WO2015172712A1 - 维生素c与抗肿瘤药物协同作用的注射用药物组合物 - Google Patents

维生素c与抗肿瘤药物协同作用的注射用药物组合物 Download PDF

Info

Publication number
WO2015172712A1
WO2015172712A1 PCT/CN2015/078797 CN2015078797W WO2015172712A1 WO 2015172712 A1 WO2015172712 A1 WO 2015172712A1 CN 2015078797 W CN2015078797 W CN 2015078797W WO 2015172712 A1 WO2015172712 A1 WO 2015172712A1
Authority
WO
WIPO (PCT)
Prior art keywords
vitamin
group
cancer
pharmaceutical composition
cell line
Prior art date
Application number
PCT/CN2015/078797
Other languages
English (en)
French (fr)
Inventor
王子厚
陈西敬
任霜霞
曲昌海
李大魁
唐伟松
陈琦
冯奉仪
马恩龙
曹日晖
赵娣
梅丹
张玲
Original Assignee
王子厚
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 王子厚 filed Critical 王子厚
Publication of WO2015172712A1 publication Critical patent/WO2015172712A1/zh

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles

Definitions

  • the invention relates to a pharmaceutical composition for treating malignant tumors, in particular to a vitamin C anticancer composition for intratumoral injection, intervening administration or intravenous administration, which uses vitamin C and one or more commonly used chemotherapy drugs. In combination, it is prepared for administration as a pharmaceutically acceptable injectable form.
  • the composition of the invention has excellent physical and chemical stability and exact anti-tumor effect, and the in vitro cell experiment and the tumor-bearing mouse experiment show that the composition is effective for various malignant tumors such as liver cancer and pancreatic cancer.
  • Vitamin C also known as ascorbic acid, is a chemical formula of C 6 H 8 O 6 . It is an antioxidant that participates in various enzymatic reactions in the body and is an important substance in life activities. Nearly 50 years ago, research on the use of vitamin C for cancer treatment has been ongoing. As early as 1969, Benade et al found that ascorbate combined with aminotriazole can synergistically kill Ehrlich ascites cancer cells. In the 1970s, "Father of Vitamin C", two Nobel Prize winners, Linus Pauline, conducted extensive and in-depth research on the biological activity and application of vitamin C and first proposed high-dose vitamin C as a drug for the treatment of tumors. Imagine. He collaborated with Scottish surgeon Ewan Cameron to give a large dose of vitamin C (10 g/day) to 100 advanced cancer patients daily, extending his average survival by 300 days. However, in 1978, the NIH study of the National Institutes of Health questioned the above conclusions.
  • Phase I clinical trial “Phase I Study of High-Dose Intravenous (IV) Vitamin C Treatment in Patients With Solid Tumors” began in August 2006 and was hosted by the Cancer Treatment Centers of America.
  • Phase II clinical trial “Phase II Trial of High Dose Intravenous Vitamin C in Patients With Refractory Non-Hodgkin Lymphoma”, hosted by Thomas Jefferson University, began in February 2008.
  • the object of the present invention is to provide a novel pharmaceutical composition with a curative effect and a small side effect, in view of the disadvantages of the current clinical cancer treatment, especially the existing drugs for treating malignant tumors, which have large systemic side effects and poor targeting.
  • the present invention adopts the following technical solutions:
  • a pharmaceutical composition mainly for the treatment of malignant tumors comprising an active ingredient and a pharmaceutically acceptable excipient, the active ingredient being vitamin C and one or more commonly used chemotherapeutic drugs.
  • the compositions of the present invention comprise vitamin C and one or more conventional tumor chemotherapeutic agents; the compositions of the present invention may comprise only vitamin C and one or more conventional tumor chemotherapeutic agents; other active ingredients may also be included.
  • the invention selects vitamin C as the main anti-tumor component in the compound, and is matched with the chemotherapy drugs which are commonly used in clinical practice and have clear effects, and acts on different physiological stages of tumor cells through different mechanisms, or directly kills tumor cells, and plays a certain synergy. It can effectively treat various malignant tumors.
  • Vitamin C is a safe and compliant chemical that is commonly used in clinical oral and injection. It can kill tumor cells without damaging the host cells, achieve high selectivity, and greatly reduce the side effects of anticancer drugs.
  • the dose of vitamin C in the present invention should be greater than 0.2 mg/mL.
  • the auxiliary therapeutic agent in the composition selects the commonly used chemotherapy drugs in the clinic, and performs preliminary selection through physical and chemical compatibility tests to ensure the chemical stability of the reducing drug vitamin C; and then compares the respective pharmaceutical compositions by the in vitro tumor cell strain test.
  • the efficacy of the drug ensures that the two drugs do not affect each other, and the effect of chemotherapy is improved, and even synergistic effect; the efficacy of the composition is further investigated by the tumor-bearing mouse test, and the intratumoral injection is used to observe the tumor.
  • An indicator such as body size, thereby determining the composition of the pharmaceutical composition.
  • the commonly used tumor chemotherapy drugs can be used in the present invention.
  • Commonly used tumor chemotherapy drugs include, but are not limited to, antibiotic antitumor drugs, antitumor botanical drugs, anti-metabolite anti-tumor drugs, platinum anti-tumor drugs, Hormone antineoplastic agents, alkylating antitumor drugs, biological immunological antitumor drugs, cell differentiation inducers, monoclonal antibodies, angiogenesis inhibitors, epidermal growth factor receptor antagonists.
  • the antibiotic antineoplastic agent is selected from the group consisting of doxorubicin, mitomycin, daunorubicin, actinomycin D, pingyangmycin, doxorubicin, pirarubicin, epirubicin;
  • the anti-tumor botanical drug is selected from the group consisting of vincristine, vinorelbine, vindesine, paclitaxel, docetaxel, and methotrexate;
  • the anti-metabolic antineoplastic agent is selected from the group consisting of fluorouracil, methotrexate, cytarabine, capecitabine, raltitrexed, gemcitabine, pemetrexed, hydroxyurea, 6-anthracene, camptothecin a base and a derivative thereof (preferably a camptothecin derivative thereof is selected from the group consisting of hydroxycamptothecin, irinotecan, topotecan);
  • the platinum antitumor agent is selected from the group consisting of cisplatin, carboplatin and oxaliplatin;
  • the hormonal antineoplastic agent is selected from the group consisting of dexamethasone, hydrocortisone, toremifene, exemestane, letrozole, bicalutamide, progestogens (preferably progestogens selected from the group consisting of Medroxyprogesterone, megestrol acetate, etc.), sex hormones (preferred sex hormones are selected from estrogen diethylstilbestrol, etc.), androgens (preferred androgen drugs are selected from testosterone propionate, etc.), luteinizing hormone releasing hormone (The preferred luteinizing hormone releasing hormone drug is selected from the group consisting of goserelin, leuprolide, etc.);
  • the alkylating antitumor agent is selected from the group consisting of cyclophosphamide, nitrogen mustard, and temozolomide;
  • the bioimmune antineoplastic agent is selected from the group consisting of interferon, tumor necrosis factor, thymosin, interleukin, imatinib, gefitinib, erlotinib, sorafenib;
  • the cell differentiation inducing agent is selected from the group consisting of retinoic acid and arsenious acid;
  • the monoclonal antibody drug is selected from the group consisting of trastuzumab and rituximab.
  • the other antitumor agent is selected from the group consisting of biological immunological antineoplastic agents (preferably biological immunological antineoplastic agents are selected from the group consisting of interferon, tumor necrosis factor, thymosin, interleukin, imatinib, gefitinib, Erlotinib, sorafenib, etc.), cell differentiation inducer (preferably cell differentiation inducer selected from retinoic acid, arsenious acid, etc.), monoclonal antibody (preferred monoclonal antibody drug is selected from trastuzumab) Anti-rituximab), angiogenesis inhibitors, epidermal growth factor receptor antagonists, and the like.
  • biological immunological antineoplastic agents are selected from the group consisting of interferon, tumor necrosis factor, thymosin, interleukin, imatinib, gefitinib, Erlotinib, sorafenib, etc.
  • cell differentiation inducer preferably cell differentiation inducer selected from retinoi
  • the molar ratio of antibiotic antineoplastic agents and vitamin C can be
  • the molar ratio of the antitumor botanical drug paclitaxel to vitamin C can be:
  • 1 to 64 500 to 8333 ⁇ 10 3 ; preferably 1 to 32: 1 ⁇ 10 3 to 8333 ⁇ 10 3
  • the molar ratio of the anti-tumor botanical drug to vitamin C can be:
  • the molar ratio of the antimetabolite antineoplastic agent to vitamin C can be:
  • the molar ratio of the anti-metabolite antineoplastic agent to vitamin C can be:
  • the molar ratio of platinum antineoplastic agents to vitamin C can be:
  • the molar ratio of platinum antineoplastic agents to vitamin C can be:
  • the molar ratio of platinum antineoplastic agents to vitamin C can be:
  • 1:5 to 20000 is preferably 1:15-20000
  • it is 1:15 to 10000 or preferably 1 to 300: 4500 to 10,000.
  • it is 1 to 300: 4500 to 10000; further preferably 3 to 300: 4500 to 10000; most preferably 100 to 300: 10000;
  • the molar ratio of the alkylating antitumor drug to vitamin C can be:
  • the molar ratio of the biological immunological antineoplastic agent to vitamin C can be:
  • the molar ratio of doxorubicin to vitamin C can be
  • the molar ratio of pingyangmycin to vitamin C can be
  • the molar ratio of vincristine paclitaxel to vitamin C can be:
  • 1 to 64 500 to 8333 ⁇ 10 3 ; preferably 1 to 32: 1 ⁇ 10 3 to 8333 ⁇ 10 3
  • the molar ratio of paclitaxel to vitamin C can be:
  • the molar ratio of gemcitabine and vitamin C can be:
  • the molar ratio of hydroxycamptothecin to vitamin C can be:
  • the molar ratio of cisplatin to vitamin C can be:
  • the molar ratio of carboplatin to vitamin C can be:
  • the molar ratio of oxaliplatin to vitamin C can be:
  • 1:5 to 20000 is preferably 1:15-20000
  • it is 1:15 to 10000 or preferably 1 to 300: 4500 to 10,000.
  • the molar ratio of temozolomide to vitamin C can be:
  • sorafenib is combined with vitamin C to prepare a pharmaceutical composition for treating cancer
  • the molar ratio of sorafenib and vitamin C can be:
  • a more preferred implementation of the present invention further includes, but is not limited to, the following technical solutions:
  • the molar ratio of doxorubicin to vitamin C can be
  • the molar ratio of pingyangmycin to vitamin C can be
  • the molar ratio of vincristine to vitamin C can be:
  • the molar ratio of paclitaxel to vitamin C can be:
  • the molar ratio of gemcitabine and vitamin C can be:
  • the molar ratio of hydroxycamptothecin to vitamin C can be:
  • the molar ratio of cisplatin to vitamin C can be:
  • the molar ratio of carboplatin to vitamin C can be:
  • the molar ratio of oxaliplatin to vitamin C can be:
  • the molar ratio of sorafenib and vitamin C can be:
  • the molar ratio of vincristine to vitamin C can be:
  • the molar ratio of paclitaxel to vitamin C can be:
  • the molar ratio of gemcitabine and vitamin C can be:
  • the molar ratio of hydroxycamptothecin to vitamin C can be:
  • the molar ratio of cisplatin to vitamin C can be:
  • the molar ratio of vincristine to vitamin C can be:
  • the molar ratio of paclitaxel to vitamin C can be:
  • the molar ratio of hydroxycamptothecin to vitamin C can be:
  • the molar ratio of cisplatin to vitamin C can be:
  • the molar ratio of oxaliplatin to vitamin C can be:
  • the molar ratio of doxorubicin to vitamin C can be:
  • the molar ratio of vincristine to vitamin C can be:
  • the molar ratio of hydroxycamptothecin to vitamin C can be:
  • the molar ratio of cisplatin to vitamin C can be:
  • the molar ratio of vincristine to vitamin C can be:
  • the molar ratio of hydroxycamptothecin to vitamin C can be:
  • the molar ratio of cisplatin to vitamin C can be:
  • the molar ratio of temozolomide to vitamin C can be:
  • the molar ratio of doxorubicin to vitamin C can be:
  • the molar ratio of vincristine to vitamin C can be:
  • the molar ratio of paclitaxel to vitamin C can be:
  • the molar ratio of hydroxycamptothecin to vitamin C can be:
  • the pharmaceutical compositions of the present invention may also comprise pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients including solvents, solubilizers, stabilizers, excipients, carriers, etc., are mainly selected from the group consisting of water for injection, physiological saline, ethanol, propylene glycol, glycerin; polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600, polyoxyethylene castor oil, polysorbate, poloxamer, polyvinylpyrrolidone, oily fatty acid and its mono or diglyceride; lactose, sucrose, xylitol, sorbitol, Mannitol, lactitol, dextran, d-xylose, glucose; phospholipids, gelatin, gum arabic, shellac, guar gum, agar, alginic acid and its salts, polyvinyl alcohol, polyethylene glycol, hydroxyl One of propyl cellulose, hydroxypropyl,
  • the dosage form of the pharmaceutical composition of the present invention is preferably prepared into an injection preparation, including a solution for injection, a suspension for injection, a lyophilized powder for injection, a sterile divided powder for injection, an oil for injection, a liposome, and a micro Controlled release dosage forms related to milk, microspheres, and nanoparticle preparations.
  • the preparation process of the compound preparation is as follows:
  • the pharmaceutical composition of the present invention has a good effect in the treatment of antitumor.
  • the tumor includes but is not limited to melanoma, gastric cancer, lung cancer, breast cancer, kidney cancer, liver cancer, oral epithelial cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, colon cancer, bladder Cancer, brain tumor, esophageal cancer, lymphoma, nervous system cancer and other tumors.
  • the brain tumors are particularly preferred from gliomas.
  • pancreatic cancer, glioma, esophageal cancer has an excellent effect.
  • the present invention provides a method of using the composition of the present invention, which can be administered for intravenous, intraarterial, interventional, etc., in addition to intratumoral injection.
  • Interventional therapy and intratumoral injection are new treatment technologies developed in recent years. They can directly inject drugs into tumor sites, so that drugs can directly act on tumor tissues and tumor cells, and have very good targeting. Greatly reduce the systemic side effects of anti-tumor drugs.
  • various forms of interventional therapy are currently the preferred treatments for malignant tumors that cannot be surgically removed (especially in the advanced stage of primary liver cancer or liver metastases). It has been accepted by the majority of clinicians.
  • Intratumoral injection is a kind of interventional treatment.
  • the composition of the present invention is also preferentially used for intratumoral injection and interventional treatment of solid malignant tumors such as liver cancer and pancreatic cancer, and various malignant tumors such as brain tumors and esophageal cancer. It is also administered by special routes such as veins, arteries, muscles, and subcutaneous, and is also used for solid tumors that cannot be treated by surgery, radiation, etc. due to body parts, and also for tumors that require comprehensive treatment in clinical practice.
  • the invention also discloses a kit comprising any of the above pharmaceutical compositions.
  • the pharmaceutical composition of the present invention can enhance the chemotherapy effect of antitumor drugs, and even has a synergistic effect.
  • the pharmaceutical composition of the present invention can reduce the toxic side effects of antitumor drugs and increase the patient's tolerated dose for antitumor drugs.
  • the present invention selects vitamin C as a main anti-tumor drug with good safety, has broad anti-tumor spectrum, clear effect, small side effects, and is not easy to produce resistance.
  • the advantages of medicinal properties, and the composition can be used for intratumoral injection, greatly improving the therapeutic effect of solid malignant tumors.
  • Figure 1a Comparison of inhibition rates of Hep G2 cells by a combination of doxorubicin alone and doxorubicin and 250 ⁇ M vitamin C
  • Figure 1c Comparison of in vitro inhibition of Hep G2 cells by a combination of pingyangmycin alone and pingyangmycin and 250 ⁇ M vitamin C;
  • Example 1 Preparation of a solution for injection
  • Example 2 lyophilized powder for injection
  • chitosan solution with 0.1M acetic acid, stir and dissolve fully; weigh the prescribed amount of vitamin C and doxorubicin, dissolve in a certain amount of ethanol, slowly add to the chitosan solution, stir while stirring, and stir for four hours; 60% sodium glycerophosphate solution.
  • the chitosan solution and the sodium glycerophosphate solution were simultaneously ice-bathed for 20 min, and the sodium glycerophosphate solution was added dropwise to the chitosan solution while stirring, and the mixture was fully mixed; the mixture was stirred for 10 minutes in an ice bath to form a compound slow-release temperature-sensitive gel.
  • Vc vitamin C
  • the cells in the logarithmic growth phase were digested with 0.25% trypsin, and then mixed into a single cell suspension with RPMI1640 medium containing 10% fetal bovine serum, and seeded in a 96-well plate at a density of 3 ⁇ 10 3 /mL.
  • the control group was added with a culture solution containing 0.1% DMSO, and cultured at 37 ° C for 48 h or 72 h. After the completion of the culture, the drug solution was aspirated, and 100 ⁇ L of PBS was added to each well to wash away the residual drug solution, and 100 ⁇ L of 10% 5 mg/mL MTT working solution was added to each well, and the culture was further continued at 37 ° C for 4 hours. Aspirate the supernatant, add 150 ⁇ L of DMSO to each well, shake for 10 min to fully dissolve the crystals, measure the OD value at 570 nm, and calculate the inhibition rate of the tumor cells after administration of the drug according to the following formula, and use SPSS data processing software. The half inhibition concentration (IC 50 ) was calculated.
  • IR (A + B) IR (A) + IR (B) - IR (A) ⁇ IR (B), the drug is only a simple superposition;
  • IR(A+B), IR(A), and IR(B) correspond to the combination of drug AB, A alone and B alone.
  • IR(A)+IR(B)-IR(A) ⁇ IR(B) is shown as a predicted value. If the inhibition ratio ⁇ IR(A+B) ⁇ of the AB combination is greater than the predicted value, it means that the synergy has synergy. effect. Mark ⁇ in the upper right corner for synergy. If the inhibition rate is negative, it is recorded as 0.
  • the above cell strain is selected from the group consisting of human hepatoma cell line HepG-II, human lung cancer cell line A549, human gastric cancer cell line SGC-7901, human prostate cancer cell line PC-3, human glioma cell line U251 and human breast cancer cell line. MCF-7, normal liver cell line.
  • Table A-1-5-1 Results of the effect of Vc with doxorubicin for 48 h on human hepatoma cell line HepG-II.
  • ⁇ means synergy; “ ⁇ ” means that Vc can improve the role of chemotherapeutic drugs
  • Table A-1-5-2 Results of the effect of Vc in combination with doxorubicin for 72 h on human hepatoma cell line HepG-II.
  • Table A-1-5-3 Results of the effect of Vc with doxorubicin for 48 h on human hepatoma cell line HepG-II.
  • Table A-1-5-4 Results of the effect of Vc in combination with doxorubicin for 72 h on human hepatoma cell line HepG-II.
  • Table B-1-7-1 Results of the effect of Vc combined with pingyangmycin for 48 h on human hepatoma cell line HepG-II.
  • Table B-1-7-2 Results of the effect of Vc combined with pingyangmycin for 72 h on human hepatoma cell line HepG-II.
  • Table B-1-7-3 Results of the effect of Vc combined with pingyangmycin for 48 h on human hepatoma cell line HepG-II.
  • Table B-1-7-4 Results of the effect of Vc combined with pingyangmycin for 72 h on human hepatoma cell line HepG-II.
  • Table C-1-8-1 Results of the effect of Vc combined with vincristine on human hepatoma cell line HepG-II for 48 h.
  • Table C-1-8-2 Results of the effect of Vc combined with vincristine on 72 h against human hepatoma cell line HepG-II.
  • Table C-1-8-3 Results of the effect of Vc combined with vincristine on human hepatoma cell line HepG-II for 48 h.
  • Table C-1-8-4 Results of the effect of Vc in combination with vincristine on human hepatoma cell line HepG-II for 72 h.
  • Table D-1-9-1 Results of the effect of Vc combined with paclitaxel on human hepatoma cell line HepG-II for 48 h.
  • Table D-1-9-2 Results of the effect of Vc combined with paclitaxel on 72 h on human hepatoma cell line HepG-II.
  • Table D-1-9-3 Results of the effect of Vc combined with paclitaxel on human hepatoma cell line HepG-II for 48 h.
  • Table D-1-9-4 Results of the effect of Vc combined with paclitaxel on 72 h on human hepatoma cell line HepG-II.
  • Table E-1-10-1 Results of the effect of Vc combined with gemcitabine on 48 h on human hepatoma cell line HepG-II.
  • Table E-1--10-2 Results of the effect of Vc combined with gemcitabine on 72 h against human hepatoma cell line HepG-II.
  • Table E-1-10-3 Results of the effect of Vc combined with gemcitabine on 48 h against human hepatoma cell line HepG-II.
  • Table E-1-10-4 Results of the effect of Vc combined with gemcitabine on 72 h against human hepatoma cell line HepG-II.
  • Table F-1-6-1 Results of the effect of Vc with hydroxycamptothecin for 48 h on human hepatoma cell line HepG-II.
  • Table F-1-6-2 Results of the effect of Vc combined with hydroxycamptothecin 72h on human hepatoma cell line HepG-II.
  • Table F-1-6-3 Results of the effect of Vc with hydroxycamptothecin for 48 h on human hepatoma cell line HepG-II.
  • Table F-1-6-4 Results of the effect of Vc with hydroxycamptothecin 72h on human hepatoma cell line HepG-II.
  • Table G-1-2-1 Results of the effect of Vc in combination with cisplatin for 48 h on human hepatoma cell line HepG-II.
  • Table G-1-2-2 Results of the effect of Vc in combination with cisplatin for 72 h on human hepatoma cell line HepG-II.
  • Table G-1-2-3 Results of the effect of Vc in combination with cisplatin for 48 h on human hepatoma cell line HepG-II.
  • Table G-1-2-4 Results of the effect of Vc combined with cisplatin for 72 h on human hepatoma cell line HepG-II.
  • Table H-1-3-1 Results of the effect of Vc combined with carboplatin for 48 h on human hepatoma cell line HepG-II.
  • Table H-1-3-2 Results of the effect of Vc combined with carboplatin for 72 h on human hepatoma cell line HepG-II.
  • Table H-1-3-3 Results of the effect of Vc in combination with carboplatin for 48 h on human hepatoma cell line HepG-II.
  • Table H-1-3-4 Results of the effect of Vc combined with carboplatin for 72 h on human hepatoma cell line HepG-II.
  • Table I-1-1-1 Results of the effect of Vc combined with oxaliplatin 48h on human hepatoma cell line HepG-II.
  • Table I-1-1-2 Results of the effect of Vc combined with oxaliplatin 72h on human hepatoma cell line HepG-II.
  • Table I-1-1-3 Results of the effect of Vc combined with oxaliplatin 48h on human hepatoma cell line HepG-II.
  • Table I-1-1-4 Results of the effect of Vc combined with oxaliplatin 72h on human hepatoma cell line HepG-II.
  • Table K-11-1 Results of the effect of Vac combined with sorafenib on 48 h against human hepatoma cell line HepG-II.
  • Table K-1-11-2 Results of the effect of Vc combined with sorafenib on 72 h against human hepatoma cell line HepG-II.
  • Table K-1-11-3 Results of the effect of Vac combined with sorafenib on 48 h against human hepatoma cell line HepG-II.
  • Table K-1-11-4 Results of the effect of Vc combined with sorafenib on 72 h against human hepatoma cell line HepG-II.
  • Table 1-A shows the IC 50 and the pharmacodynamic increase factor of the chemotherapeutic drug alone in the human hepatoma cell line HepG-II and in combination with different concentrations of Vc.
  • Table C-2-1-1 Results of the effect of Vc combined with vincristine for 48 h on human lung cancer cell line A549.
  • Table C-2-1-2 Results of the effect of Vc combined with vincristine 72h on human lung cancer cell line A549.
  • Table D-2-4-1 Results of the effect of Vc combined with paclitaxel for 48 h on human lung cancer cell line A549.
  • Table D-2-4-2 Results of the effect of Vc combined with paclitaxel for 72 h on human lung cancer cell line A549.
  • Table E-2-5-1 Results of the effect of Vc combined with gemcitabine for 48 h on human lung cancer cell line A549.
  • Table E-2-5-2 Results of the effect of Vc combined with gemcitabine 72h on human lung cancer cell line A549.
  • Table F-2-2-1 Results of the effect of Vc with hydroxycamptothecin for 48 h on human lung cancer cell line A549.
  • Table F-2-2-2 Results of the effect of Vc combined with hydroxycamptothecin 72h on human lung cancer cell line A549.
  • Table G-2-3-1 Results of the effect of Vc combined with cisplatin for 48 h on human lung cancer cell line A549.
  • Table G-2-3-2 Results of the effect of Vc in combination with cisplatin for 48 h on human lung cancer cell line A549.
  • Table 2-A shows the IC 50 and the pharmacodynamic increase factor of chemotherapeutic drugs acting on human lung cancer cell line A549 alone and in combination with different concentrations of Vc.
  • Table C-3-1-1 Results of the effect of Vc combined with vincristine for 48 h on human gastric cancer cell line SGC-7901.
  • Table C-3-1-2 Results of the effect of Vc combined with vincristine for 72 h on human gastric cancer cell line SGC-7901.
  • Table D-3-4-1 Results of the effect of Vc combined with paclitaxel for 48 h on human gastric cancer cell line SGC-7901.
  • Table D-3-4-2 Results of the effect of Vc combined with paclitaxel for 72 h on human gastric cancer cell line SGC-7901.
  • Table F-3-2-1 Results of the effect of Vc with hydroxycamptothecin for 48 h on human gastric cancer cell line SGC-7901.
  • Table F-3-2-2 Results of the effect of Vc with hydroxycamptothecin 72h on human gastric cancer cell line SGC-7901.
  • Table G-3-3-1 Results of the effect of Vc combined with cisplatin for 48 h on human gastric cancer cell line SGC-7901.
  • Table G-3-3-2 Results of the effect of Vc in combination with cisplatin for 72 h on human gastric cancer cell line SGC-7901.
  • Table I-3-5-1 Results of the effect of Vc combined with oxaliplatin 48h on human gastric cancer cell line SGC-7901.
  • Table I-3-5-2 Results of the effect of Vc combined with oxaliplatin 72h on human gastric cancer cell line SGC-7901.
  • Table 3-A shows the IC 50 and the pharmacodynamic increase factor of chemotherapeutic drugs acting on human gastric cancer cell line SGC-7901 alone and in combination with different concentrations.
  • Table A-4-4-1 Results of the effect of Vc with doxorubicin for 48 h on human prostate cancer cell line PC-3.
  • Table A-4-4-2 Results of the effect of Vc in combination with doxorubicin for 72 h on human prostate cancer cell line PC-3.
  • Table C-4-2-1 Results of the effect of Vc with vincristine for 48 h on human prostate cancer cell line PC-3.
  • Table C-4-2-2 Results of the effect of Vc with vincristine 72h on human prostate cancer cell line PC-3.
  • Table F-4-1-1 Results of the effect of Vc with hydroxycamptothecin for 48 h on human prostate cancer cell line PC-3.
  • Table F-4-1-2 Results of the effect of Vc combined with hydroxycamptothecin 72h on human prostate cancer cell line PC-3.
  • Table G-4-3-1 Results of the effect of Vc in combination with cisplatin for 48 h on human prostate cancer cell line PC-3.
  • Table G-4-3-2 Results of the effect of Vc in combination with cisplatin for 72 h on human prostate cancer cell line PC-3.
  • Table 4-A shows the IC 50 and the pharmacodynamic increase factor of chemotherapeutic drugs acting on human prostate cancer cell line PC-3 alone and in combination with different concentrations.
  • Table C-5-1-1 Results of the effect of Vc with vincristine for 48 h on human glioma cell line U251.
  • Table C-5-1-2 Results of the effect of Vc with vincristine 72h on human glioma cell line U251.
  • Table F-5-2-1 Results of the effect of Vc with hydroxycamptothecin 48h on human glioma cell line U251.
  • Table F-5-2-2 Results of the effect of Vc with hydroxycamptothecin 72h on human glioma cell line U251.
  • Table G-5-3-1 Results of the effect of Vc in combination with cisplatin for 48 h on human glioma cell line U251.
  • Table G-5-3-2 Results of the effect of Vc in combination with cisplatin for 72 h on human glioma cell line U251.
  • Table J-5-4-1 Results of the effect of Vc combined with temozolomide 48h on human glioma cell line U251.
  • Table J-5-4-2 Results of the effect of Vc combined with temozolomide 72h on human glioma cell line U251.
  • Table 5-A shows the IC 50 and the pharmacodynamic increase factor of chemotherapeutic drugs acting on human glioma cell line U251 alone and in combination with different concentrations.
  • Table A-6-1-1 Results of the effect of Vc with doxorubicin for 48 h on human breast cancer cell line MCF-7.
  • Table A-6-1-2 Results of the effect of Vc with doxorubicin for 72 h on human breast cancer cell line MCF-7.
  • Table C-6-3-1 Results of the effect of Vc with vincristine for 48 h on human breast cancer cell line MCF-7.
  • Table C-6-3-2 Results of the effect of Vc with vincristine 72h on human breast cancer cell line MCF-7.
  • Table D-6-4-1 Results of the effect of Vc combined with paclitaxel for 48 h on human breast cancer cell line MCF-7.
  • Table D-6-4-2 Results of the effect of Vc combined with paclitaxel for 72 h on human breast cancer cell line MCF-7.
  • Table F-6-2-1 Results of the effect of Vc with hydroxycamptothecin for 48 h on human breast cancer cell line MCF-7.
  • Table F-6-2-2 Results of the effect of Vc combined with hydroxycamptothecin 72h on human breast cancer cell line MCF-7.
  • Table 6-A shows the IC50 and the pharmacodynamic increase factor of four chemotherapy drugs acting on breast cancer cell line MCF-7 alone and in combination with different concentrations of chemotherapy drugs.
  • Table 7-A shows the IC 50 of chemotherapeutic drugs after chemotherapeutic drugs alone in human normal liver cell line L-02 and Vc
  • Kunming male ICR mice were used to ascite ascites from mice on the 8th day of the third passage, diluted with serum-free RPMI1640 medium, adjusted to a cell concentration of 1 ⁇ 10 7 cells/ml, and the mice were anesthetized with rapid ether. Thereafter, the back skin was sterilized, and each mouse was inoculated with about 0.2 ml of H22 tumor cell suspension under the skin, and the entire inoculation process was completed within 2 hours.
  • Intratumoral injection was divided into normal saline (Normal Saline), 20 mg/kg doxorubicin + 500 mg/kg VC group (VC+DOX), and 20 mg/kg doxorubicin group (DOX).
  • Normal Saline normal saline
  • VC+DOX 20 mg/kg doxorubicin + 500 mg/kg VC group
  • DOX 20 mg/kg doxorubicin group
  • Test results As shown in Figure 2, the injection of doxorubicin or a mixture of doxorubicin and VC in the tumor can inhibit the growth of the tumor well, but the tumor volume is 21 days after the high dose of vitamin C is added. Compared with the day of administration, the reduction was more, and the tumor size was better inhibited, which was consistent with the in vitro MTT assay.
  • Test results The cardiotoxicity of doxorubicin can be reflected from the body weight of mice. If the body weight of mice decreases rapidly, it indicates that the mice are very toxic. As can be seen from Figure 3, the addition of high-dose VC prevented the mice from rapidly decreasing in weight compared with the DOX group. After 21 days, the body weight was close to the blank group, indicating that the toxicity gradually decreased and the mice slowly returned to normal. .
  • Test results As shown in the figure, compared with the DOX group, the addition of high-dose vitamins reduced the mortality of the mice, indicating that the toxicity was well reduced, and the results of the changes in body weight were consistent, indicating that the VC+DOX group was less toxic.
  • This may be related to vitamin C as an antioxidant, which can remove excess oxygen free radicals produced by doxorubicin, improve the resistance of mice and improve survival rate.

Abstract

本发明提供一种用于注射给药治疗恶性肿瘤的药物组合物，它以维生素C为抗肿瘤成分，配以一种或多种常用化疗药物，制备成药学上可接受的注射剂型给药，或与一种或多种常用化疗药物联合注射用药，尤其是用于瘤内注射、介入给药或静脉、动脉、肌肉、皮下等给药。本发明的维生素C组合物制剂，可用于治疗肝癌、胰腺癌及其脑瘤、食管癌等多种恶性肿瘤。

Description

维生素C与抗肿瘤药物协同作用的注射用药物组合物 技术领域
本发明涉及一种治疗恶性肿瘤的药物组合物，尤其是用于瘤内注射、介入给药或静脉内给药的维生素C抗癌组合物，它以维生素C和一种或多种常用化疗药物合用，制备成药学上可接受的注射剂型给药。本发明的组合物，有优良的物理化学稳定性和确切的抗肿瘤作用，体外细胞实验及荷瘤小鼠实验表明，本组合物对肝癌、胰腺癌等多种恶性肿瘤有效。
背景技术
维生素C又称抗坏血酸，化学分子式是C6H8O6，是一种抗氧化剂，参与体内多种酶促反应过程，是生命活动的重要物质。近50年以前，维生素C用于肿瘤治疗的研究就一直在进行着。早在1969年，Benade等发现抗坏血酸盐与氨基三唑合用可协同杀死艾氏腹水癌细胞。上世纪70年代，“维生素C之父”，两次诺贝尔奖获得者Linus Pauline，对维生素C的生物活性及其应用进行了广泛深入的研究并首先提出了高剂量维生素C作为药物治疗肿瘤的设想。他与苏格兰外科医生Ewan Cameron合作，给100个晚期癌症患者每天口服大剂量的维生素C(10g/天)，使其平均生存期延长了300天。但是在1978年，美国国立卫生研究院NIH的研究却对上述结论提出了质疑。
虽然遇到前述质疑，但一些科学家仍坚持从多方面进行探索，其中在治疗或作为辅助药联合其他抗癌药物治疗恶性肿瘤方面的研究显示，使用大剂量的维生素C具有很大抗癌潜能,同时体外及动物实验证实它对多种肿瘤有明显的抑制作用，其发现与70年代的相关研究相比，主要差别是维生素C不再口服给药，而是大剂量地用于静脉注射给药，这正是维生素C能充分发挥抗肿瘤药效的关键所在。
在国外，静脉注射维生素C治疗肿瘤的临床试验研究正在进行中。两个I 期治疗肿瘤的临床试验表明，高达1.5g/kg的维生素C具有很好的耐受性和安全性。I期临床试验“Phase I Study of High-Dose Intravenous(IV)Vitamin C Treatment in Patients With Solid Tumors”已经于2006年8月开始，由美国癌症治疗中心(Cancer Treatment Centers of America)主持。II期临床试验“Phase II Trial of High Dose Intravenous Vitamin C in Patients With Refractory Non-Hodgkin Lymphoma”，由Thomas Jefferson University主持，于2008年2月开始。
发明内容
本发明的目的在于针对目前临床癌症的治疗，特别是治疗恶性肿瘤的现有药物中存在的全身副作用大、靶向性差的缺点，提供一种疗效确切、副作用小的新型药物组合物，以瘤内、介入或静脉注射形式给药。
为实现上述目的，本发明采用下列技术方案：
一种主要用于恶性肿瘤治疗的药物组合物，由活性成分和药学可接受的辅料组成，活性成分为维生素C和一种或多种常用化疗药物。本发明组合物包括维生素C和一种或多种常用肿瘤化疗药物；本发明的组合物可以只有维生素C和一种或多种常用肿瘤化疗药物组成；也可以包括其他活性成分。
本发明选择维生素C作为复方中的主要抗肿瘤成份，配以临床常用、效果明确的化疗药物，通过不同机理、同时作用于肿瘤细胞的不同生理阶段，或直接杀伤肿瘤细胞，起到一定的协同作用，可以有效地治疗各种恶性肿瘤。
维生素C是临床口服、注射常用的安全、依从性好的化学药。可以在杀伤肿瘤细胞的同时不损伤宿主细胞，达到高选择性，大大降低抗癌药物的毒副作用。优选的本发明中维生素C的剂量应大于0.2mg/mL。
组合物中的辅助治疗药，选择临床常用的化疗药物，通过物理、化学配伍试验，进行初步选择，保证还原性药物维生素C的化学稳定性；然后通过体外肿瘤细胞株试验，比较各药物组合物的药效，保证二者药效不相互影响，且有提高化疗效果、甚至协同作用；通过荷瘤小鼠试验对组合物的药效进行进一步的考察，采用瘤内注射方式给药，观察瘤体大小等指标，从而决定该药物组合物的组成。
所述的临床常用肿瘤化疗药物均可运用于本发明，常用肿瘤化疗药物包括但不限定于抗生素类抗肿瘤药、抗肿瘤植物药、抗代谢类抗肿瘤药、铂类抗肿瘤药、 激素类抗肿瘤药、烷化类抗肿瘤药、生物免疫类抗肿瘤药、细胞分化诱导剂、单克隆抗体、血管生成抑制剂、表皮生长因子受体拮抗剂。
所述的抗生素类抗肿瘤药选自阿霉素、丝裂霉素、柔红霉素、放线菌素D、平阳霉素、多柔比星、吡柔比星、表柔比星；
所述的抗肿瘤植物药选自长春新碱、长春瑞宾、长春地辛、紫杉醇、多西紫杉醇、甲异靛；
所述的抗代谢类抗肿瘤药选自氟尿嘧啶、甲氨喋呤、阿糖胞苷、卡培他滨、雷替曲塞、吉西他滨、培美曲塞、羟基脲、6-巯嘌呤、喜树碱及其衍生物(优选的喜树碱其衍生物选自羟基喜树碱、伊立替康、拓扑替康)；
所述的铂类抗肿瘤药选自顺铂、卡铂、奥沙利铂；
所述的激素类抗肿瘤药选自地塞米松、氢化可的松、托瑞米芬、依西美坦、来曲唑、比卡鲁胺、孕激素类(优选的孕激素类药物选自甲羟孕酮、甲地孕酮等)、性激素类(优选的性激素类药物选自雌激素己烯雌酚等)、雄激素(优选的雄激素药物选自丙酸睾丸酮等)、促黄体生成素释放激素(优选的促黄体生成素释放激素药物选自戈舍瑞林、亮丙瑞林等)；
所述的烷化类抗肿瘤药选自环磷酰胺、氮芥、替莫唑胺；
所述的生物免疫类抗肿瘤药选自干扰素、肿瘤坏死因子、胸腺肽、白细胞介素、伊马替尼、吉非替尼、埃罗替尼、索拉菲尼；
所述的细胞分化诱导剂选自维甲酸、亚砷酸；
所述的单克隆抗体药物选自曲妥珠单抗、利妥昔单抗。
所述的其它类抗肿瘤药选自生物免疫类抗肿瘤药(优选的生物免疫类抗肿瘤药选自干扰素、肿瘤坏死因子、胸腺肽、白细胞介素、伊马替尼、吉非替尼、埃罗替尼、索拉菲尼等)、细胞分化诱导剂(优选的细胞分化诱导剂选自维甲酸、亚砷酸等)、单克隆抗体(优选的单克隆抗体药物选自曲妥珠单抗、利妥昔单抗)、血管生成抑制剂、表皮生长因子受体拮抗剂等。
1.、抗生素类抗肿瘤药与维生素C合用制备治疗癌症的药物组合物时，
抗生素类抗肿瘤药和维生素C的摩尔比例范围可以是
1：100～500×103；或优选1：33～250×103；或1:1×103～1×106
或优选1:1.5×103～750×103或优选1～300:450×103～750×103
更优选1～300:200×103；最优选1～100:80×103～200×103
更优选1～300:225×103；最优选1～100:90×103～225×103
更优选1～300:250×103；最优选1～100:100×103～250×103
或者抗生素类抗肿瘤药和维生素C的摩尔比例范围可以是
1：10-30000；优选1：33-15000；
更优选1～100:33333
更优选1～100:41667；
更优选1～100:50000；
2、抗肿瘤植物药与维生素C合用制备治疗癌症的药物组合物时，
抗肿瘤植物药紫杉醇和维生素C的摩尔比例范围可以是：
1～64:500～8333×103；优选1～32:1×103～8333×103
更优选1～32:40×103～6667×103；最优选8～16:40×103～6667×103
更优选1～32:60×103～7500×103；最优选16～32:60×103～7500×103
更优选1～32:80×103～8333×103；最优选1～16:80×103～8333×103
或者抗肿瘤植物药和维生素C的摩尔比例范围可以是：
1：10～1000×103；优选1:1.5×103～1000×103；进一步优选:1.8×103～850×103
更优选1～300:450×103～800×103；最优选1～30:450×103～1000×103
更优选1～300:900×103；最优选1～30:600×103～1250×103
更优选1～300:1000×103；最优选1～30:750×103～1500×103
3、抗代谢类抗肿瘤药与维生素C合用制备治疗癌症的药物组合物时，
抗代谢类抗肿瘤药和维生素C的摩尔比例范围可以是：
1：10-30000；优选1：33-15000；更优选1:137.5～6800
更优选1～300:3334～550×103；最优选1～10:550×103
更优选1～300:4167～700×103；最优选1～10:700×103
更优选1～300:850×103～5000×103；最优选1～33:850×103～5000×103
或者抗代谢类抗肿瘤药和维生素C的摩尔比例范围可以是：
1:1～83333或1～333:550～83333
或优选1:2.5～2833；或优选1:5.5～2833；或优选1～333:1833～2833
或优选1～333:833～1667；或优选1～333:66667～83333
更优选1～333:550～66667；最优选1～33:550～66667
更优选1～333:700～75000；最优选1～33:700～75000
更优选1～333:850～83333；最优选10～33:850～83333
4、铂类抗肿瘤药与维生素C合用制备治疗癌症的药物组合物时，
铂类抗肿瘤药和维生素C的摩尔比例范围可以是：
1：30-20000；或优选1：33-15000；或1:1～25000或优选1:2.5～2833；或优选1～333:833～1667
更优选1～333:833～20000；最优选1～100:833～20000
更优选1～333:1250～22500；最优选1～100:1250～22500
更优选1～333:1667～25000；最优选1～100:1667～25000
或者铂类抗肿瘤药和维生素C的摩尔比例范围可以是：
1：1-900；优选1：5-480；
更优选8～64:320；
更优选1～64:400；
更优选1～64:480；进一步优选1～32:480；
或者铂类抗肿瘤药和维生素C的摩尔比例范围可以是：
1:5～20000优选1：15-20000；
优选1:15～10000或优选1～300:4500～10000
更优选1～300:4500～10000；进一步优选3～300:4500～10000；最优选 100～300:10000；
更优选1～300:6000～12500；进一步优选3～300:6000～12500；最优选100～300:6000～12500；
更优选1～300:7500～15000；进一步优选3～300:7500～15000；最优选10～100:7500～15000；
5、烷化类抗肿瘤药与维生素C合用制备治疗癌症的药物组合物时，
烷化类抗肿瘤药和维生素C的摩尔比例范围可以是：
1:1～5000；优选1:2.5～2833；或优选1～333:833～1667
更优选1～32:8；最优选2～8:8
更优选1～32:12；最优选8～32:12
更优选1～32:16；最优选8～32:16
6、生物免疫类抗肿瘤药与维生素C合用制备治疗癌症的药物组合物时，
生物免疫类抗肿瘤药和维生素C的摩尔比例范围可以是：
1：10-30000；优选1：33-15000；
更优选1～32:3200
更优选1～32:4000；最优选2～4:4000；
更优选1～32:4800；最优选1～4:4800；
本发明的优选实施技术方案进一步包括但不限定于如下技术方案：
1.1阿霉素与维生素C合用制备治疗癌症的药物组合物时，
阿霉素和维生素C的摩尔比例范围可以是
1：100～500×103；或优选1：33～250×103；或1:1×103～1×106
或优选1:1.5×103～750×103或优选1～300:450×103～750×103
更优选1～300:200×103；最优选1～100:80×103～200×103
更优选1～300:225×103；最优选1～100:90×103～225×103
更优选1～300:250×103；最优选1～100:100×103～250×103
1.2平阳霉素与维生素C合用制备治疗癌症的药物组合物时，
平阳霉素和维生素C的摩尔比例范围可以是
1：10-30000；优选1：33-15000；
更优选1～100:33333
更优选1～100:41667；
更优选1～100:50000；
1.3长春新碱与维生素C合用制备治疗癌症的药物组合物时，
长春新碱紫杉醇和维生素C的摩尔比例范围可以是：
1～64:500～8333×103；优选1～32:1×103～8333×103
更优选1～32:40×103～6667×103；最优选8～16:40×103～6667×103
更优选1～32:60×103～7500×103；最优选16～32:60×103～7500×103
更优选1～32:80×103～8333×103；最优选1～16:80×103～8333×103
1.4紫杉醇与维生素C合用制备治疗人肝癌的药物组合物时，
紫杉醇和维生素C的摩尔比例范围可以是：
1：10～1000×103；优选1:1.5×103～1000×103；进一步优选:1.8×103～850×103
更优选1～300:450×103～800×103；最优选1～30:450×103～1000×103
更优选1～300:900×103；最优选1～30:600×103～1250×103
更优选1～300:1000×103；最优选1～30:750×103～1500×103
1.5吉西他滨与维生素C合用制备治疗癌症的药物组合物时，
吉西他滨和维生素C的摩尔比例范围可以是：
1：10-30000；优选1：33-15000；更优选1:137.5～6800
更优选1～300:3334～550×103；最优选1～10:550×103
更优选1～300:4167～700×103；最优选1～10:700×103
更优选1～300:850×103～5000×103；最优选1～33:850×103～5000×103
1.6羟基喜树碱与维生素C合用制备治疗癌症的药物组合物时，
羟基喜树碱和维生素C的摩尔比例范围可以是：
1:1～83333或1～333:550～83333
或优选1:2.5～2833；或优选1:5.5～2833；或优选1～333:1833～2833
或优选1～333:833～1667；或优选1～333:66667～83333
更优选1～333:550～66667；最优选1～33:550～66667
更优选1～333:700～75000；最优选1～33:700～75000
更优选1～333:850～83333；最优选10～33:850～83333
1.7顺铂与维生素C合用制备治疗癌症的药物组合物时，
顺铂和维生素C的摩尔比例范围可以是：
1：30-20000；或优选1：33-15000；或1:1～25000或优选1:2.5～2833；或优选1～333:833～1667
更优选1～333:833～20000；最优选1～100:833～20000
更优选1～333:1250～22500；最优选1～100:1250～22500
更优选1～333:1667～25000；最优选1～100:1667～25000
1.8卡铂与维生素C合用制备治疗癌症的药物组合物时，
卡铂和维生素C的摩尔比例范围可以是：
1：1-900；优选1：5-480；
更优选8～64:320；
更优选1～64:400；
更优选1～64:480；进一步优选1～32:480；
1.9奥沙利铂与维生素C合用制备治疗癌症的药物组合物时，
奥沙利铂和维生素C的摩尔比例范围可以是：
1:5～20000优选1：15-20000；
优选1:15～10000或优选1～300:4500～10000
更优选1～300:4500～10000；进一步优选3～300:4500～10000；最优选100～300:10000；
更优选1～300:6000～12500；进一步优选3～300:6000～12500；最优选100～300:6000～12500；
更优选1～300:7500～15000；进一步优选3～300:7500～15000；最优选10～100:7500～15000；
1.10替莫唑胺与维生素C合用制备治疗癌症的药物组合物时，
替莫唑胺和维生素C的摩尔比例范围可以是：
1:1～5000；优选1:2.5～2833；或优选1～333:833～1667
更优选1～32:8；最优选2～8:8
更优选1～32:12；最优选8～32:12
更优选1～32:16；最优选8～32:16
1.11索拉菲尼与维生素C合用制备治疗癌症的药物组合物时，
索拉菲尼和维生素C的摩尔比例范围可以是：
1：10-30000；优选1：33-15000；
更优选1～32:3200
更优选1～32:4000；最优选2～4:4000；
更优选1～32:4800；最优选1～4:4800；
本发明的更优选实施技术方案进一步包括但不限定于如下技术方案：
1.1阿霉素与维生素C合用制备治疗人肝癌的药物组合物时，
阿霉素和维生素C的摩尔比例范围可以是
1：1×103～500×103；优选1：33～15×103；
更优选33～333:333×103
更优选1～333:417×103；
更优选3.3～333:500×103；
1.2平阳霉素与维生素C合用制备治疗人肝癌的药物组合物时，
平阳霉素和维生素C的摩尔比例范围可以是
1：10-30000；优选1：33-15000；
更优选1～100:33333
更优选1～100:41667；
更优选1～100:50000；
1.3长春新碱与维生素C合用制备治疗人肝癌的药物组合物时，
长春新碱和维生素C的摩尔比例范围可以是：
1：10-30000；优选1：33-15000；
更优选1～333:333×103
更优选1～333:417×103
更优选1～100:500×103；进一步优选1～10:500×103
1.4紫杉醇与维生素C合用制备治疗人肝癌的药物组合物时，
紫杉醇和维生素C的摩尔比例范围可以是：
1：10-30000；优选1：33-15000；
更优选30～300:1000×103
更优选1～300:1250×103
更优选1～300:1500×103；进一步优选3～30:1500×103
1.5吉西他滨与维生素C合用制备治疗人肝癌的药物组合物时，
吉西他滨和维生素C的摩尔比例范围可以是：
1：10-30000；优选1：33-15000；
更优选1～33:3334
更优选1～33:4167
更优选1～33:5000×103；进一步优选6.7～33:5000×103；
1.6羟基喜树碱与维生素C合用制备治疗人肝癌的药物组合物时，
羟基喜树碱和维生素C的摩尔比例范围可以是：
1：10-30000；优选1：33-15000；
更优选3～300:10000
更优选1～300:12500；
更优选1～300:15000；
1.7顺铂与维生素C合用制备治疗人肝癌的药物组合物时，
顺铂和维生素C的摩尔比例范围可以是：
1：30-20000；优选1：33-15000；
更优选30～1000:10000；
更优选1～1000:12500；
更优选1～1000:15000；
1.8卡铂与维生素C合用制备治疗人肝癌的药物组合物时，
卡铂和维生素C的摩尔比例范围可以是：
1：1-900；优选1：5-480；
更优选8～64:320；
更优选1～64:400；
更优选1～64:480；进一步优选1～32:480；
1.9奥沙利铂与维生素C合用制备治疗人肝癌的药物组合物时，
奥沙利铂和维生素C的摩尔比例范围可以是：
1：30-20000；优选1：33-15000；
更优选1～300:10000；进一步优选30～300:10000；最优选100～300:10000；
更优选1～300:12500；进一步优选3～300:12500；最优选100～300:12500；
更优选1～300:15000；
1.10索拉菲尼与维生素C合用制备治疗人肝癌的药物组合物时，
索拉菲尼和维生素C的摩尔比例范围可以是：
1：10-30000；优选1：33-15000；
更优选1～32:3200
更优选1～32:4000；最优选2～4:4000；
更优选1～32:4800；最优选1～4:4800；
2.1长春新碱与维生素C合用制备治疗人肺癌的药物组合物时，
长春新碱和维生素C的摩尔比例范围可以是：
1:1×103～1088×103
优选1:11×103～1088×103
或优选1～64:704×103～1088×103
更优选1～64:704×103；最优选选1～32:704×103
更优选1～64:896×103；最优选1～32:896×103
更优选1～64:1088×103；最优选1～32:1088×103
2.2紫杉醇与维生素C合用制备治疗人肺癌的药物组合物时，
紫杉醇和维生素C的摩尔比例范围可以是：
1:1×103～1×106
优选1:1.8×103～850×103
或优选1～300:550×103～850×103
更优选1～300:550×103；最优选1～10:550×103
更优选1～300:700×103；最优选1～10:700×103
更优选1～300:850×103；最优选1～10:850×103
2.3吉西他滨与维生素C合用制备治疗人肺癌的药物组合物时，
吉西他滨和维生素C的摩尔比例范围可以是：
1:50～10000
优选1:137.5～6800
或优选1～32:4400～6800
更优选1～300:550×103；最优选1～10:550×103
更优选1～300:700×103；最优选1～10:700×103
更优选1～300:850×103；最优选1～10:850×103
2.4羟基喜树碱与维生素C合用制备治疗人胃癌的药物组合物时，
羟基喜树碱和维生素C的摩尔比例范围可以是：
1:2～5000
优选1:5.5～2833
或优选1～333:1833～2833
更优选1～333:550；最优选1～10:550
更优选1～333:700；最优选10～33:700
更优选1～300:850；最优选1～100:850
2.5顺铂与维生素C合用制备治疗人胃癌的药物组合物时，
顺铂和维生素C的摩尔比例范围可以是：
1:5～10000
优选1:18.3～8500
或优选1～300:5500～8500
更优选1～300:5500；最优选10～300:5500
更优选1～300:7000；最优选3～300:7000
更优选1～300:8500；最优选100～300:8500
3.1长春新碱与维生素C合用制备治疗人胃癌的药物组合物时，
长春新碱和维生素C的摩尔比例范围可以是：
1:1×103～1×106
优选1:9×103～480×103
或优选1～32:288×103～480×103
更优选1～32:288×103；最优选4～8:288×103
更优选1～32:384×103；最优选2～32:384×103
更优选1～32:480×103；最优选2～4:480×103
3.2紫杉醇与维生素C合用制备治疗人胃癌的药物组合物时，
紫杉醇和维生素C的摩尔比例范围可以是：
1:1×103～1×106
优选1:1.5×103～750×103
或优选1～300:450×103～750×103
更优选1～300:450×103；最优选3～100:450×103
更优选1～300:600×103；最优选3～30:600×103
更优选1～300:750×103；最优选1～10:750×103
3.3羟基喜树碱与维生素C合用制备治疗人胃癌的药物组合物时，
羟基喜树碱和和维生素C的摩尔比例范围可以是：
1:2～5000
优选1:5.5～2833
或优选1～333:1833～2833
更优选1～300:4500；最优选10～300:4500
更优选1～300:6000；最优选10～100:6000
更优选1～300:7500；最优选30～300:7500
3.4顺铂与维生素C合用制备治疗人胃癌的药物组合物时，
顺铂和维生素C的摩尔比例范围可以是：
1:5～10000
优选1:15～7500
或优选1～300:4500～7500
更优选1～300:4500；最优选30～300:4500
更优选1～300:6000；最优选1～3:6000
更优选1～300:7500；最优选3～100:7500
3.5奥沙利铂与维生素C合用制备治疗人胃癌的药物组合物时，
奥沙利铂和维生素C的摩尔比例范围可以是：
1:5～10000
优选1:15～7500
或优选1～300:4500～7500
更优选1～300:4500；最优选3～30:4500
更优选1～300:6000；最优选3～300:6000
更优选1～300:7500；最优选10～100:7500
4.1阿霉素和维生素C合用制备治疗人前列腺癌的药物组合物时，
阿霉素和维生素C的摩尔比例范围可以是：
1:1×103～1×106
优选1:1.5×103～750×103
或优选1～300:450×103～750×103
更优选1～300:200×103；最优选1～10:200×103
更优选1～300:225×103；最优选3～100:225×103
更优选1～300:250×103；最优选3～300:250×103
4.2长春新碱和维生素C合用制备治疗人前列腺癌的药物组合物时，
长春新碱和维生素C的摩尔比例范围可以是：
1:10×103～1×107
优选1:20×103～8333×103
或优选1～333:6667×103～8333×103
更优选1～333:6667×103；最优选10-100:6667×103
更优选1～333:7500×103；最优选1～100:7500×103
更优选1～333:8333×103；最优选1～100:8333×103
4.3羟基喜树碱和维生素C合用制备治疗人前列腺癌的药物组合物时，
羟基喜树碱和维生素C的摩尔比例范围可以是：
1:2～5000
优选1:5.5～2833
或优选1～333:66667～83333
更优选1～333:66667；最优选1～10:66667
更优选1～333:75000；最优选1～100:75000
更优选1～333:83333；最优选1～10:83333
4.4顺铂和和维生素C合用制备治疗人前列腺癌的药物组合物时，
顺铂和维生素C的摩尔比例范围可以是：
1:5～10000
优选1:15～7500
或优选1～300:4500～7500
更优选1～300:20000；最优选1～100:20000
更优选1～300:22500；最优选10～100:22500
更优选1～300:25000；最优选1～100:25000
5.1长春新碱与维生素C合用制备治疗人胶质瘤的药物组合物时，
长春新碱和维生素C的摩尔比例范围可以是：
1:500～160×103
优选1:1×103～80×103
或优选1～32:40×103～80×103
更优选1～32:40×103；最优选8～16:40×103
更优选1～32:60×103；最优选16～32:60×103
更优选1～32:80×103；最优选1～16:80×103
5.2羟基喜树碱与维生素C合用制备治疗人胶质瘤的药物组合物时，
羟基喜树碱和维生素C的摩尔比例范围可以是：
1:1～5000
优选1:2.5～2833
或优选1～333:833～1667
更优选1～333:833；最优选1～33:833
更优选1～333:1250；最优选1～33:1250
更优选1～333:1667；最优选10～33:1667
5.3顺铂与维生素C合用制备治疗人胶质瘤的药物组合物时，
顺铂和维生素C的摩尔比例范围可以是：
1:1～5000
优选1:2.5～2833
或优选1～333:833～1667
更优选1～333:833；最优选100～333:833
更优选1～333:1250；最优选10～333:1250
更优选1～333:1667；最优选10～333:1667
5.4替莫唑胺与维生素C合用制备治疗人胶质瘤的药物组合物时，
替莫唑胺和维生素C的摩尔比例范围可以是：
1:1～5000
优选1:2.5～2833
或优选1～333:833～1667
更优选1～32:8；最优选2～8:8
更优选1～32:12；最优选8～32:12
更优选1～32:16；最优选8～32:16
6.1阿霉素与维生素C合用制备治疗人乳腺癌的药物组合物时，
阿霉素和维生素C的摩尔比例范围可以是：
1:100～100×103
优选1:267～100×103
或优选1～300:80×103～100×103
更优选1～300:80×103；最优选3～300:80×103
更优选1～300:90×103；最优选1～100:90×103
更优选1～300:100×103；最优选1～100:100×103
6.2长春新碱与维生素C合用制备治疗人乳腺癌的药物组合物时，
长春新碱和维生素C的摩尔比例范围可以是：
1:1×103～100×104
优选1:4×103～100×103
或优选1～32:128×103～160×103
更优选1～32:128×103；最优选3～32:128×103
更优选1～32:140×103；最优选2～16:140×103
更优选1～32:160×103；最优选1～16:160×103
6.3紫杉醇与维生素C合用制备治疗人乳腺癌的药物组合物时，
紫杉醇和维生素C的摩尔比例范围可以是：
1:1.0×103～1000×103
优选1:2.7×103～1000×103
或优选1～300:800×103～1000×103
更优选1～300:800×103；最优选3～30:800×103
更优选1～300:900×103；最优选1～10:900×103
更优选1～300:1000×103；最优选1～10:1000×103
6.4羟基喜树碱与维生素C合用制备治疗人乳腺癌的药物组合物时，
羟基喜树碱和维生素C的摩尔比例范围可以是：
1:2～5000
优选1:5.5～2833
或优选1～333:1833～2833
更优选1～300:8000；最优选1～100:8000
更优选1～300:9000；最优选1～10:9000
更优选1～300:10000；最优选1～10:10000
为了使用的方便本发明的药物组合物还可以包含药剂学上可接受的辅料。所述药剂学可接受的辅料，包括溶媒、增溶剂、稳定剂、赋形剂、载体等，主要选自注射用水、生理盐水、乙醇、丙二醇、甘油；聚乙二醇200、聚乙二醇400、聚乙二醇600、聚氧乙烯蓖麻油类、聚山梨醇酯，泊洛沙姆、聚乙烯吡咯烷酮、油性脂肪酸及其单或二甘油酯；乳糖、蔗糖、木糖醇、山梨醇、甘露醇、乳糖醇、右旋糖苷、d-木糖、葡萄糖；磷脂、明胶、阿拉伯胶、虫胶、瓜耳豆胶、琼脂、海藻酸及其盐、聚乙烯醇、聚乙二醇、羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、乙烯－醋酸乙烯共聚物、聚酰胺、醋酸纤维素、聚丙烯酸树脂、乙基纤维素、卡波姆、血清白蛋白中的一种、二种或多种同时用。
本法药物组合物的剂型优选制备成注射用制剂，包括注射用溶液剂、注射用混悬剂、注射用冻干粉针、注射用无菌分装粉末、注射用油、脂质体、微乳、微球、纳米粒制剂等有关的控释剂型。
例如以注射用溶液剂为例，该复方制剂的制备工艺如下：
精密称取处方量的维生素C、化疗药物，置适当容器中，加入增溶剂或助溶剂，充分搅拌使溶解，加入80％用量的注射用水，充分搅拌使溶解分散均匀，用注射用水定容至刻度。混匀后于百级条件下灌封，灭菌，即得。
本发明的药物组合物在抗肿瘤的治疗中具有良好的效果。尤其是对于恶性肿瘤，所述的肿瘤包括但不限定于黑色素瘤、胃癌、肺癌、乳腺癌、肾癌、肝癌、口腔表皮癌、宫颈癌、卵巢癌、胰腺癌、前列腺癌、结肠癌、膀胱癌、脑瘤、食管癌、淋巴瘤、神经系统癌症等肿瘤。所述的脑瘤特别优选自胶质瘤。特别是对于肝癌、胰腺癌、胶质瘤、食管癌具有优秀的效果。
本发明提供了本发明组合物的使用方法，该维生素C药物组合物除用于瘤内注射外，还可用于静脉、动脉注射、介入治疗等方式给药。介入治疗和瘤内注射，是近年来新发展起来的一门治疗技术，它们可以直接将药物注射入肿瘤部位，使药物能够直接作用于肿瘤组织和肿瘤细胞，具有非常好的靶向性，可大大降低抗肿瘤药物的全身性毒副作用。临床上多种形式的介入治疗，是目前公认的不能手术切除的恶性肿瘤(尤其是中晚期原发性肝癌或肝脏转移癌)的首选治疗手段， 已为广大临床医生所普通接受。瘤内注射属于介入治疗的一种，它是将药物通过特殊的设备，直接注射至实体瘤组织中，从而发挥杀灭肿瘤细胞的作用。大剂量维生素C的杀肿瘤细胞作用，在体外试验中已得到充分的证实，故选择维生素C介入或瘤内注射方式给药，能够达到最好的抗癌效果。本发明的组合物除可用于静脉注射或静脉滴注外，在临床还优先用于肝癌、胰腺癌等实体恶性肿瘤及其它脑瘤、食管癌等多种恶性肿瘤等的瘤内注射、介入治疗和静脉、动脉、肌肉、皮下等特殊途径给药，也用于因身体部位的原因无法用手术、放射等进行治疗的实体瘤，还用于临床需要综合手段治疗的肿瘤。
本发明还公开了一种药盒，包含上述任意一种药物组合物。
有益技术效果：
1)本发明药物组合物能增强抗肿瘤药物的化疗作用，甚至具有协同作用。
2)本发明药物组合物能降低抗肿瘤药物的毒副作用，增加患者对于抗肿瘤药物的耐受剂量。
3)与市场已有的治疗恶性肿瘤的药物或常用化疗药物相比，本发明选择安全性好的维生素C作为抗肿瘤的主药，具有抗瘤谱广、作用明确、副作用小、不易产生耐药性的优点，且本组合物可以用于瘤内注射给药，极大地提高了实体恶性肿瘤的治疗效果。
附图说明
图1.
图1a.阿霉素单用及阿霉素和250μM的维生素C的复方制剂对Hep G2细胞抑制率比较
图1b.不同浓度的维生素C对Hep G2细胞的抑制率研究
图1c.平阳霉素单用及平阳霉素和250μM的维生素C的复方制剂对Hep G2细胞体外抑制率的比较；
图2.荷瘤小鼠体内抗肿瘤试验结果(肿瘤体积)；
图3.荷瘤小鼠体内抗肿瘤试验结果(体重变化)；
图4.荷瘤小鼠体内抗肿瘤试验结果(死亡率)。
具体实施方式
下面结合附图和具体实施方式对本发明作进一步说明，该部分并非对本发明 的限定，依照本领域公知的现有技术，本发明的实施方式并不限于此，因此凡依照本发明公开内容所作出的本领域的等同替换，均属于本发明的保护范围。
实施例1：注射用溶液剂的制备
Figure PCTCN2015078797-appb-000001
称取处方量的维生素C和5-氟尿嘧啶，溶于适量注射用水中，持续搅拌使溶解完全。加入0.1％的活性炭，搅拌20min后，依次经钛棒、0.8μm滤膜和0.22μm微孔滤膜过滤，进行中间体测定，并补加水至全量。在充氮保护的条件下，按5ml/支分装，即得。
实施例2：注射用冻干粉针
Figure PCTCN2015078797-appb-000002
称取处方量的维生素C和阿霉素，溶于适量注射用水中，持续搅拌使溶解完全。加入0.1％的活性炭，搅拌20min后，依次经钛棒、0.8μm滤膜和0.22μm微孔滤膜过滤，进行中间体测定，并补加水至全量；在氮气保护的条件下，分装至西林瓶中，5ml/瓶，-80℃预冻后，置冷冻干燥机中，程序升温干燥至疏松粉末，即得。
实施例3：注射用脂质体
Figure PCTCN2015078797-appb-000003
称取处方量的磷脂和胆固醇，溶于5ml的氯仿中，并置旋蒸仪中减压干燥，使成一均匀的脂质薄膜；另取处方量的平阳霉素和维生素C，溶于一定体积的生 理盐水液中，充分溶解后，加入上述脂质薄膜中，超声使薄膜脱落并水化。反复冻融三次后，经探针超声处理或高压均质处理，最后经0.22μm微孔滤膜过滤整粒，即得。
实施例4：注射用温敏凝胶
Figure PCTCN2015078797-appb-000004
用0.1M醋酸配制壳聚糖溶液，搅拌溶解充分；称取处方量的维生素C和阿霉素，溶于一定量乙醇后缓慢加入到壳聚糖溶液，边加边搅拌，搅拌四小时；配制60％甘油磷酸钠溶液。壳聚糖溶液及甘油磷酸钠溶液同时冰浴20min,将甘油磷酸钠溶液逐滴加入壳聚糖溶液中，边加边搅拌，混合充分；继续冰浴搅拌10min即成复方缓释温敏凝胶。
药理实验：
实验例1、Vc与各种化疗药合用对肿瘤细胞的作用
实验方法
药物配置
称取88mg的维生素C(以下简称Vc)溶于0.5mL高压灭菌水中，制成1mol/L储备液，在超净工作台内以0.22μm一次性针式滤器过滤，保存于-80℃冰箱，用时直接加入培养液中配成相应浓度的药液。
MTT法测定细胞活性
取对数生长期的细胞株经0.25％胰酶消化后，用含10％胎牛血清的RPMI1640培养液配成单细胞悬液，以3×103个/mL的密度接种于96孔板中，每孔加入100μL细胞悬液，置于37℃、5％CO2培养箱中无菌培养箱中培养24h，待细胞充分贴壁后，去除原有的培养液，每孔加入用培养液配制的不同浓度的抗肿瘤药物溶液50μL，再加入用用培养液配置的不同浓度维生素C 50μL。对照组加入含0.1％DMSO的培养液，37℃培养48h或72h。培养结束后吸弃药液，每孔加入PBS 100μL洗去残留的药液，每孔加入含10％5mg/mL MTT工作液培养液100μL，37℃继续培养4h。吸弃上清液，每孔加入150μL DMSO，振荡10min以 充分溶解结晶物，在酶标仪570nm下测定OD值，按下列公式计算给予药物后，肿瘤细胞的抑制率，并采用SPSS数据处理软件计算半数抑制浓度(IC50)。
Figure PCTCN2015078797-appb-000005
根据各浓度药物的抑制率，应用SPSS统计分析软件计算半数抑制浓度IC50，并依据IC50计算化疗药物与不同浓度的维生素C合用后IC50减少倍数。
Vc提高了药物A的化疗作用的判断方法
IR(A+Vc)>IR(A)，表示Vc的存在提高了药物A的化疗作用，右上角标记为▲。
协同作用判断方法
用以下的计算方法对协同作用进行判断：
IR(A+B)>IR(A)+IR(B)-IR(A)×IR(B)，药物间存在协同作用；
IR(A+B)＝IR(A)+IR(B)-IR(A)×IR(B)，药物间只是简单叠加作用；
IR(A+B)<IR(A)+IR(B)-IR(A)×IR(B)，药物间存在拮抗作用；
其中IR(A+B)，IR(A)，IR(B)分别对应药物AB联用，A单独作用及B单独作用时的生长抑制率。
IR(A)+IR(B)-IR(A)×IR(B)的结果示为预测值，如AB联用的抑制率{IR(A+B)}大于预测值，则表示合用具有协同作用。右上角标记▲▲为具有协同作用。如抑制率为负值者记为0。
上述细胞株选自：人肝癌细胞株HepG-Ⅱ、人肺癌细胞株A549、人胃癌细胞株SGC-7901，人前列腺癌细胞株PC-3、人胶质瘤细胞株U251和人乳腺癌细胞株MCF-7、正常肝细胞株。
表A-1-5-1:Vc合用阿霉素48h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000006
Figure PCTCN2015078797-appb-000007
注：“▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表A-1-5-2:Vc合用阿霉素72h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000008
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表A-1-5-3:Vc合用阿霉素48h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000009
Figure PCTCN2015078797-appb-000010
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表A-1-5-4:Vc合用阿霉素72h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000011
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表B-1-7-1:Vc合用平阳霉素48h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000012
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表B-1-7-2:Vc合用平阳霉素72h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000013
Figure PCTCN2015078797-appb-000014
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表B-1-7-3:Vc合用平阳霉素48h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000015
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表B-1-7-4:Vc合用对平阳霉素72h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000016
Figure PCTCN2015078797-appb-000017
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表C-1-8-1:Vc合用长春新碱对48h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000018
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表C-1-8-2:Vc合用长春新碱对72h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000019
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表C-1-8-3:Vc合用长春新碱对48h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000020
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表C-1-8-4:Vc合用长春新碱对72h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000021
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表D-1-9-1:Vc合用紫杉醇对48h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000022
Figure PCTCN2015078797-appb-000023
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表D-1-9-2:Vc合用紫杉醇对72h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000024
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表D-1-9-3:Vc合用紫杉醇对48h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000025
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表D-1-9-4:Vc合用紫杉醇对72h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000026
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表E-1-10-1:Vc合用吉西他滨对48h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000027
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表E-1--10-2:Vc合用吉西他滨对72h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000028
Figure PCTCN2015078797-appb-000029
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表E-1-10-3:Vc合用吉西他滨对48h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000030
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表E-1-10-4:Vc合用吉西他滨对72h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000031
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表F-1-6-1:Vc合用羟基喜树碱48h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000032
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表F-1-6-2:Vc合用羟基喜树碱72h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000033
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表F-1-6-3:Vc合用羟基喜树碱48h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000034
Figure PCTCN2015078797-appb-000035
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表F-1-6-4:Vc合用羟基喜树碱72h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000036
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表G-1-2-1:Vc合用顺铂48h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000037
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表G-1-2-2:Vc合用顺铂72h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000038
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表G-1-2-3:Vc合用顺铂48h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000039
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表G-1-2-4:Vc合用顺铂72h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000040
Figure PCTCN2015078797-appb-000041
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表H-1-3-1:Vc合用卡铂48h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000042
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表H-1-3-2:Vc合用卡铂72h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000043
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表H-1-3-3:Vc合用卡铂48h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000044
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表H-1-3-4:Vc合用卡铂72h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000045
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表I-1-1-1:Vc合用奥沙利铂48h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000046
Figure PCTCN2015078797-appb-000047
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表I-1-1-2:Vc合用奥沙利铂72h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000048
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表I-1-1-3:Vc合用奥沙利铂48h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000049
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表I-1-1-4:Vc合用奥沙利铂72h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000050
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表K-11-1:Vc合用索拉菲尼对48h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000051
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表K-1-11-2:Vc合用索拉菲尼对72h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000052
Figure PCTCN2015078797-appb-000053
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表K-1-11-3:Vc合用索拉菲尼对48h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000054
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表K-1-11-4:Vc合用索拉菲尼对72h对人肝癌细胞株HepG-Ⅱ的作用结果。
Figure PCTCN2015078797-appb-000055
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表1-A为化疗药物单独作用人肝癌细胞株HepG-Ⅱ和与不同浓度Vc合用后 化疗药物的IC50及药效增加倍数
Figure PCTCN2015078797-appb-000056
Figure PCTCN2015078797-appb-000057
2.五种化疗药与Vc合用作用于人肺癌细胞株A549
表C-2-1-1:Vc合用长春新碱48h对人肺癌细胞株A549的作用结果。
Figure PCTCN2015078797-appb-000058
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表C-2-1-2:Vc合用长春新碱72h对人肺癌细胞株A549的作用结果。
Figure PCTCN2015078797-appb-000059
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表D-2-4-1:Vc合用紫杉醇48h对人肺癌细胞株A549的作用结果。
Figure PCTCN2015078797-appb-000060
Figure PCTCN2015078797-appb-000061
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表D-2-4-2:Vc合用紫杉醇72h对人肺癌细胞株A549的作用结果。
Figure PCTCN2015078797-appb-000062
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表E-2-5-1:Vc合用吉西他滨48h对人肺癌细胞株A549的作用结果。
Figure PCTCN2015078797-appb-000063
Figure PCTCN2015078797-appb-000064
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表E-2-5-2:Vc合用吉西他滨72h对人肺癌细胞株A549的作用结果。
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表F-2-2-1:Vc合用羟基喜树碱48h对人肺癌细胞株A549的作用结果。
Figure PCTCN2015078797-appb-000066
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表F-2-2-2:Vc合用羟基喜树碱72h对人肺癌细胞株A549的作用结果。
Figure PCTCN2015078797-appb-000067
Figure PCTCN2015078797-appb-000068
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表G-2-3-1:Vc合用顺铂48h对人肺癌细胞株A549的作用结果。
Figure PCTCN2015078797-appb-000069
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表G-2-3-2:Vc合用顺铂48h对人肺癌细胞株A549的作用结果。
Figure PCTCN2015078797-appb-000070
Figure PCTCN2015078797-appb-000071
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表2-A为化疗药物单独作用于人肺癌细胞株A549和与不同浓度Vc合用后化疗药物的IC50及药效增加倍数
Figure PCTCN2015078797-appb-000072
3.五种化疗药与Vc合用作用于人胃癌细胞株SGC-7901
表C-3-1-1:Vc合用长春新碱48h对人胃癌细胞株SGC-7901的作用结果。
Figure PCTCN2015078797-appb-000073
Figure PCTCN2015078797-appb-000074
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表C-3-1-2:Vc合用长春新碱72h对人胃癌细胞株SGC-7901的作用结果。
Figure PCTCN2015078797-appb-000075
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表D-3-4-1:Vc合用紫杉醇48h对人胃癌细胞株SGC-7901的作用结果。
Figure PCTCN2015078797-appb-000076
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表D-3-4-2:Vc合用紫杉醇72h对人胃癌细胞株SGC-7901的作用结果。
Figure PCTCN2015078797-appb-000077
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表F-3-2-1:Vc合用羟基喜树碱48h对人胃癌细胞株SGC-7901的作用结果。
Figure PCTCN2015078797-appb-000078
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表F-3-2-2:Vc合用羟基喜树碱72h对人胃癌细胞株SGC-7901的作用结果。
Figure PCTCN2015078797-appb-000079
Figure PCTCN2015078797-appb-000080
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表G-3-3-1:Vc合用顺铂48h对人胃癌细胞株SGC-7901的作用结果。
Figure PCTCN2015078797-appb-000081
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表G-3-3-2:Vc合用顺铂72h对人胃癌细胞株SGC-7901的作用结果。
Figure PCTCN2015078797-appb-000082
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表I-3-5-1:Vc合用奥沙利铂48h对人胃癌细胞株SGC-7901的作用结果。
Figure PCTCN2015078797-appb-000083
Figure PCTCN2015078797-appb-000084
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表I-3-5-2:Vc合用奥沙利铂72h对人胃癌细胞株SGC-7901的作用结果。
Figure PCTCN2015078797-appb-000085
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表3-A为化疗药物单独作用于人胃癌细胞株SGC-7901和与不同浓度合用后化疗药物的IC50及药效增加倍数
Figure PCTCN2015078797-appb-000086
Figure PCTCN2015078797-appb-000087
4.四种化疗药与Vc合用作用于人前列腺癌细胞株PC-3
表A-4-4-1:Vc合用阿霉素48h对人前列腺癌细胞株PC-3的作用结果。
Figure PCTCN2015078797-appb-000088
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表A-4-4-2:Vc合用阿霉素72h对人前列腺癌细胞株PC-3的作用结果。
Figure PCTCN2015078797-appb-000089
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表C-4-2-1:Vc合用长春新碱48h对人前列腺癌细胞株PC-3的作用结果。
Figure PCTCN2015078797-appb-000091
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表C-4-2-2:Vc合用长春新碱72h对人前列腺癌细胞株PC-3的作用结果。
Figure PCTCN2015078797-appb-000092
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表F-4-1-1:Vc合用羟基喜树碱48h对人前列腺癌细胞株PC-3的作用结果。
Figure PCTCN2015078797-appb-000093
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表F-4-1-2:Vc合用羟基喜树碱72h对人前列腺癌细胞株PC-3的作用结果。
Figure PCTCN2015078797-appb-000094
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表G-4-3-1:Vc合用顺铂48h对人前列腺癌细胞株PC-3的作用结果。
Figure PCTCN2015078797-appb-000095
Figure PCTCN2015078797-appb-000096
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表G-4-3-2:Vc合用顺铂72h对人前列腺癌细胞株PC-3的作用结果。
Figure PCTCN2015078797-appb-000097
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表4-A为化疗药物单独作用于人前列腺癌细胞株PC-3和与不同浓度合用后化疗药物的IC50及药效增加倍数
Figure PCTCN2015078797-appb-000098
Figure PCTCN2015078797-appb-000099
5.四种化疗药与Vc合用作用于人胶质瘤细胞株U251
表C-5-1-1:Vc合用长春新碱48h对人胶质瘤细胞株U251的作用结果。
Figure PCTCN2015078797-appb-000100
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表C-5-1-2:Vc合用长春新碱72h对人胶质瘤细胞株U251的作用结果。
Figure PCTCN2015078797-appb-000101
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表F-5-2-1:Vc合用羟基喜树碱48h对人胶质瘤细胞株U251的作用结果。
Figure PCTCN2015078797-appb-000102
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表F-5-2-2:Vc合用羟基喜树碱72h对人胶质瘤细胞株U251的作用结果。
Figure PCTCN2015078797-appb-000103
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表G-5-3-1:Vc合用顺铂48h对人胶质瘤细胞株U251的作用结果。
Figure PCTCN2015078797-appb-000104
Figure PCTCN2015078797-appb-000105
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表G-5-3-2:Vc合用顺铂72h对人胶质瘤细胞株U251的作用结果。
Figure PCTCN2015078797-appb-000106
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表J-5-4-1:Vc合用替莫唑胺48h对人胶质瘤细胞株U251的作用结果。
Figure PCTCN2015078797-appb-000107
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表J-5-4-2:Vc合用替莫唑胺72h对人胶质瘤细胞株U251的作用结果。
Figure PCTCN2015078797-appb-000108
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表5-A为化疗药物单独作用于人胶质瘤细胞株U251和与不同浓度合用后化疗药物的IC50及药效增加倍数
Figure PCTCN2015078797-appb-000109
6.四种化疗药与Vc合用作用于人乳腺癌细胞株MCF-7
表A-6-1-1:Vc合用阿霉素48h对人乳腺癌细胞株MCF-7的作用结果。
Figure PCTCN2015078797-appb-000110
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表A-6-1-2:Vc合用阿霉素72h对人乳腺癌细胞株MCF-7的作用结果。
Figure PCTCN2015078797-appb-000111
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表C-6-3-1:Vc合用长春新碱48h对人乳腺癌细胞株MCF-7的作用结果。
Figure PCTCN2015078797-appb-000112
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表C-6-3-2:Vc合用长春新碱72h对人乳腺癌细胞株MCF-7的作用结果。
Figure PCTCN2015078797-appb-000113
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表D-6-4-1:Vc合用紫杉醇48h对人乳腺癌细胞株MCF-7的作用结果。
Figure PCTCN2015078797-appb-000114
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表D-6-4-2:Vc合用紫杉醇72h对人乳腺癌细胞株MCF-7的作用结果。
Figure PCTCN2015078797-appb-000115
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表F-6-2-1:Vc合用羟基喜树碱48h对人乳腺癌细胞株MCF-7的作用结果。
Figure PCTCN2015078797-appb-000116
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表F-6-2-2:Vc合用羟基喜树碱72h对人乳腺癌细胞株MCF-7的作用结果。
Figure PCTCN2015078797-appb-000117
注：“▲▲”表示具有协同作用；“▲”表示Vc可以提高化疗药作用
表6-A为四种化疗药物单独作用于乳腺癌细胞株MCF-7和与不同浓度合用后化疗药物的IC50及药效增加倍数
Figure PCTCN2015078797-appb-000118
Figure PCTCN2015078797-appb-000119
表7-A为化疗药物单独作用于人正常肝细胞株L-02和Vc合用后化疗药物的IC50
Figure PCTCN2015078797-appb-000120
通过计算药物单独作用于人正常肝细胞株L-02和与1000μM浓度维生素C合用后的IC50，发现化疗药物与维生素C合用后所计算的IC50远高于药物单独作用于细胞的IC50，而这一现象在其他肿瘤细胞系中是从未发生过的，由此可以证明化疗药与维生素C合用对人正常肝细胞株L-02与人肝癌细胞株HepG-Ⅱ的作用存在显著地差异。实验证明维生素C与化疗药合用确实可以达到减小毒性的作用。
实验例2：荷瘤小鼠体内抗肿瘤实验：
取一定浓度的阿霉素与VC复方制剂，与阿霉素注射液对比进行荷瘤小鼠体内抗肿瘤试验。以生理盐水作为阴性对照。
1.动物模型的建立
采用昆明种雄性ICR小白鼠，无菌抽取第三次传代第8天的小鼠的腹水，用无血清RPMI1640培养基稀释，调细胞浓度至1×107个/ml，将小鼠迅速乙醚麻醉后，背部皮肤消毒，每只小鼠接种约0.2ml H22肿瘤细胞悬液于背部皮下，整个 接种过程在2小时内完成。
2.试验方案：
采用瘤内注射给药方式，分为生理盐水组(Normal Saline)，20mg/kg的阿霉素+500mg/kg的VC组(VC+DOX)，20mg/kg的阿霉素组(DOX)。每三天测量小鼠肿瘤的大小和小鼠体重，并观察小鼠的身体状况和死亡情况。
3.抑制肿瘤效果(见附图2和表2)
试验结果：如图2所示，瘤内单独注射阿霉素或注射阿霉素与VC的混合液，均能很好抑制肿瘤的生长，但是加入高剂量的维生素C后21天，肿瘤的体积和给药当天相比减少的更多，更好的抑制了肿瘤的大小，和体外MTT实验吻合。
表2.瘤内注射生理盐水(Normal saline)、阿霉素(DOX)以及阿霉素与维生素C复方(VC+DOX)后的肿瘤体积(mm3，X±SD)
Figure PCTCN2015078797-appb-000121
4.小鼠体重变化(见附图3)
试验结果：阿霉素的心脏毒性可以从小鼠的体重可以反映出，如果小鼠体重迅速下降，说明小鼠的毒性很大。从图3中可以看出，与DOX组相比，高剂量的VC的加入能阻止小鼠体重迅速下降，21天后，体重和空白组接近，说明毒性慢慢减退，小鼠也慢慢恢复正常。
5.死亡率(见附图4)
试验结果：如图显示，与DOX组相比，高剂量的维生素的加入降低小鼠的死亡率，说明很好的降低了毒性，和体重变化结果一致，都说明VC+DOX组毒性小。这可能与维生素C作为一种抗氧化剂有关，能清除体内的过多由于阿霉素产生的氧自由基，提高了小鼠的抵抗力，提高存活率。

Claims (12)

  1. 一种药物组合物，其特征在于：活性成分选自维生素C和至少一种抗肿瘤化疗药物。
  2. 根据权利要求1的药物组合物，其特征在于：所述的抗肿瘤化疗药物选自抗生素类抗肿瘤药、抗肿瘤植物药、抗代谢类抗肿瘤药、铂类抗肿瘤药、激素类抗肿瘤药、烷化类抗肿瘤药、生物免疫类抗肿瘤药、细胞分化诱导剂、单克隆抗体、血管生成抑制剂、表皮生长因子受体拮抗剂。
  3. 根据权利要求2的药物组合物，其特征在于：
    所述的抗生素类抗肿瘤药选自阿霉素、丝裂霉素、柔红霉素、放线菌素D、平阳霉素、多柔比星、吡柔比星、表柔比星；
    所述的抗肿瘤植物药选自长春新碱、长春瑞宾、长春地辛、紫杉醇、多西紫杉醇、甲异靛；
    所述的抗代谢类抗肿瘤药选自氟尿嘧啶、甲氨喋呤、阿糖胞苷、卡培他滨、雷替曲塞、吉西他滨、培美曲塞、羟基脲、6-巯嘌呤、喜树碱及其衍生物；
    所述的铂类抗肿瘤药选自顺铂、卡铂、奥沙利铂；
    所述的激素类抗肿瘤药选自地塞米松、氢化可的松、托瑞米芬、依西美坦、来曲唑、比卡鲁胺、孕激素类、性激素类、雄激素、促黄体生成素释放激素；
    所述的烷化类抗肿瘤药选自环磷酰胺、氮芥、替莫唑胺；
    所述的生物免疫类抗肿瘤药选自干扰素、肿瘤坏死因子、胸腺肽、白细胞介素、伊马替尼、吉非替尼、埃罗替尼、索拉菲尼；
    所述的细胞分化诱导剂选自维甲酸、亚砷酸；
    所述的单克隆抗体药物选自曲妥珠单抗、利妥昔单抗。
  4. 根据权利要求3的药物组合物，其特征在于：
    所述的喜树碱其衍生物选自羟基喜树碱、伊立替康、拓扑替康。
    所述的孕激素类药物选自甲羟孕酮、甲地孕酮；
    所述的性激素类药物选自雌激素己烯雌酚；
    所述的雄激素药物选自丙酸睾丸酮；
    所述的促黄体生成素释放激素药物选自戈舍瑞林、亮丙瑞林。
  5. 根据权利要求1-4中任一项的药物组合物，其特征在于：所述的组合物还包含药剂学上可接受的辅料。
  6. 根据权利要求5的药物组合物，其特征在于：所述药剂学上可接受的辅料选自注射用水、生理盐水、乙醇、丙二醇、甘油；聚乙二醇200、聚乙二醇400、聚乙二醇600、聚氧乙烯蓖麻油类、聚山梨醇酯，泊洛沙姆、聚乙烯吡咯烷酮、油性脂肪酸及其单或二甘油酯；乳糖、蔗糖、木糖醇、山梨醇、甘露醇、乳糖醇、右旋糖苷、d-木糖、葡萄糖；磷脂、明胶、阿拉伯胶、虫胶、瓜耳豆胶、琼脂、海藻酸及其盐、聚乙烯醇、聚乙二醇、羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、乙烯－醋酸乙烯共聚物、聚酰胺、醋酸纤维素、聚丙烯酸树脂、乙基纤维素、卡波姆、血清白蛋白。
  7. 根据权利要求6的药物组合物，其特征在于：所述药物组合物的剂型选自注射用制剂。
  8. 根据权利要求7的药物组合物，其特征在于：注射用制剂选自各种可用的注射用溶液剂、粉针、注射用油和缓控释制剂。
  9. 权利要求1-8任一项的药物组合物在制备抗肿瘤药物中的应用。
  10. 根据权利要求9的应用，其特征在于：所述的肿瘤选自黑色素瘤、胃癌、肺癌、乳腺癌、肾癌、肝癌、口腔表皮癌、宫颈癌、卵巢癌、胰腺癌、前列腺癌、结肠癌、膀胱癌、脑瘤、食管癌。
  11. 根据权利要求10的应用，其特征在于：所述的肿瘤选自肝癌、胰腺癌、胶质瘤、食管癌。
  12. 一种药盒，其特征在于，包含权利要求1-8中任意一种药物组合物。
PCT/CN2015/078797 2014-05-12 2015-05-12 维生素c与抗肿瘤药物协同作用的注射用药物组合物 WO2015172712A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201410198567.4 2014-05-12
CN201410198567 2014-05-12

Publications (1)

Publication Number Publication Date
WO2015172712A1 true WO2015172712A1 (zh) 2015-11-19

Family

ID=54479334

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/078797 WO2015172712A1 (zh) 2014-05-12 2015-05-12 维生素c与抗肿瘤药物协同作用的注射用药物组合物

Country Status (1)

Country Link
WO (1) WO2015172712A1 (zh)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017192502A1 (en) * 2016-05-03 2017-11-09 The American University In Cairo Liposomal delivery systems for oxaliplatin and in dual drug delivery in combination with chemo-sensitizing and chemo-therapeutic agents
CN112220795A (zh) * 2019-07-14 2021-01-15 北京恒润泰生医药科技有限公司 维生素c-吉西他滨,其制备,抗肿瘤活性和应用
CN112220796A (zh) * 2019-07-14 2021-01-15 北京恒润泰生医药科技有限公司 抗坏血酸-吉西他滨,其制备,抗肿瘤活性和应用
CN113893332A (zh) * 2021-11-26 2022-01-07 暨南大学附属第一医院（广州华侨医院） 一种治疗巨块型肝癌的联合药物组合物及其在制备治疗巨块型肝癌药物中的应用
EP4000618A1 (de) * 2020-11-13 2022-05-25 Manfred Motz Kombination wenigstens eines hemmstoffes des xc-transporters mit wenigstens einem hemmstoff der membranständigen katalase zur hemmung und/oder inaktivierung von tumorzellen

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101002772A (zh) * 2007-01-26 2007-07-25 刘祥华 10－羟基喜树碱的纳米粒靶向制剂及其制备方法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101002772A (zh) * 2007-01-26 2007-07-25 刘祥华 10－羟基喜树碱的纳米粒靶向制剂及其制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WEI HUIJIE ET AL.: "Relationship of Ascorbic Acid to Proliferation and Apoptosis of Breast Cancer MDA-MB-231 Cells", CHIN J BIOLOGICALS, vol. 24, no. 1, 31 January 2011 (2011-01-31), pages 48 - 51 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017192502A1 (en) * 2016-05-03 2017-11-09 The American University In Cairo Liposomal delivery systems for oxaliplatin and in dual drug delivery in combination with chemo-sensitizing and chemo-therapeutic agents
US20190307690A1 (en) * 2016-05-03 2019-10-10 The American University In Cairo Liposomal Delivery Systems for Oxaliplatin and in Dual Drug Delivery in Combination with Chemo-sensitizing and Chemo-therapeutic agents
CN112220795A (zh) * 2019-07-14 2021-01-15 北京恒润泰生医药科技有限公司 维生素c-吉西他滨,其制备,抗肿瘤活性和应用
CN112220796A (zh) * 2019-07-14 2021-01-15 北京恒润泰生医药科技有限公司 抗坏血酸-吉西他滨,其制备,抗肿瘤活性和应用
CN112220796B (zh) * 2019-07-14 2023-05-19 北京奇明达企业管理有限公司 抗坏血酸-吉西他滨,其制备,抗肿瘤活性和应用
CN112220795B (zh) * 2019-07-14 2023-05-30 北京奇明达企业管理有限公司 维生素c-吉西他滨,其制备,抗肿瘤活性和应用
EP4000618A1 (de) * 2020-11-13 2022-05-25 Manfred Motz Kombination wenigstens eines hemmstoffes des xc-transporters mit wenigstens einem hemmstoff der membranständigen katalase zur hemmung und/oder inaktivierung von tumorzellen
CN113893332A (zh) * 2021-11-26 2022-01-07 暨南大学附属第一医院（广州华侨医院） 一种治疗巨块型肝癌的联合药物组合物及其在制备治疗巨块型肝癌药物中的应用
CN113893332B (zh) * 2021-11-26 2024-02-06 暨南大学附属第一医院（广州华侨医院） 一种治疗巨块型肝癌的联合药物组合物及其在制备治疗巨块型肝癌药物中的应用

Similar Documents

Publication Publication Date Title
US9814734B2 (en) Bufalin liposome, preparation method therefor and application thereof
WO2015172712A1 (zh) 维生素c与抗肿瘤药物协同作用的注射用药物组合物
EP3034076B1 (en) Combined application of isothiocyanate compound and anti-cancer medicine
CN105338973A (zh) 使用辅酶q10联合疗法治疗癌症
KR20080030559A (ko) 비뇨 생식기암 및 이의 전이 치료용 비소산, 이것의나트륨염 및 이것의 유도체를 함유하는 약학 조성물
JP2014101387A (ja) 癌の処置のための方法および組成物
EP2049121B1 (en) Compositions for promoting activity of anti-cancer therapies
AU2015267897A1 (en) Pharmaceutical solution having anti-tumor effect-enhancing and toxicity-reducing effect, and pharmaceutical composition comprising same
KR20180100309A (ko) 데옥시콜산 및 이의 염을 사용한 축적된 지방의 치료 방법
CN106139151A (zh) 抗坏血酸棕榈酰酯与抗肿瘤药物协同作用的药物组合物
KR20100031759A (ko) 흑색종의 치료
TW202038932A (zh) 使用6,8-雙-苄硫基-辛酸和自噬抑制劑治療癌症之治療方法及組成物
AU2021218871B2 (en) Use of mitoxantrone hydrochloride liposome for treating breast cancer
JP2022508807A (ja) 腫瘍内注射製剤
WO2012034540A1 (zh) 抗肿瘤药物组合物
EP3949966A1 (en) Chiauranib for treatment of small cell lung cancer
WO2018203127A1 (en) Compositions for treatment of malignant tumors and precancerous conditions, methods of use thereof and methods for manufacturing medicaments
WO2015191576A1 (en) Combination therapy comprising a liposomal prodrug of mitomycin c and radiotherapy
CN104800858B (zh) Hsp90抑制肽偶联物及其在肿瘤治疗中的应用
JP7311177B2 (ja) Ａ－ＮＯＲ－５αアンドロスタン薬物と抗がん薬物との併用
TW200901989A (en) Anti-tumor activity of CCI-779 in papillary renal cell cancer
CN103054802A (zh) 介入治疗肝癌的前阳离子/阳离子脂质体姜黄素制剂及其制备方法
CN102793663B (zh) 一种含抗肿瘤药物2-甲氧基雌二醇的缓释微球注射剂
TW202000207A (zh) 膀胱癌用抗腫瘤劑及膀胱癌的處置方法
KR101698003B1 (ko) 퀴닌 염 현탁액을 포함하는 항암 치료를 위한 국소 투여용 주사제 조성물

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15793317

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15793317

Country of ref document: EP

Kind code of ref document: A1