention, the following drugs are particularly suitable: vincristine, vinblastine, vinorelbine, vindesine, vinflutamine; dostatins, such as romidepsin; paclitaxel, nab-paclitaxel, docetaxel, carbitaxel; epothilone, ixabepilone.

[0344] Most preferably, the spindle poison for combination with the composition or kit of parts of the present invention is selected from the group consisting of docetaxel, paclitaxel, vincristine, vinblastine, vindesine, and vinorelbine.

[0345] More preferred spindle poisons for combination with the composition of the present invention are selected from TAXOL, docetaxel, paclitaxel, vincristine, vinorelbine, vindesine and vinblastine (Velbe).

[0346] The most preferred spindle poison for combination with the composition of the present invention is selected from TAXOL, TAXOTERE (docetaxel), Paclitaxel, vincristine.

[0347] Eribulin (Halaven) is a microtubule inhibitor. It is a synthetic, simplified analog of halichondrin B, a substance isolated from the Haichondria okadai sea sponge.

[0348] An object of the present invention is to combine eribulin with a composition or kit of parts according to the present invention.

[0349] The term "alkylating agent" as used herein includes, but is not limited to: i) nitrogen mustards, such as melphalan, chlorambucil, estramutine; ii) oxazaphosphine heterocyclic compounds, such as cyclophosphamide, ifosfamide; iii) triazene and hydrazine compounds, such as procarbazine, dacarbazine, temozolomide; iv) ethyleneimines, aziridines, such as thiotepa, mitomycin C; v) nitrosourea compounds, such as BCNU, CCNU, fotemustine, streptozotocin; vi) alkyl alkane sulfonates, such as busulfan; vii) organic platinums or "platinum compounds".

[0350] Any one or more of these alkylating agents may be combined with the composition or kit of the present invention.

[0351] The term "platinum compound" as used herein includes, but is not limited to, carboplatin, cisplatin, oxaliplatin, satraplatin, and platinum preparations such as ZD0473. For example, carboplatin can be administered in its marketed form (such as CARBOPLATE); oxaliplatin can be administered in the form of ELOXATIN.

[0352] Trabectedine may also be combined with the composition or kit of parts of the present invention.

[0353] The composition of the present invention can be used in combination with an insert selected from melphalan, chlorambucil, BCNU, platinum salts, aziridine, and mitomycin C.

[0354] In inserts, anthracyclines such as doxorubicin Epi or doxorubicin Idabit Particularly suitable for use in combination with the composition or kit of the present invention.

[0355] According to another embodiment, the composition of the present invention can be combined with any one insert selected from cyclophosphamide, ifosfamide, melphalan, BCNU (or Gliadel), temozolomide (TEMODAR), cisplatin, carboplatin, platinum in free or salt form, bendamustine and Temodal and administered to the patient.

[0356] Cyclophosphamide can be used with the compositions of the invention, for example, in the form of the commercially available CYCLOSTIN; and ifosfamide in the form of HOLOXAN.

[0357] According to a preferred embodiment, the composition of the present invention is used in combination with cyclophosphamide (endoxan).

[0358] According to a preferred embodiment, the composition or kit of parts of the present invention is used in combination with cyclophosphamide (endoxan) and another drug.

[0359] According to a preferred embodiment, the composition or kit of parts of the invention is used in combination with bendamustine.

[0360] According to a preferred embodiment, the composition or kit of parts according to the invention is used in combination with Temodal.

[0361] Antimetabolites interfere with DNA synthesis; they are structural analogs of purine and pyrimidine bases (or the corresponding nucleosides) on the one hand and of the folate coenzyme on the other hand, since the latter is involved in many stages of purine and pyrimidine biosynthesis. Antimetabolites are very powerful but are often accompanied by strong side effects.

[0362] Therefore, the composition or kit of the present invention is particularly suitable for use in combination with antimetabolites.

[0363] As a primary object, the present invention provides any one of the compositions or kits disclosed herein for use in alleviating drug-induced side effects or disease-induced symptoms, preferably weight loss.

[0364] Side effects are minor, typical undesirable reactions to drugs or medical treatments.

[0365] The drug causing the side effect or side effects may be any drug.

[0366] By definition, a drug or pharmaceutical product has a therapeutic effect on a patient population and may also have one or several side effects.

[0367] For example, the appropriate dosage of 5-FU in humans is determined by a physician and may be in the range of 100-1500 mg per day, such as 200-1000 mg / day, such as 200, 400, 500, 600, 800, 900 or 1000 mg / day, administered once or twice a day. 5-FU may be administered to humans in a dosage range of about 50-1000 mg / m2 / day, such as 500 mg / m2 / day.

[0368] When used in combination with the composition of the present invention, the dose of 5-FU can be reduced, preferably by 10% to 50%.

[0369] When used in combination with the composition of the present invention, the dosage can be reduced by at least 10%.

[0370] When used in combination with the composition or kit of the present invention, such dosage can be reduced by at least 0% and at least one side effect can be reduced.

[0371] Olaparib works by inhibiting poly (ADP-ribose) polymerase (PARP). The composition of the present invention can be used in combination with Olaparib.

[0372] As used herein, the term "proteasome inhibitor" includes compounds that target, reduce or inhibit protease activity. Compounds that target, reduce or inhibit protease activity include, but are not limited to, PS-341, MLN 341, bortezomib or velcade.

[0373] The composition or kit of the invention may be used in combination with bortezomib.

[0374] The term "topoisomerase I inhibitor" as used herein includes irinotecan, topotecan, camptothecin and their active derivatives.

[0375] Camptothecin acts by interfering with the unfolding of DNA super wounds through the cellular enzyme topoisomerase I, thereby inducing apoptosis of malignant cells and leading to programmed cell death.

[0376] The topoisomerase I inhibitor Capto (irinotecan) is combined with the composition according to the present invention to form a pharmaceutical composition or set of the present invention.

[0377] The term "topoisomerase II inhibitors" as used herein includes, but is not limited to: anthracyclines (intercalating agents): doxorubicin, daunomycin, epirubicin, idarubicin and nemorubicin; anthracenediones, anthraquinones: mitoxantrone and losoxantrone; epidophyllotoxins: etoposide, teniposide; or amsacrine and even bleomycin.

[0378] Epidophyllotoxins (etoposide)

[0379] The trade name of etoposide is ETOPOPHOS; the trade name of teniposide is VM 26-BRISTOL; the trade name of doxorubicin is ADRIBLASTIN or ADRIAMYCIN; the trade name of epirubicin is FARMORUBICIN; the name of idarubicin is ZAVEDOS; the name of mitoxantrone is NOVANTRON. Doxorubicin includes liposomal preparations such as DAUNOSOME.

[0380] Preferably, doxorubicin is used in combination with the composition of the present invention. Doxorubicin includes liposomal formulations, such as CAELYX.

[0381] Preferably, epirubicin is used in combination with the composition according to the invention.

[0382] Etoposide, sold under the trade name ETOPOPHOS, is preferably used in combination with the compositions of the present invention.

[0383] The combination of a topoisomerase II inhibitor selected from Etopophos (etoposide), topotecan, innotecan and the composition of the invention is a pharmaceutical composition or set according to the invention.

[0384] Bricatinib is an inhibitor of ALK ("anaplastic lymphoma kinase") and EGF receptor.

[0385] According to the present invention, Bricatinib and the composition of the present invention or Bricatinib and the composition of the present invention constitute a pharmaceutical composition or a set.

[0386] Palbociclib (Ibrance) is a molecule that inhibits two cyclin-dependent kinases, CDK4 and CDK6, which are proteins essential for the cell cycle.

[0387] Palbociclib and any composition of the invention described herein constitute a pharmaceutical composition or set according to the invention.

[0388] Sorafenib (Nexavar) is a tyrosine kinase inhibitor. FAD and sorafenib or sorafenib and the combination according to the invention constitute a pharmaceutical composition or set according to the invention.

[0389] Preferred classical chemotherapeutic drugs used in combination with any one of the compositions according to the present invention are selected from any one of the following classical chemotherapeutic drugs: Taxol, Taxotere (docetaxel), Paclitaxel, 5-FU, Etopophos (etoposide), Doxorubicin, Vincristine, Capecitabine (xeloda), Vincristine (Velbe), Cyclophosphamide (endoxan), Alimta (pemetrexed), Cytarabine, Cisplatin, Carboplatin, Free Platinum, Olaparib, Epirubicin, Capetop (irinotecan), Gemcitabine (gemzar), Bricatinib, Eribulin (Halaven), Bortezomib (Velcade), Bendamustine, Palbociclib (Ibrance), Temodal, Sorafenib (Nexavar), Tomudex (raltitrexed), Letrozole (anti-aromatase, supplemental hormone therapy); combinations of these drugs.

[0390] According to a specific implementation, when a conventional anticancer chemotherapy drug is used in combination with a composition or set according to the present invention (compared to the side effects observed when the composition or set according to the present invention is not used), the conventional dosage of the conventional anticancer chemotherapy drug (prescribed by a doctor or physician) can be increased, and / or the side effects caused by the conventional anticancer chemotherapy drug can be greatly reduced. Thus, the conventional anticancer chemotherapy time can be shortened, and the therapeutic effect achieved can be maintained or improved.

[0391] According to a specific implementation, when conventional anti-cancer chemotherapy drugs are used in combination with the composition or kit according to the present invention, the conventional dosage (doctor's prescription) of the conventional anti-cancer chemotherapy drugs can remain unchanged and the side effects can be greatly reduced.

[0392] According to other specific implementation methods, when conventional anti-cancer chemotherapy drugs are used in combination with FAD, ATP, GSH, and myristic acid according to the present invention, the conventional dose (doctor's prescription) of the conventional anti-cancer chemotherapy drugs can be reduced by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%; the anti-cancer activity of the combination of the present invention is equivalent to or better than that of conventional anti-cancer chemotherapy drugs with 100% active dose.

[0393] The compositions of the present invention may also be used in combination with other therapies, such as surgery, hyperthermia, immunotherapy, and / or radiation therapy.

[0394] disease

[0395] The composition or kit of the present invention may be provided as a medicine or a dietary supplement.

[0396] The composition or kit of the present invention can be used in any of the above-mentioned treatment methods or to reduce the side effects of drugs.

[0397] The composition or kit of the present invention can be used as a medicine for treating or preventing diseases.

[0398] Diseases or conditions significantly affected by the treatment methods of the present invention can be selected from the group consisting of, for example, inflammation, infection, atherosclerosis, hypertension, cancer, radiation damage, nervous system diseases, neurodegenerative diseases, ischemia / reperfusion injury, aging, wound healing, glutathione deficiency, acquired immunodeficiency syndrome, sickle cell anemia and diabetes.

[0399] The compositions of the present invention can be used to prevent or treat the following disorders and diseases: memory loss; Parkinson's disease; aging; liver poisoning caused by toxins; inflammation; cirrhosis; chronic hepatitis; and diabetes caused by cirrhosis; indigestion; fatigue; stress; cough; infertility; tissue inflammation; cancer; anxiety; panic disorder; rheumatism; pain; manic depression; alcoholism paranoia; schizophrenia; fever; insomnia; infertility; aging; skin inflammation and diseases; alcoholism; anemia; carbuncle; convalescence; emaciation; HIV; AIDS; immune system problems; back pain; multiple sclerosis ; sarcopenia; paralysis; swollen glands; ulcers; dyspnea; inflammation; psoriasis; cancer (such as prostate, lung, and breast cancer); pain; cardiovascular disease (such as arteriosclerosis and atherosclerosis); ischemia / reperfusion injury; anxiety; attention deficit disorder; leprosy; arthritis (such as psoriatic arthritis, ankylosing spondylitis, and rheumatoid arthritis); hemorrhoids, tuberculosis, hypertension, congestive heart failure, venous insufficiency (blood accumulation in the veins, usually in the legs), sore throat, hepatitis, syphilis, stomach ulcers, epilepsy, diarrhea, asthma, burns, hemorrhoids, sunburn, Wrinkles, headaches, insect bites, cuts, ulcers, sores, herpes, jaundice, bursitis, mouth ulcers, gum pain, poison ivy rash, gastritis, high cholesterol, heart disease, bacterial infections, viral infections, acne, aging, immune disorders, caries, periodontitis, bad breath, dandruff, cardiovascular disease (such as high blood pressure, thrombosis, arteriosclerosis), migraines, diabetes, elevated blood sugar, digestive and respiratory diseases, age-related physical and mental decline (such as Alzheimer's disease and age-related dementia), cardiovascular disease, cerebrovascular insufficiency and impaired brain function, premenstrual syndrome congestive symptoms; allergies; age-related vision loss, depression, Raynaud's disease, peripheral vascular disease, intermittent claudication, vertigo, imbalance, prevention of altitude sickness, tinnitus (ringing in the ears), liver fibrosis, macular degeneration, asthma, transplant rejection, immune disorders predisposing to toxic shock, bronchopulmonary disease (such as cystic fibrosis), chronic bronchitis, gastritis, heart attack, angina pectoris, chronic obstructive pulmonary disease, renal injury during coronary angiography, Unverricht-Lundborg disease, pseudoporphyria, pneumonia, and paracetamol hepatotoxicity.

[0400] In certain embodiments, the disease is cancer.

[0401] One definition of cancer is a disease characterized by the presence of abnormal cells that divide uncontrollably and have the ability to infiltrate and destroy normal body tissues.

[0402] Since the composition or kit of the present invention is a selective potent regulator of cell growth, its efficacy is applicable to cancer. In a specific embodiment, the cancer is selected from the group consisting of breast cancer, prostate cancer, liver cancer, pancreatic cancer, lung cancer, tracheal cancer, upper and / or lower digestive tract cancer, digestive organ cancer, kidney cancer, urethra cancer, reproductive organ cancer, skin cancer, ENT cancer, lymphatic organ cancer, liquid cancer, etc.

[0403] The composition or kit of the present invention can be used for preventing and / or treating pancreatic cancer, especially metastatic pancreatic cancer.

[0404] The composition or kit of the present invention is used for preventing and / or treating pancreatic cancer, and is used as an adjuvant or neoadjuvant for anti-pancreatic cancer treatment.

[0405] The composition or kit of the present invention is used for preventing and / or treating liver cancer, especially metastatic liver cancer.

[0406] The composition of the present invention is used for preventing and / or treating liver cancer, and is used as an auxiliary drug or a new auxiliary drug for treating liver cancer.

[0407] Any of the above compositions may be used in combination with another drug.

[0408] Most notably, Applicants have discovered that the above-mentioned compositions themselves have potent activity in the prevention and / or treatment of cancer, particularly metastatic cancer, more particularly metastatic cancer of the liver or pancreas.

[0409] The present invention relates to the composition or kit according to the above-mentioned embodiments, which is used as a drug for treating a disease or disease complications (such as angiogenesis, metastatic spread) alone, or in the late stage of a disease.

[0410] The present invention relates to the anti-cancer and / or anti-metastatic properties of the composition of the present invention, which is used as a medicament for preventing and / or treating cancer, in particular liver cancer or pancreatic cancer, especially metastatic liver cancer or pancreatic cancer.

[0411] While studying the activity of the composition of the present invention, the applicant discovered that the novel composition of the present invention also has strong activity in preventing or inhibiting side effects experienced by patients receiving drug treatment, particularly side effects associated with anticancer drugs, such as antimetabolites or antifolates, for example, 5-FU or a precursor of 5-FU, such as capecitabine.

[0412] It is noteworthy that the composition of the present invention, when administered to a person affected by the side effects of a drug, is found to be able to significantly reduce the side effects caused by the drug.

[0413] Therefore, the composition or kit provided according to the present invention is used to alleviate the side effects caused by drugs, especially any drug mentioned herein.

[0414] The side effects that can be alleviated by the composition or kit of the present invention can be any side effects caused by the drug. Therefore, the composition or kit according to any one of the compositions or kits described herein can be used to prevent and / or treat side effects caused by the drug, preferably side effects selected from weight loss, nausea, vomiting, headache, bleeding, alopecia, rash, eye irritation, neutropenia, pain, thrombosis, lymphedema, and combinations of the above side effects, advantageously weight loss.

[0415] Example

[0416] Example 1. Effect of a composition consisting of FAD, ATP, GSH and myristic acid on an in vivo model of invasive pancreatic cancer.

[0417] method

[0418] Reagents: FAD molecules were purchased from AlfaAesar or abcr.

[0419] PEG was purchased from Sigma Aldricht with the number 8.43912.

[0420] Myristic acid was purchased from Sigma Aldricht with the catalog number 8.00399.

[0421] Glutathione was purchased from Sigma Aldricht, number G4251.

[0422] ATP was purchased from Sigma Aldricht, number A26209.

[0423] The preparation method of FAD-polymer and FAD-polymer-metal salt is as previously disclosed in WO2021084166A1, the entire contents of which are included herein. Composition A and composition B are obtained by mixing FAD-polymer and FAD-polymer-metal salt with ATP, as well as GSH and myristic acid (for composition A).

[0424] Pan02 cell suspension (5×10 5 Each mouse was injected subcutaneously in the right axilla of the forelimb. When the tumor size reached 100 mm 3 -150 mm 3At 1 pm, mice were randomly divided into the following treatment groups (n=10): model group (n=10), group A (n=10), group B (n=10), 5-FU group (1.5 mg / kg, n=10), group A+5-FU (1.5 mg / kg, n=10) or group A+5-FU (0.75 mg / kg), group B+5-FU (1.5 mg / kg, n=10) (Table 1). 100 microliters of different compositions were injected intravenously (iv) or / and intraperitoneally (ip) once every other day (see Table 1 below). Body weight was measured every three days. The volume of solid tumors was measured every three days with a digital caliper. The survival of animals was monitored and recorded every day.

[0425] result

[0426] Compared with the model group, neither A nor B changed the weight changes of Pan02 tumor-bearing mice. The weight of mice in the positive control drug 5-FU group (1.5 mg / kg) decreased over time. It is worth noting that the weight of mice in the A+5-FU (1.5 mg / kg) group did not decrease at all.

[0427] On the 82nd day, the mortality rates of mice in each group were: 90% and 100% in the model group (in two different independent experiments); 70% in group A; 90% in group B; 90% in 5-FU (1.5 mg / kg) group; 70% in A+5-FU (1.5 mg / kg) group; 90% in A+5-FU (0.75 mg / kg) group; and 90% in B+5-FU (1.5 mg / kg) group.

[0428] The results of the tumor volume growth curve showed that the tumor volume of the model group mice increased rapidly. In contrast, the tumor volume of the A+5-FU (1.5 mg / kg) group was significantly reduced, and the reduction was the most significant compared with the other groups ( Figure 1 ).

[0429] Involving mortality Figure 2 The results showed that due to the extremely rapid growth of Pan02 transplanted pancreatic tumors, all mice in the model group died within 82 days. The median survival time of mice in each group was as follows: model group, 48.5 days; group A, 58.5 days; group B, 51.5 days; 5-FU (1.5 mg / kg) group, 53.5 days; A+5-FU (1.5 mg / kg) group, 63.5 days; A+5-FU (0.75 mg / kg) group, 59.5 days; B+5-FU (1.5 mg / kg) group, 53.5 days. These research results clearly show that treatment in the A+5-FU group significantly prolonged the survival of Pan02 tumor-bearing mice compared with the model / control group.

[0430] Summarize

[0431] Both composition A and composition B can reduce tumor volume, and the effect of reducing tumor volume by composition A is better than that by composition B. The anti-tumor effect of composition A is equivalent to or slightly higher than that of the 5-FU (1.5 mg / kg) group. The anti-tumor effect and the effect of prolonging the survival of pancreatic cancer mice treated with composition A combined with 5-FU (1.5 mg / kg) group are better than the effect of treating mice with composition A alone or 5-FU alone.

[0432] 2. Compliance

[0433] This study was conducted according to non-GLP regulations, and mice were used in this study and housed in an SPF animal room.

[0434] 3. Abbreviation

[0435] w week h hour

[0436] ℃ Celsius mL microliter

[0437] g gram mg microgram

[0438] ng nanograms second

[0439] kg kilogramd day

[0440] mmol millimole L liter

[0441] min minute μL microliter

[0442] μm micromolar ip intraperitoneal injection

[0443] iv intravenous injectionMean mean

[0444] SD Standard deviation

[0445] 4. Purpose

[0446] The effects of composition A and composition B on the lifespan extension of Pan02 tumor-bearing mice were investigated.

[0447] 5. Materials and Instruments

[0448] 5.1. Materials

[0449] FAD was purchased from abcr, number AB252055, with a dose of 5 mg / ml.

[0450] PEG was purchased from Sigma Aldricht, reference number 8.43912-500 μL, for 20 ml of 5 mg / mL FAD.

[0451] Myristic acid was purchased from Sigma Aldricht with the catalog number 8.00399 at a concentration of 2 mg / mL.

[0452] Glutathione was purchased from Sigma Aldricht, No. G4251, with a concentration of 5 mg / ml.

[0453] All materials were dissolved or suspended in deionized water.

[0454] ATP was purchased from Sigma Aldricht with the number A26209 and a concentration of 5 mg / ml.

[0455] Test product: FAD / PEG600 complex prepared in WO2020089310A1.

[0456] Purity: At least 98%.

[0457] Appearance: Liquid.

[0458] Storage: 4℃, protected from light.

[0459] Registration procedure: The quantity, date, user and purpose of the test samples must be registered each time.

[0460] Prepare the solution in advance according to the dosage and store it at 4°C away from light.

[0461] 20 ml of FAD (100 mg dissolved in 20 ml of deionized water) was mixed with 500 μl of PEG600 and stirred at room temperature (18-25°C) for 60 minutes. Then, 5 mg / ml of GSH was added, and the mixture was allowed to stand for 10 minutes, followed by 5 mg / ml of ATP (optional) and 2 mg / ml of myristic acid (applicable only to composition A). The resulting solution was sonicated for 2 hours and then purified by dialyzing through a Spectra / pore 3 membrane dialysis tube (molecular weight cutoff 1500 Da, Serva Electrophoresis, Germany).

[0462] Composition A: FAD (flavin adenine dinucleotide disodium salt hydrate) + (PEG) polyethylene glycol diacid 600 + myristic acid + reduced L-reduced glutathione (GSH) + ATP (5' adenosine triphosphate disodium salt hydrate).

[0463] Composition B: FAD (flavin adenine dinucleotide disodium salt hydrate) + (PEG) polyethylene glycol diacid 600 + L-reduced glutathione (GSH) + ATP (adenosine-5' triphosphate disodium salt hydrate).

[0464] Positive control drug 5-fluorouracil (5-FU), batch number: H31020593.

[0465] Manufacturer: Shanghai Xudong Haipu Pharmaceutical Co., Ltd. Storage: Sealed, storage temperature below 4°C.

[0466] Registration procedure: Register the number, date, user and purpose of each test sample.

[0467] Basement membrane matrix HC, manufacturer: Corning Incorporated, USA.

[0468] DMEM: Catalog number: 11965092; Manufacturer: Gibco, USA.

[0469] Fetal bovine serum, certified, Australia, catalog number: 10099141C; manufacturer: Gibco, USA.

[0470] Trypsin-EDTA (0.05%), phenol red, product number: 25300054; manufacturer: Gibco Company, USA.

[0471] HBSS, calcium-free, magnesium-free, phenol red-free, product number: HBSS, manufacturer: Sigma-Aldrich, USA.

[0472] PBS powder, manufacturer: Sigma-Aldrich, USA.

[0473] Paraformaldehyde, product number: 20100601-1; manufacturer: Guangzhou Chemical Reagent Factory.

[0474] Isoflurane, expiration date: 2019-12-28; Manufacturer: Shenzhen Ruiwode Life Science Technology Co., Ltd.

[0475] 5.2. Instrumentation

[0476] Animal weighing balance, item number: JCS-11001C; manufacturer: Shanghai Ranhao Electronics Co., Ltd.

[0477] Pharmaceutical weighing balance, item number: BSM-1204, manufacturer: Shanghai Zhuojing Electronic Technology Co., Ltd.

[0478] Zinc alloy digital display caliper, item number: 20050430; manufacturer: Shenzhen Cebao Electronic Tools Store.

[0479] Variable speed multi-purpose oscillator, item number: HY-4A; manufacturer: Hunan Frontier Technology Co., Ltd.

[0480] Inverted fluorescence microscope: Olympus IX71; Manufacturer: Olympus Corporation.

[0481] CO2 incubator, Manufacturer: Thermo Fisher Scientific Ltd.

[0482] Low-temperature high-speed centrifuge, product number: 5430 / 5430R; manufacturer: Eppendorf.

[0483] Direct water purification system, item number: Advantage A10; manufacturer: Millipore, Merck KGaA, Darmstadt, Germany.

[0484] 5.3. Animals

[0485] Species: rodents; strain: C57BL / 6j mice; grade: SPF; sex: female; age: 6-8 weeks. The animals were randomly divided into groups of 10 mice and treated as shown in Table 1: model group (n=10), group A (n=10), group B (n=10), 5-FU group (1.5 mg / kg, n=10), group A+5-FU (1.5 mg / kg, n=10), group B+5-FU (1.5 mg / kg, n=10).

[0486] Animal production license number: SCXK(Guangdong)2021-0059, Guangzhou Rege Biotechnology Co., Ltd.

[0487] Animal certificate number: 44827200002020; 44827200002058; Animal use license number: SYXK(Guangdong)2021-0259, Guangzhou Ruige Biotechnology Co., Ltd.; Receipt date: August 5 and August 7, 2022.

[0488] 6. Experimental Methods

[0489] 6.1. Pan02 cell culture

[0490] Pan02 mouse pancreatic cancer cell line was purchased from Shanghai Enzyme Biotechnology Co., Ltd. (cell line number: CC-Y2144) and stored at -80°C upon arrival. Pan02 cells were cultured in DMEM supplemented with 10% FBS (v / v), 100 U / mL penicillin G (Sigma-Aldrich, USA) and 100 μg / mL streptomycin (Sigma-Aldrich, USA). The culture was maintained at 37°C and 5% CO 2 Cultured in a humidified incubator.

[0491] 6.2. Isolation and Quarantine

[0492] After the nude mice enter the SPF experimental center, they are strictly isolated and quarantined in accordance with the relevant technical requirements of the SPF experimental animal center of Guangzhou Ruige Biotechnology Co., Ltd. The isolation and quarantine time is 3 to 5 days. Observe and record the general appearance and movement status of the rats, including consciousness, gait, response to stimulation, walking balance and limb coordination.

[0493] 6.3. Grouping and Dosing

[0494] Table 1: Experimental animals were randomly divided into several groups:

[0495]

[0496] Different experimental drugs were injected intravenously (iv) and intraperitoneally (ip) every other day at 10:00 am. Drug A or drug B was injected into the tail vein first, and 5-FU was injected intraperitoneally 24 hours later.

[0497] 6.4. Model establishment, grouping and drug administration

[0498] Pan02 cell suspension (5×10 5 Each mouse was injected subcutaneously in the right axilla of the forelimb. When the tumor grew to 100 mm 3 -150 mm 3 The mice were randomly divided into treatment groups: model group (n=10), group A (n=10), group B (n=10), 5-FU group (1.5 mg / kg, n=10), A+5-FU group (1.5 mg / kg, n=10), and B+5-FU group (1.5 mg / kg, n=10) (Table 1).

[0499] 6.5. Detection indicators

[0500] Weigh your body every three days. Measure the length and width of the solid tumor with a digital caliper every three days. The tumor volume is calculated using the modified ellipsoid formula: V = π / 6 × (length × width 2 ). The survival time of the animals was monitored and recorded every day. The experiment lasted for 82 days, and the animals that survived more than 82 days were counted as 82 days by default. The survival rate (%) was calculated using the following formula: survival rate (%) = [(10-number of mice that died in each group) / 10] × 100%. Cytokines / quantity in the blood were measured.

[0501] Statistical analysis

[0502] Data were analyzed using GraphPad Prism 9.0 software (San Diego, CA, USA). Data are presented as mean ± SD. One-way ANOVA, two-way ANOVA, and Tukey's test were used for comparison among groups. P < 0.05 was considered statistically significant.

[0503] 7. Results

[0504] 7.1A and B reversed 5-FU-induced weight loss

[0505] like Figure 3 As shown, A and B had no effect on the body weight of Pan02 tumor-bearing mice compared with the model group. As expected, the body weight of mice in the positive control drug 5-FU group (1.5 mg / kg) decreased during the administration period. Surprisingly, the body weight of mice in the A+5-FU (1.5 mg / kg) group or the B group did not decrease.

[0506] Figure 3 Figure 2 Effects of A (right histogram) or B (left histogram) on 5-FU-induced weight loss in Pan 02 tumor-bearing mice. Body weights are shown as mean ± SD. All data were analyzed using two-way ANOVA followed by Tukey's multiple comparison test.

[0507] 7.2A reduces the mortality of Pan02 tumor-bearing mice

[0508] like Figure 2 As shown, on day 82, the mortality rates of mice in each group were: model group, 90% or 100% (in two different experiments); group A, 70%; group B, 90%; 5-FU (1.5 mg / kg) group, 90%; group A+5-FU (1.5 mg / kg) group, 70%; group B+5-FU (1.5 mg / kg), 90%. A reduced the mortality rate of Pan02 tumor-bearing mice.

[0509] 2. Effects of A and B on mortality of Pan 02 tumor-bearing mice.

[0510] Effects of 7.3A and B on Pan02 tumor growth

[0511] Figure 1 The antitumor effects of A and B on Pan02 tumor-bearing mice were summarized. Figure 1 As shown in the figure, the tumor volume growth curve results clearly show that the tumor volume of mice in the model group and the B treatment group grew rapidly over a duration of 82 days. It is worth noting that 5-FU and A can significantly reduce tumor volume, and the reduction degree of A is the same as that of 5-FU. The tumor volume of the A+5-FU (1.5 mg / kg) group has the most significant reduction.

[0512] The therapeutic effects of A and B reduced tumor growth in vivo. The longest diameter and perpendicular short diameter of the tumor were recorded every 3 days. Tumor volume is expressed as mean ± SD.

[0513] Effects of 7.4A and B on extending the lifespan of mice

[0514] The effects of A and B on the lifespan extension of Pan02 tumor-bearing mice were evaluated. Figure 2 . The results showed that due to the extremely rapid growth of Pan02 transplanted tumors, all mice in the model group died within 82 days. The median survival time of mice in each group was as follows: model group, 48.5 days and 49.5 days; group A, 58.5 days; group B, 51.5 days; 5-FU (1.5 mg / kg) group, 53.5 days; A+5-FU (1.5 mg / kg) group, 63.5 days; A+5-FU (0.75 mg / kg) group, 59.5 days; B+5-FU (1.5 mg / kg) group, 53.5 days. These results clearly show that the A+5-FU group significantly prolonged the survival of Pan02 tumor-bearing mice.

[0515] Figure 2 In the experiment, administration of A and B prolonged the survival of Pan 02 tumor-bearing mice. The log-rank (Mantel-Cox) test (recommended) was used for analysis. *P<0.05 vs model group, #P<0.05 vs 5-FU (1.5 mg / kg) group.

[0516] 8. Conclusion

[0517] Both A and B can reduce the size of pancreatic tumors, and the anti-tumor effect of A is better than that of B. The anti-tumor effect and the effect of prolonging the survival of pancreatic cancer mice in the A combined with 5-FU (1.5 mg / kg) group are better than those in the A alone or 5-FU alone group.

[0518] Example 2. Evaluation of the effects of compositions A and B on the lifespan extension of H22 tumor-bearing (aggressive liver cancer) mice

[0519] Experimental methods

[0520] H22 cell suspension (2 × 10 6 Each mouse was injected subcutaneously in the right axilla of the forelimb. When the tumor grew to 100 mm 3 -150 mm 3 The mice were randomly divided into 8 treatment groups: model group (n=10), group A (n=10), group B (n=10), 5-FU group (2.5 mg / kg, n=10), group A+5-FU group (1.5 mg / kg, n=10), group B+5-FU group (1.5 mg / kg, n=10). Different experimental drugs were injected intravenously (iv) or / and intraperitoneally (ip) once every two days. The body weight was measured every three days. The volume of solid tumors was measured once every three days with a digital caliper. The survival time of the animals was monitored and recorded every day.

[0521] result

[0522] Compared with the model group, A and B did not affect the body weight of H22 tumor-bearing mice. However, the body weight of mice in the positive control drug 5-FU group (2.5 mg / kg) decreased during the experiment. On day 22, the mortality rates of mice in each group were: model group, 100%; A group, 50%; B group, 60%; 5-FU (2.5 mg / kg) group, 30%; A+5-FU (1.5 mg / kg) group, 30%; B+5-FU (1.5 mg / kg) group, 40%. The mortality rate of the A+5-FU (1.5 mg / kg) group was comparable to that of the 5-FU (2.5 mg / kg) group. This shows that the cancer is developing rapidly, even compared to the pancreatic cancer used in the first experiment.

[0523] The results of the tumor volume growth curve clearly showed that the tumor volume of the model group mice increased over a 22-day duration. In contrast, the treatment of A+5-FU significantly inhibited the growth of the tumor. Starting from the 13th day, the average tumor volume of the mice in the A combined with 5-FU treatment group grew relatively slowly. The results showed that all the mice in the model group died within 22 days due to the significantly faster growth rate of the H22 transplanted tumor. The median survival time of mice in each group was as follows: model group, 15.5 days; group A, 20 days; group B, 18 days; 5-FU (2.5 mg / kg) group, 22 days; A+5-FU (1.5 mg / kg) group, 22 days; B+5-FU (1.5 mg / kg) group, 22 days. These results clearly show that the treatment of the A+5-FU group greatly prolonged the survival of H22 tumor-bearing mice.

[0524] in conclusion

[0525] Both A and B can reduce the size of tumors, but A is more effective than B. The anti-tumor effects of A and B are mild but significant. The anti-tumor effect and the effect of prolonging survival of the A+5-FU (1.5 mg / kg) group and the 5-FU (2.5 mg / kg) group on H22 tumor-bearing mice are comparable.

[0526] 5. Materials and Instruments

[0527] 5.1. Materials

[0528] Test articles: FAD and FAD / PEG complex.

[0529] Storage: Store at 4℃ away from light.

[0530] Registration procedure: The quantity, date, user and purpose of the test sample must be registered each time; the solution should be prepared in advance according to the dosage and stored at 4°C away from light.

[0531] Positive control drug: 5-fluorouracil injection, batch number: H31020593.

[0532] Manufacturer: Shanghai Xudong Haipu Pharmaceutical Co., Ltd. Storage: Store in sealed containers at a temperature below 4°C.

[0533] Registration Procedure: Register the number, date, user and purpose of each test sample.

[0534] Basement membrane matrix HC, manufacturer: Corning Incorporated, USA.

[0535] RPMI-1640, product number: 61870036; manufacturer: Gibco, USA.

[0536] Fetal bovine serum, certified, Australia, catalog number: 10099141C; manufacturer: Gibco, USA.

[0537] Trypsin-EDTA (0.05%), phenol red, product number: 25300054; manufacturer: Gibco Company, USA.

[0538] HBSS, calcium-free, magnesium-free, phenol red-free, product number: HBSS, manufacturer: Sigma-Aldrich, USA.

[0539] PBS powder, manufacturer: Sigma-Aldrich, USA.

[0540] Paraformaldehyde, product number: 20100601-1; manufacturer: Guangzhou Chemical Reagent Factory.

[0541] Isoflurane, expiration date: 2019-12-28; Manufacturer: Shenzhen Ruiwode Life Science Technology Co., Ltd.

[0542] 5.2. Instrumentation

[0543] Animal weighing balance, item number: JCS-11001C; manufacturer: Shanghai Ranhao Electronics Co., Ltd.

[0544] Pharmaceutical weighing balance, item number: BSM-1204, manufacturer: Shanghai Zhuojing Electronic Technology Co., Ltd.

[0545] Zinc alloy digital display caliper, item number: 20050430; manufacturer: Shenzhen Cebao Electronic Tools Store.

[0546] Variable speed multi-purpose oscillator, item number: HY-4A; manufacturer: Hunan Frontier Technology Co., Ltd.

[0547] Inverted fluorescence microscope: Olympus IX71; Manufacturer: Olympus Corporation.

[0548] Carbon dioxide incubator, manufacturer: Thermo Fisher Scientific Co., Ltd.

[0549] Low-temperature high-speed centrifuge, product number: 5430 / 5430R; manufacturer: Eppendorf

[0550] Direct water purification system, product number: Advantage A10; manufacturer: Millipore, Merck KGaA, Darmstadt, Germany

[0551] 5.3. Animals

[0552] Species: Rodent; Strain: BALB / c mouse; Grade: SPF; Gender: Female; Age: 5 - 6 weeks; Female; Age: 5 - 6 weeks. Animal production license number SCXK(Guangdong)2020 - 0051, Zhuhai Bestong Biotechnology Co., Ltd.

[0553] Animal certificate numbers: 44822700008254; 44822700008373.

[0554] Animal use license number: SYXK(Guangdong)2021 - 0259, Guangzhou Regene Biotechnology Co., Ltd.

[0555] The animals were housed in the SPF - level animal facility of Guangzhou Regene Biotechnology Co., Ltd. The mice had free access to food and water throughout the experiment and were housed under a 12 - h light / dark cycle at a temperature controlled at 20 - 26°C and a humidity controlled at 40 - 70%. The experimental procedure was approved by the Laboratory Animal Ethics Committee of Guangzhou Regene Biotechnology Co., Ltd.

[0556] Number of mice: The mice were randomly divided into 6 groups: model group (n = 10), group A (n = 10), group B (n = 10), 5 - FU group (2.5 mg / kg, n = 10), A + 5 - FU group (1.5 mg / kg, n = 10), B + 5 - FU group (1.5 mg / kg, n = 10).

[0557] 6. Experimental methods

[0558] 6.1. H22 cell culture

[0559] H22 mouse hepatoma cell line was purchased from Wuhan Pronocell Life Science Co., Ltd. (Wuhan, China, Contract No.: XD-000-2022-03-30-0029). It was stored at -80°C upon arrival. H22 cells were cultured in RPMI-1640 supplemented with 10% FBS (v / v), 100 U / mL penicillin G (Sigma-Aldrich, USA), and 100 μg / mL streptomycin (Sigma-Aldrich, USA). The culture was maintained at 37°C and 5% CO 2 Cultured in a humidified incubator.

[0560] 6.2. Isolation and Quarantine

[0561] After the nude mice entered the SPF experimental center, they were strictly isolated and quarantined in accordance with the relevant technical requirements of the SPF experimental animal center of Guangzhou Ruige Biotechnology Co., Ltd. The isolation and quarantine period was 3 days. The general appearance and movement status of the rats, including consciousness, gait, response to stimulation, walking balance and limb coordination, were observed and recorded.

[0562] 6.3. Grouping and Dosing

[0563] Table 2: Experimental animals were randomly divided into 6 groups:

[0564]

[0565] Different experimental drugs (Table 2) were injected intravenously (iv) and intraperitoneally (ip) at 10:00 am every two days. Drug A or drug B was injected into the tail vein first, and 5-FU was injected intraperitoneally 24 hours later.

[0566] 6.4. Model establishment, grouping and drug administration

[0567] Under sterile conditions, H22 cells (1×10 7 Balb / c mice were intraperitoneally injected with 0.2 mL of 10 cells / mL and sacrificed 7 days later to collect ascites (the collected ascites tumor fluid was viscous and ivory-colored). The ascites tumor fluid was then diluted with Matrigel to adjust the cell concentration to 2×10 7 Each mouse was injected subcutaneously with 0.1 mL of cell suspension in the right axilla of the forelimb. When the tumor grew to 100 mm 3 -150 mm 3 The mice were randomly divided into treatment groups: model group (n=10), group A (n=10), group B (n=10), 5-FU group (n=10), A+5-FU group (2.5 mg / kg, n=10), and B+5-FU group (n=10).

[0568] 6.5. Detection indicators

[0569] Weigh your body every three days. Measure the length and width of the solid tumor with a digital caliper every three days. The tumor volume is calculated using the modified ellipsoid formula: V = π / 6 × (length × width 2 The survival time of the animals was monitored and recorded every day. The experiment lasted for 22 days, and the animals that survived for more than 22 days were assumed to have survived for 22 days. The survival rate (%) was calculated using the following formula: survival rate (%) = [(10-number of mice that died in each group) / 10] × 100%.

[0570] Statistical analysis

[0571] Data were analyzed using GraphPad Prism 9.0 software (San Diego, CA, USA). Data are presented as mean ± SD. One-way ANOVA, two-way ANOVA, and Tukey's test were used for comparison among groups. P < 0.05 was considered statistically significant.

[0572] 7. Results

[0573] 7.1A and B do not affect weight changes caused by chemotherapy, but can prevent side effects caused by 5-FU

[0574] like Figure 6 As shown, A and B did not affect the body weight of H22 tumor-bearing mice compared with the model group. However, the body weight of mice in the positive control drug 5-FU group (2.5 mg / kg) decreased during the administration period, but did not decrease if A or B was injected at the same time.

[0575] Figure 6 The effects of A and B on the body weight of H22 tumor-bearing mice. Body weight is expressed as mean ± SD. All data were analyzed by two-way ANOVA followed by Tukey's multiple comparison test.

[0576] 7.2A combined with 5-FU reduced the mortality of H22 tumor-bearing mice

[0577] like Figure 5 As shown, on the 22nd day, the mortality rates of mice in each group were: model group, 100%; group A, 50%; group B, 60%; 5-FU (2.5 mg / kg) group, 30%; A+5-FU (1.5 mg / kg) group, 30%, 50%; B+5-FU (1.5 mg / kg) group, 40%. The mortality rate of A+5-FU (1.5 mg / kg) group was equivalent to that of 5-FU (2.5 mg / kg) group.

[0578] Effects of 7.3A and B on H22 tumor growth

[0579] Figure 4 The antitumor effects of A and B on H22 tumor-bearing mice were summarized. Figure 4As shown in the figure, the results of the tumor volume growth curve clearly show that the tumor volume of mice in the model group grew rapidly over a duration of 22 days. However, the treatment of A+5-FU inhibited the growth of tumors. From the 13th day, the average tumor volume of mice treated with A combined with 5-FU grew relatively slowly.

[0580] 7.4 Effects of Composition A and Composition B on Prolonging the Lifespan of Mice with Hepatocellular Carcinoma

[0581] like Figure 5 As shown, the effects of composition A and composition B on the extension of the life span of H22 tumor-bearing mice were evaluated. The results showed that due to the extremely rapid growth of H22 transplanted tumors, all mice in the model group died within 21 days. The median survival time of mice in each group was as follows: model group, 15.5 days; group A, 20 days; group B, 18 days; 5-FU (2.5 mg / kg) group, 22 days; A+5-FU (1.5 mg / kg) group, 22 days, 21.5 days; B+5-FU (1.5 mg / kg) group, 22 days. These research results clearly show that the A+5-FU group greatly extended the survival of H22 tumor-bearing mice.

[0582] 8. Conclusion

[0583] Both A and B can reduce the size of liver tumors, but A is more effective than B.

[0584] Both A and B can eliminate the side effects of 5-FU, especially weight loss.

Claims

1. A composition comprising flavin adenine dinucleotide (FAD) or a salt thereof, reduced glutathione (GSH), adenosine triphosphate (ATP) or a salt thereof, optionally myristic acid or a salt thereof, and a carrier.

2. The composition according to claim 1, wherein the salt of FAD is flavin adenine dinucleotide disodium salt hydrate, the salt of ATP is adenosine triphosphate disodium salt hydrate, and GSH is reduced L-glutathione.

3. The composition according to claim 1 or 2, wherein the carrier is selected from the group consisting of metal salts, polymers, liposomes, excipients and combinations thereof.

4. The composition according to claim 3, wherein the carrier comprises a polymer selected from polyethylene glycol (PEG), chitosan, collagen, starch, hyaluronic acid, preferably PEG or chitosan or hyaluronic acid, more preferably PEG 600, more preferably PEG-600-diacid, more preferably hyaluronic acid.

5. The composition according to claim 3, wherein the carrier comprises a metal salt, preferably a gold salt, more preferably HAuCl4·6H2O.

6. A composition according to any one of the preceding claims 1 to 5, wherein the composition is in a form suitable for intravenous injection (iv), oral administration including sublingual administration (po), rectal administration, intratumoral administration, intraocular administration, intramucosal administration, intravesical administration or intraurethral administration, preferably iv or po administration.

7. The composition according to claim 1, wherein the composition is administered to an individual at a dose of 0.1 mg to 10 g of FAD or a salt thereof, a dose of 0.1 to 10 g of GSH, a dose of 0.1 mg to 10 g of ATP or a salt thereof, and a dose of 0.1 mg to 10 g of myristic acid or a salt thereof.

8. The composition according to claim 1, which is a therapeutically effective amount of the composition and a pharmaceutically acceptable carrier or a nutritionally acceptable carrier.

9. A composition comprising the composition of any one of claims 1 to 8 and a medicament.

10. Use of the composition according to any one of claims 1 to 9 in the preparation of a medicament for preventing and / or treating a disease. The use according to claim 10 , wherein the disease is cancer.

12. The use according to claim 11, wherein the medicament is used as an adjuvant (supplement) or neoadjuvant (scavenger) for cancer treatment.

13. The use according to any one of claims 11 to 12, wherein the disease is selected from the group consisting of brain cancer, breast cancer, prostate cancer, lung cancer, tracheal cancer, upper and / or lower digestive tract cancer, stomach cancer, kidney cancer, pancreatic cancer, liver cancer, urethral cancer, reproductive organ cancer, skin cancer, ear, nose and throat (ENT) cancer and lymphatic organ cancer, preferably pancreatic cancer or liver cancer, more preferably invasive metastatic tumor cancer.

14. Use of the composition according to any one of claims 1 to 8 in the preparation of a medicament for preventing and / or treating side effects caused by a drug or a disease.

15. The use according to claim 14, wherein the side effects are side effects caused by 5-FU.

16. The use according to claim 14, wherein the side effect is selected from the group consisting of weight loss, nausea, vomiting, headache, bleeding, alopecia, neutropenia, pain, thrombosis, lymphedema and a combination thereof, preferably weight loss.

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