WO2015180600A1 - 一种具有抗肿瘤增效减毒效果的药用溶液及包含其的药用组合物 - Google Patents
一种具有抗肿瘤增效减毒效果的药用溶液及包含其的药用组合物 Download PDFInfo
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- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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- 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
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- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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Definitions
- the invention belongs to the field of medicine and relates to a pharmaceutical solution having anti-tumor synergistic effect and attenuating effect, and a pharmaceutical composition comprising the same.
- anti-tumor drugs must be injected by systemic administration or local lavage injection due to the physical and chemical properties, pharmacokinetics, and pharmacodynamics of the drug.
- Commonly used carrier solutions are physiological saline and dextrose solution. Such a solution serves only as a carrier solution for antitumor drugs, and does not have antitumor effects by itself, nor does it enhance the efficacy of other antitumor drugs.
- Heavy water (chemical name: yttrium oxide, English: Deuterium oxide, molecular formula: D 2 O, molecular weight: 20.03, CAS number: 7789-20-0) can be isolated from seawater. Normal adults contain about 5 grams of heavy water. Animal experiments using dogs as models have confirmed that exogenous heavy water has a toxic reaction when the concentration reaches 30% or more in vivo. Based on the above experiments, in theory, when the adult weight is 60 kg, when the body's heavy water reaches 18 kg, it is toxic, and it is impossible to have 18 kg of heavy water in the human body. In addition, the California State Government clearly indicates in the California Chemicals Catalog that heavy water does not cause cancer and reproductive development defects.
- heavy water should be a non-toxic substance [DMCzajka: Am. J. Physiol. 201 (1961): 357-362; California Proposition 65].
- Gross PR et al. found that heavy water inhibited cellular DNA deoxysynthesis enzymes (Science 133 (1961): 1131-1133).
- Laissue et al. used a mouse model to study the anti-tumor effect of heavy water (Cancer Res. 42 (1982) 1125-1129).
- Altermatt et al. used a human tumor cell line nude mouse tumor model to study the anti-tumor effect of oral heavy water in animals (Cancer 62 (1988): 462-466. Int. J. Cancer.
- the above-mentioned heavy water anti-tumor research is mainly based on in vitro cell tests. It is well known that in drug development, candidates are effective in in vitro cell tests, and the probability of effective in vivo is only one in ten. The results of in vitro cell culture model are not predictive.
- the only two animal studies are the traditional simple heavy water oral solution, which is a hypotonic solution. The mechanism of action is: to increase the content of strontium in the body, and thus to fight tumors. In order to achieve an effective in vivo therapeutic dose, a large dose of oral heavy water oral solution is required for the animal.
- the dose can not be quantified, and the treatment effect of different people cannot be compared, and it is digested, absorbed and metabolized. Due to the influence of pharmacokinetic factors, the intake is large and the efficacy is limited, and the possibility of drug formation is small. 3) The patient needs to drink heavy water in a short time, it is difficult to take it, the clinical compliance is poor, and the cost is high; 4) Many Patients with advanced cancer have dysphagia or digestive tract surgery, can not eat water, and can not take oral heavy water.
- thoracic and intraperitoneal hyperthermic perfusion chemotherapy has become an effective therapy in the prevention or treatment of metastasis or recurrence of tumor and thoracic peritoneum, but currently use ordinary saline to dissolve or dilute anti-tumor drugs, direct body cavity (heat) Perfusion and lavage administration also has a problem of low efficacy, and the saline itself is also Does not have a synergistic anti-tumor effect.
- the present invention is based on the following findings of the inventors: 1) using heavy water to make different pharmaceutical solutions, dissolving or diluting other anti-tumor drugs, injecting or body cavity (thermal) perfusion lavage; 2) direct injection of small doses of heavy water , changed the cell cycle of tumor cells, tumor cell death; 3) synergistic and attenuated, using direct dilution or dilution of small doses of anti-tumor drugs, injection or body cavity (thermal) perfusion lavage, large doses can be obtained
- the anti-tumor drug has the same pharmacological effect, but avoids the toxicity of high-dose anti-tumor drugs; 4) Improves the drug-forming properties: heavy water injection can be quantified, overcome the drug-deficient defects of random drinking without quantitative indicators; 5) Safety: use a certain dose Direct in vivo injection of body water or body cavity (thermal) perfusion lavage is safe for mammals.
- heavy water itself has anti-tumor efficacy, combined with a variety of different types of anti-tumor drugs, significantly synergistically increase anti-tumor effect, while reducing the anti-tumor drug toxicity, for the treatment of malignant tumors, and achieved unexpected results.
- One aspect of the present invention provides a pharmaceutical solution characterized in that it uses heavy water as a solvent.
- Another aspect of the present invention provides a pharmaceutical composition characterized by comprising a pharmaceutical solution of the present invention, at least one antitumor agent, and optionally a pharmaceutically acceptable adjuvant.
- Another aspect of the invention resides in a pharmaceutical solution for treating or preventing a malignant tumor, characterized in that the pharmaceutical solution uses heavy water as a solvent.
- compositions for treating or preventing a malignant tumor characterized in that the pharmaceutical composition comprises a pharmaceutical solution of the invention, at least one antineoplastic agent and optionally A pharmaceutically acceptable excipient.
- Another aspect of the invention is to provide the use of a pharmaceutical solution or pharmaceutical composition of the invention in the preparation of an antineoplastic agent.
- Another aspect of the present invention provides a combination drug, characterized in that the combination drug comprises heavy water and at least one antitumor drug, wherein the heavy water and the antitumor drug can be administered separately, They are administered sequentially or simultaneously.
- a further aspect of the invention provides a method of treating or preventing a malignancy comprising administering to a tumor patient a therapeutically effective amount of a pharmaceutical solution or a pharmaceutical composition or a combination drug of the invention.
- Another aspect of the invention is to provide the use of heavy water in the preparation of a pharmaceutical solution.
- the pharmaceutical composition or the combination drug of the present invention is effective against tumors and is less toxic than existing antitumor drugs.
- the pharmaceutical composition or the combination drug of the present invention can be used for treating or preventing malignant tumors.
- Heavy water has the synergistic effect of increasing anti-tumor drugs; low-dose anti-tumor drugs can achieve the equivalent efficacy of high-dose anti-tumor drugs, thereby reducing the amount of anti-tumor drugs and reducing the toxicity of anti-tumor drugs.
- the pharmaceutical composition or combination of the present invention can be used for preventing and reducing tumor invasion, metastasis, recurrence, and drug resistance.
- Figure 5 Effect of aqueous glucose solution combined with 5-FU on the volume of human colon cancer HCT-116 cells transplanted tumor in nude mice.
- Figure 7 Effect of aqueous glucose solution combined with 5-FU on body weight of human colon cancer HCT-116 cells transplanted tumor-bearing animals in nude mice.
- Figure 8 Effect of sodium chloride heavy aqueous solution combined with gemcitabine on the volume of human breast cancer MCF-7 cells transplanted tumor in nude mice.
- Figure 9 Effect of sodium chloride heavy aqueous solution combined with gemcitabine on the weight of human breast cancer MCF-7 cells transplanted in nude mice.
- Figure 10 Effect of sodium chloride heavy aqueous solution combined with gemcitabine on the body weight of human breast cancer MCF-7 cells transplanted tumor-bearing animals in nude mice.
- Figure 12 Effect of sodium chloride heavy aqueous solution combined with gemcitabine on tumor weight of human lung cancer A549 cells in nude mice.
- Figure 13 Effect of sodium chloride heavy aqueous solution combined with gemcitabine on body weight of human lung cancer A549 cells transplanted tumor-bearing animals in nude mice.
- Embodiment 1 A pharmaceutical solution characterized in that it uses heavy water as a solvent.
- Embodiment 2 The pharmaceutical solution of Embodiment 1, which is suitable for parenteral administration.
- Embodiment 3 The pharmaceutical solution according to Embodiment 1, characterized in that the medicinal solution comprises sodium chloride, wherein 100 ml of the medicinal solution comprises 0.1 g to 5 g of sodium chloride, preferably 0.5 g to 2.5 g of chlorinated solution.
- Embodiment 4 The pharmaceutical solution according to Embodiment 1, characterized in that the medicinal solution is a sodium chloride solution prepared from heavy water and sodium chloride, and contains 0.9 g of sodium chloride per 100 ml of the medicinal solution and the pH is A heavy aqueous solution of sodium chloride at 4.5-7.0.
- the medicinal solution is a sodium chloride solution prepared from heavy water and sodium chloride, and contains 0.9 g of sodium chloride per 100 ml of the medicinal solution and the pH is A heavy aqueous solution of sodium chloride at 4.5-7.0.
- Embodiment 5 The pharmaceutical solution according to Embodiment 1, characterized in that the pharmaceutical solution comprises glucose, wherein the glucose solution comprises 0.1 g to 50 g glucose, preferably 5 g to 50 g glucose per 100 ml of the pharmaceutical solution. .
- Embodiment 6 The pharmaceutical solution according to Embodiment 1, characterized in that the medicinal solution is a glucose concentration prepared from heavy water and glucose, containing 5 g or 10 g of glucose per 100 ml of the medicinal solution and having a pH of 3.2-6.5. A heavy aqueous solution of glucose.
- Embodiment 7 The pharmaceutical solution according to Embodiment 1, characterized in that the medicinal solution comprises 0.9 g of sodium chloride and 5 g of glucose per 100 ml of the pharmaceutical solution prepared from heavy water, sodium chloride and glucose. It is a 3.5-5.5 dextrose aqueous solution of glucose chloride.
- Embodiment 8 The pharmaceutical solution according to Embodiment 1, characterized in that the medicinal solution comprises 0.85 g of sodium chloride per 100 ml of the medicinal solution prepared from heavy water, sodium chloride, potassium chloride and calcium chloride.
- Embodiment 9 The pharmaceutical solution according to Embodiment 1, characterized in that the medicinal solution comprises 0.310 g of sodium lactate per 100 ml of the medicinal solution prepared from heavy water, sodium lactate, sodium chloride, potassium chloride and calcium chloride.
- a heavy aqueous solution of sodium lactate Ringer having 0.600 g of sodium chloride, 0.030 g of potassium chloride and 0.020 g of calcium chloride (CaCI 2 ⁇ 2H 2 O) and having a pH of 6.0-7.5.
- Embodiment 10 The pharmaceutical solution according to Embodiment 1, characterized in that the medicinal solution comprises 0.310 per 100 ml of the medicinal solution prepared from heavy water, sodium lactate, glucose, sodium chloride, potassium chloride and calcium chloride.
- Embodiment 11 The pharmaceutical solution according to Embodiment 1, characterized in that the medicinal solution is a fructose comprising 50 g to 100 g of fructose and having a pH of 4.0-6.5 per 1000 ml of the medicinal solution prepared from heavy water and fructose. Aqueous solution.
- Embodiment 12 The pharmaceutical solution according to Embodiment 1, characterized in that the medicinal solution comprises 50 g of fructose and 9 g of sodium chloride per pH of the 1000 ml pharmaceutical solution prepared from heavy water, fructose and sodium chloride. It is a 4.0-6.5 fructose sodium chloride heavy aqueous solution.
- Embodiment 13 The pharmaceutical solution according to Embodiment 1, characterized in that the medicinal solution comprises 100 g of glycerin, 50 g of fructose and 9 per 1000 ml of the pharmaceutical solution prepared from heavy water, glycerin, fructose and sodium chloride.
- Embodiment 14 The pharmaceutical solution according to Embodiment 1, characterized in that the medicinal solution comprises 1.9 g per 500 ml of the medicinal solution prepared from heavy water, sodium acetate, sodium chloride, potassium chloride and calcium chloride. Sodium acetate, 3.0 g of sodium chloride, 0.15 g of potassium chloride and 0.1 g of calcium chloride (CaCI 2 ⁇ 2H 2 O) and a pH 6.0-7.4 sodium acetate Ringer aqueous solution.
- Embodiment 15 The pharmaceutical solution according to Embodiment 1, characterized in that the medicinal solution comprises 1-50 g of sodium hydrogencarbonate per 100 ml of the medicinal solution prepared for heavy water and sodium bicarbonate, preferably 5 g to 10 g.
- Sodium bicarbonate most preferably 5 g of sodium bicarbonate and a heavy aqueous solution of sodium bicarbonate having a pH of 7.5-8.5.
- Embodiment 16 The pharmaceutical solution according to Embodiment 1, characterized in that the medicinal solution is prepared from heavy water, sodium chloride, potassium chloride, glucose, potassium dihydrogen phosphate, disodium hydrogen phosphate and sodium hydrogencarbonate.
- Each 100 ml of the medicinal solution contains 0.8 g of sodium chloride, 0.04 g of potassium chloride, 0.1 g of glucose, 0.006 g of potassium dihydrogen phosphate, 0.00475 g of disodium hydrogen phosphate and 0.035 g of sodium hydrogencarbonate and pH. It is a heavy aqueous solution of Hank's balanced salt of 6.0-7.5.
- Embodiment 17 The pharmaceutical solution according to Embodiment 1, characterized in that the medicinal solution is prepared from heavy water, sodium chloride, potassium chloride, glucose, potassium dihydrogen phosphate, disodium hydrogen phosphate and sodium hydrogencarbonate.
- Each 100 ml of the medicinal solution contains 0.8 g of sodium chloride, 0.04 g of potassium chloride, 0.1 g of glucose, 0.006 g of potassium dihydrogen phosphate, 0.00475 g of disodium hydrogen phosphate, and 0.22 g of sodium hydrogencarbonate, and the pH is 6.0-7.5. Balance the aqueous salt solution.
- Embodiment 18 The pharmaceutical solution according to Embodiment 1, characterized in that the medicinal solution is prepared per 100 ml of heavy water, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium acetate and sodium citrate.
- the pharmaceutical solution comprises 0.64 grams of sodium chloride, 0.075 grams of potassium chloride, 0.048 grams of calcium chloride, 0.03 grams of magnesium chloride, 0.39 grams of sodium acetate, 0.17 grams of sodium citrate, and a balanced salt aqueous solution having a pH of 6.0-7.5.
- Embodiment 19 A pharmaceutical composition, comprising the pharmaceutical solution of any one of embodiments 1-18, at least one antineoplastic agent, and optionally a pharmaceutically acceptable excipient .
- antineoplastic agent is selected from the group consisting of an anti-tumor cytotoxic drug and a monoclonal antibody antitumor drug.
- Embodiment 21 The pharmaceutical composition of embodiment 20, wherein the anti-tumor cytotoxic drug comprises an antimetabolite, a plant antineoplastic agent, a tumor antibiotic, an alkylating agent, and a platinum formulation.
- Embodiment 22 The pharmaceutical composition of embodiment 21, wherein the antimetabolite comprises 5-fluorouracil, gemcitabine, fluorouridine, pemetrexed, raltitrexed, fludarabine, cytarabine, said Tumor antibiotics include mitomycin, epirubicin, pingyangmycin, daunorubicin, doxorubicin, pirarubicin, arubicin, and the platinum preparation includes cisplatin, oxaliplatin, card Platinum, nedaplatin, the plant antineoplastic agent comprises paclitaxel, paclitaxel liposome, paclitaxel albumin, docetaxel, etoposide, hydroxycamptothecin, the alkylating agent comprises thiotepa, card Mustine, nitustine, formoterol, estramustine, cyclophosphamide, maliland.
- the Tumor antibiotics include mitomycin, epirubicin,
- Embodiment 23 The pharmaceutical composition of embodiment 20, wherein the monoclonal antibody antineoplastic agent comprises bevacizumab, cetuximab, trastuzumab, panituxumab, nimotuzumab, Recombinant human endostatin.
- Embodiment 24 The pharmaceutical solution of any of Embodiments 1-18 or Embodiments 19-23 Use of a pharmaceutical composition according to any of the invention for the preparation of an antitumor drug.
- Embodiment 26 A combination drug comprising heavy water and at least one antitumor drug, wherein the heavy water and the antitumor drug are administered separately, sequentially or simultaneously.
- Embodiment 27 A method of treating or preventing a malignancy comprising administering to a tumor patient a therapeutically effective amount of the pharmaceutical solution of any of embodiments 1-18 or the pharmaceutical combination of any of embodiments 19-23 Or a combination of the drugs of embodiment 27.
- the malignant tumor is selected from the group consisting of: lung cancer, colorectal cancer, primary liver cancer, esophageal cancer, gastric cancer and cardiac cancer, pancreatic cancer, renal cell carcinoma, bladder cancer, prostate cancer, Head and neck cancer, nasopharyngeal cancer, cervical cancer, ovarian cancer, breast cancer, brain tumor, bone and joint sarcoma, thyroid cancer, skin cancer, malignant melanoma, malignant lymphoma, leukemia, complications and recurrence of various malignant tumors Tumor cells, chest and abdomen pelvic metastasis and implantation, malignant chest and abdomen pelvic fluid.
- the lung cancer comprises small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC); colorectal cancer comprises early colorectal cancer, advanced colorectal cancer; primary liver cancer including hepatocytes Type, hepatic duct cell type, mixed type; esophageal cancer including adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, small cell carcinoma; gastric cancer and cardiac cancer including adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, small cell carcinoma, malignant gastrointestinal Carcinoma; pancreatic cancer including ductal cell carcinoma, osteoclast-like giant cancer cells; renal cell carcinoma including clear cell carcinoma, papillary renal cell carcinoma; bladder cancer including urothelial carcinoma, squamous cell carcinoma, adenocarcinoma; prostate cancer Including adenocarcinoma, ductal adenocarcinoma, urothelial carcinoma, s
- SCLC small cell
- Embodiment 30 Use of heavy water in the pharmaceutical solution of any of Embodiments 1-18.
- Embodiment 31 The use of embodiment 30, wherein the pharmaceutical solution is capable of acting as a broad-spectrum anti-tumor synergist synergistic anti-tumor effect.
- each 100 ml of the medicinal solution or pharmaceutical composition comprises heavy water of 1-99.9 ml of heavy water, preferably 9-99.9 ml of heavy water, more preferably 20-99.9 ml of heavy water, more preferably 30-99.9 ml of heavy water, more preferably 40-99.9 ml of heavy water, more preferably 50-99.9 ml of heavy water, more preferably 60-99.9 ml of heavy water, more preferably 70-99.9 ml of heavy water, more preferably 80-99.9 ml of heavy water, more preferably 90- 99.9 ml of heavy water, most preferably 95-99.9 ml of heavy water.
- the heavy water used in the present invention is derived from a heavy water plant and is commercially available, wherein the isotope abundance of the cerium element is from 1 to 99.9%, preferably from 30 to 99.9%, more preferably from 50 to 99.9%, more preferably. It is 70-99.9%, most preferably 90-99.9%.
- heavy water provided by Cambridge Isotope Laboratory, Inc. in which the isotope abundance of strontium element is 90-99.9% (D 90-99.9%) can be used.
- the pharmaceutically acceptable excipients water, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium lactate, sodium acetate, sodium citrate, sodium hydrogencarbonate, potassium dihydrogen phosphate, disodium hydrogen phosphate, sodium hydrogencarbonate , glucose, fructose, albumin, liposome, hyaluronic acid, polyethylene glycol.
- the antineoplastic agent is selected from the group consisting of an anti-tumor cytotoxic drug and a monoclonal antibody antitumor drug.
- the anti-tumor cytotoxic drugs are selected from the group consisting of antimetabolites, plant antineoplastic agents, tumor antibiotics, alkylating agents, and platinum preparations.
- Antimetabolites include 5-fluorouracil, gemcitabine, fluorouridine, pemetrexed, raltitrexed, fludarabine, cytarabine, preferably 5-fluorouracil, gemcitabine and pemetrexed.
- Tumor antibiotics include mitomycin, epirubicin, pingyangmycin, daunorubicin, doxorubicin, pirarubicin, arubicin, preferably mitomycin and epirubicin.
- Platinum formulations include cisplatin, oxaliplatin, carboplatin, nedaplatin, preferably cisplatin and oxaliplatin.
- Plant antineoplastic agents include paclitaxel, paclitaxel liposome, paclitaxel albumin, docetaxel, etoposide, hydroxycamptothecin, preferably paclitaxel, paclitaxel liposome, paclitaxel albumin, and docetaxel.
- Alkylating agents include thiotepa, carmustine, nimustine, formoterol, estramustine, cyclophosphamide, maliline, preferably thiotepa and carmustine.
- Monoclonal antibody antineoplastic agents include bevacizumab, cetuximab, trastuzumab, panituzumab, nimotuzumab, recombinant human endostatin, preferably bevacizumab And recombinant human endostatin.
- the pharmaceutical solutions of the present invention are prepared using standard methods for preparing solutions in the pharmaceutical field, in accordance with the corresponding standards in the Chinese Pharmacopoeia, the United States Pharmacopoeia, and the European Pharmacopoeia.
- the ratio of the dissolution or dilution of the medicinal solution and the antitumor drug prescribed by the Chinese Pharmacopoeia, the United States Pharmacopoeia, and the European Pharmacopoeia is followed.
- compositions may be administered separately, sequentially or simultaneously.
- the pharmaceutical solution or composition of the present invention is a preparation for lavage perfusate, injection, suspension or emulsion or embolic internal solution, preferably lavage perfusate and injection.
- the pharmaceutical solution or pharmaceutical composition of the present invention is suitable for body cavity (thermal) perfusion lavage, intravenous injection, arterial interventional injection, intrathecal injection and intratumoral injection, preferably body cavity (thermal) perfusion lavage administration and Administered intravenously.
- the dosage is: 1 ml/kg-20 ml/kg.
- the malignant tumor is selected from the group consisting of: lung cancer, colorectal cancer, primary liver cancer, esophageal cancer, gastric cancer and gastric cardia cancer, pancreatic cancer, renal cell carcinoma, bladder cancer, prostate cancer, head and neck cancer, nasopharyngeal cancer, cervical cancer, ovary Cancer, breast cancer, brain tumor, bone and joint sarcoma, thyroid cancer, skin cancer, malignant melanoma, malignant lymphoma, leukemia, complications and recurrence of various malignant tumors such as tumor cells, chest and abdomen pelvic metastasis and implantation, malignant chest Abdominal pelvic fluid and so on.
- Lung cancer includes small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), etc.; colorectal cancer includes early colorectal cancer, advanced colorectal cancer, etc.; primary liver cancer includes hepatocyte type, hepatic duct cell type, mixed type Esophageal cancer includes adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, small cell carcinoma, etc.; gastric cancer and cardiac cancer include adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, small cell carcinoma, malignant gastrointestinal stromal tumor, etc.; Catheter cell carcinoma, osteoclast-like giant cancer cells, others; renal cell carcinoma including clear cell carcinoma, papillary renal cell carcinoma; bladder cancer including urothelial carcinoma, squamous cell carcinoma, adenocarcinoma, etc.; prostate cancer including gland Cancer, ductal adenocarcinoma, urothelial carcinoma, squamous cell carcinoma
- the invention comprises a heavy aqueous glucose solution containing 5 grams of glucose per 100 ml of the pharmaceutical solution.
- the present invention comprises 10 g of a glucose aqueous solution of glucose per 100 ml of the pharmaceutical solution.
- MTT thiazole blue
- a 12-well cell culture plate was taken, and 300 ⁇ l of the cell suspension was added to each well. The process of adding cells should be controlled within 4 hours. The plate was incubated for 24 hours at 37 ° C in a 5% CO 2 incubator.
- RPMI Medium1640 (Gibco Life Company, USA: No. 31800-022) provided by the Cambridge Isotope Laboratory Company of the United States is used as a cell culture liquid (the culture medium not specifically described in the following examples is powdered RPMI Medium). 1640 and heavy water were prepared), and the concentrations were as shown in Table 1, respectively, and added to the cell culture plates.
- MTT was formulated into a 1 mg/ml solution in serum-free RPMI 1640 medium, 200 ⁇ l was added to each well, and incubated at 37 ° C for 4 hours to reduce MTT to formazan.
- RESULTS The tumor cells treated with saline control were used as the control group, and the growth inhibition rate of heavy water on tumor cells was calculated. A dose response curve was obtained by plotting the different contents of heavy water and the inhibition rate of cells, and the half-inhibitory concentration (IC 50 ) of heavy water was determined therefrom.
- Tumor cell growth inhibition rate% (1-OD experiment/OD control) ⁇ 100%
- Table 1 (b) shows the heavy water (expressed as a volume percentage) for different types of tumor cells IC 50 and IC 10.
- Cell line Human colon cancer cell HCT-116, provided by Nanjing Kaiji Biotechnology Development Co., Ltd.
- Test drug 5-fluorouracil (5-FU), a sodium chloride heavy aqueous solution prepared in Example 1.
- Aqueous sodium chloride solution was used to dilute 5-fluorouracil in the amount shown in Table 2, and added to the cell culture plate to inhibit the growth of tumor cells in vitro.
- the MTT method was the same as in Example 16.
- Table 2 shows that heavy water combined with 5-FU increased the inhibition of growth of drug-resistant tumor cells (medium-resistant strains), especially when 5-FU was at low concentration, the effect of heavy water sensitization was more It is obvious that heavy water has an anti-drug sensitizing effect.
- Test drug gemcitabine (GEM), 5-fluorouracil (5-FU), and a sodium chloride heavy aqueous solution prepared in Example 1.
- Transwell detects cell invasion
- test drug according to the cell treatment group: dilute gemcitabine or 5-FU alone with physiological saline; or take a heavy aqueous solution of sodium chloride to dilute gemcitabine (heavy water + gemcitabine) or 5-FU as shown in Table 3. (heavy water +5-FU), respectively, on A549 and HCT116 cells, then the cells were incubated at 37 ° C, 5% CO 2 incubator for 24h;
- Matrigel Matrigel was placed in advance at 4 ° C overnight to melt;
- the 24-well cell culture plate was incubated at 37 ° C in a 5% CO 2 incubator for 24 hours;
- 5-FU (0.195 ug/ml) was taken as an example, which indicated that physiological saline was used as a vehicle, and the concentration of 5-FU was 0.195 ug/ml.
- heavy water (30%) + 5-FU (0.195 ug/ml) is taken as an example, which means that the concentration of heavy water in the cell culture solution is 30% (v/v), and the concentration of 5-FU is 0.195 ug/ml. The same below.
- Human lung adenocarcinoma A549 cells and colon cancer cells HCT-116 cells were provided by Nanjing Kaiji Biotechnology Development Co., Ltd., and cultured in an incubator at 37 ° C, 5% CO 2 , and saturated humidity.
- KGA511 Cell Cycle Detection Kit is provided by Nanjing Kaiji Biotechnology Development Co., Ltd., China.
- the flow cytometer is a FACS Calibur supplied by Becton-Dickinson, USA.
- Test drug gemcitabine (GEM), 5-fluorouracil (5-FU), and a sodium chloride heavy aqueous solution prepared in Example 1.
- the prepared single cell suspension was fixed with 70% ethanol in volume fraction for 2 hours (or overnight), stored at 4 ° C, and the fixing solution was washed away with PBS before staining (if necessary, the cell suspension was filtered once with a 200 mesh sieve);
- 5-FU and gemcitabine are cytotoxic metabolites, mainly acting on S-phase tumor cells during DNA synthesis, as shown in Tables 8 and 9 and Figures 1-4: Heavy water blocks tumor cells from S phase into G2 In combination, heavy water combined with 5-FU and gemcitabine made 5-FU and gemcitabine more effective in killing S-phase tumor cells, and S-phase tumor cells were significantly reduced, which played a synergistic effect.
- Test animals ICR mice, weekly age: 4-5w, gender: male, provided by Shanghai Xipuer-Beikai Experimental Animal Co., Ltd.
- Ehrlich ascites cell line was provided by Nanjing Kaiji Biotechnology Development Co., Ltd.
- Test drug 5-fluorouracil (5-FU), a sodium chloride heavy aqueous solution prepared in Example 1.
- the drug and dosing schedule are shown in Table 10.
- 0.1 ml of fresh sodium chloride solution / only +5-FU 20 mg/kg means that 0.1 ml of a sodium chloride heavy aqueous solution was administered to each mouse, and 5-FU was dissolved in a sodium chloride heavy aqueous solution. A dose of 20 mg/kg was reached.
- mice were ascites were taken from each group, and the volume of ascites and the number of tumor cells in ascites were counted.
- the other groups continued to be reared, and the median survival time (MST) of each group was observed to evaluate each. The survival time of the group.
- T MST treatment group MST
- C MST negative control group MST.
- the evaluation criteria are bounded by 125% when T/C% ⁇ 125%. It is considered valid, otherwise it is invalid.
- the mean value was expressed by X ⁇ SD, and the inter-group analysis was statistically processed by t-test.
- the results were statistically analyzed using SPSS (Staffstical Package for the Social Science) 17.0.
- Liver cancer H22 ascites tumor cell line was provided by Nanjing Kaiji Biotechnology Development Co., Ltd.
- Test drug cisplatin, epirubicin, and Ringer's aqueous solution prepared in Example 5.
- mice After vaccination for 7-8 days, mice were randomly divided into groups of 18 animals.
- Cisplatin and epirubicin were dissolved in the abdominal cavity of the lotus rat in a 42 ° C Ringer heavy aqueous solution.
- Blank control group (42 ° C ordinary Ringer injection, 10 ml / kg);
- Heavy water dose + cisplatin group (42 ° C Ringer heavy aqueous solution 20ml / kg + cisplatin 0.6mg / kg);
- Heavy water high dose + cisplatin group (42 ° C Ringer heavy aqueous solution 40ml / kg + cisplatin 0.6mg / kg);
- Heavy water dose + cisplatin group + epirubicin (42 ° C Ringer heavy aqueous solution 20ml / kg + cisplatin 0.6mg / kg + epirubicin 0.2mg / kg);
- Heavy water high dose + cisplatin group + epirubicin (42 ° C Ringer heavy aqueous solution 40 ml / kg + cisplatin 0.6 mg / kg + epirubicin 0.2 mg / kg).
- mice The abdominal cavity of the mice was lavaged with the above composition, and the intraperitoneal cavity was kept for 10 minutes, repeated 3 times, once every other day for 5 times, and the body weight and abdominal circumference of the mice were measured before daily administration, and the daily living state was observed. Eight hours after the end of the treatment (day 11), 8 mice in each group were sacrificed to measure the amount of ascites, and the mice were dissected to observe the metastasis of the abdominal organs and lungs. The remaining mice were observed for survival time and the life extension rate was calculated.
- Cisplatin is a representative of anti-tumor platinum preparations
- epirubicin is a broad-spectrum anti-tumor antibiotic
- heavy water has a broad-spectrum anti-tumor synergistic effect.
- intraperitoneal warm (42 °C) heavy water combined with cisplatin and epirubicin could significantly prolong the survival time of mice with H22 ascites tumor, inhibit the formation of ascites in mice with H22 ascites tumor, and improve the tumor-bearing
- the quality of life of mice has anti-tumor efficacy.
- sarcoma S180 (ascites type) cell line was provided by Nanjing Kaiji Biotechnology Development Co., Ltd.
- Model preparation 0.2 ml of 1 ⁇ 10 7 /ml S180 tumor cell suspension was inoculated into the peritoneal cavity of mice.
- Test drug oxaliplatin, mitomycin, and a heavy aqueous solution of glucose prepared in Example 2.
- mice After vaccination for 7-8 days, mice were randomly divided into groups of 12 each.
- Oxaliplatin and mitomycin were dissolved in a heavy aqueous solution of glucose at 42 ° C to irrigate the abdominal cavity of the rat.
- Blank control group (42 ° C ordinary 5% glucose injection, 5 ml / kg);
- Heavy water dose + oxaliplatin group (42 ° C glucose heavy aqueous solution 20ml / kg + oxaliplatin 0.8mg / kg);
- Heavy water high dose + oxaliplatin group (42 ° C glucose heavy aqueous solution 40 ml / kg + oxaliplatin 0.8 mg / kg).
- Heavy water dose + oxaliplatin group + mitomycin 42 ° C glucose heavy aqueous solution 20ml / kg + oxaliplatin 0.8mg / kg + mitomycin mg / kg;
- the abdominal cavity was irrigated with a combination of different concentrations of glucose in water at 42 ° C. After the administration, the abdominal cavity was kept for 10 minutes, repeated 3 times, once every other day for 5 times. The body weight and abdominal circumference of the mice were measured before daily administration, and observed. Daily life. Four hours after the end of the treatment (day 11), 4 mice in each group were sacrificed to measure the amount of ascites, and the mice were dissected to observe the metastasis of the abdominal organs and lungs. The remaining mice were observed for survival time and the life extension rate was calculated.
- Oxaliplatin is a third-generation anti-tumor platinum preparation.
- Mitomycin is an anti-tumor antibiotic. It is sensitive to G0-S stage tumor cells. Heavy water has broad-spectrum anti-tumor synergistic effect, and S-phase tumor cells are also very Sensitive, combined with strengthening anti-tumor efficacy. The results showed that heavy water combined with oxaliplatin and mitomycin in the intraperitoneal warm (42 °C) heavy water lavage can also prolong the survival time of sarcoma S180 mice and inhibit the formation of ascites in sarcoma S180 mice.
- Example 21 and Example 22 illustrate that universal application of heavy water in combination with platinum-based formulations and anti-tumor antibiotics inhibits different tumor growth.
- mice BALB/c nude mice, age: 6-7 weeks, body weight: 18-20 g, sex: female. Provided by Shanghai Slack Laboratory Animal Co., Ltd.
- Cell line Human colon cancer HCT-116 cells were provided by Nanjing Kaiji Biotechnology Development Co., Ltd.
- Test drug 5-fluorouracil (5-FU), a solution of glucose heavy water (5%) prepared in Example 2 (containing 5 g of glucose per 100 ml).
- Nude mice were transplanted with vernier calipers to measure the diameter of the transplanted tumor. After 10 days of inoculation, the animals were randomly divided into groups of 8 animals each growing to 100-110 mm 3 . At the same time, administration was started, and administration was carried out by tail vein injection once every 3 days for 21 consecutive days. Using the method of measuring the tumor diameter, the anti-tumor effect of the test sample was dynamically observed, and the animal body weight was recorded to observe the toxicity of the test sample. The nude mice were sacrificed 21 days after the administration, and the tumor pieces were surgically removed and weighed and photographed.
- the bone marrow nucleated cells were routinely isolated, the cell DNA was extracted, the OD value was determined by UV-260 ultraviolet spectrophotometer, and the OD value was used as a representative value of the DNA content to observe the effect of the test sample on inhibiting DNA synthesis.
- Negative control group 5% glucose injection 10 ml/kg.
- Paclitaxel positive drug control group Paclitaxel (8 mg/kg) was diluted with physiological saline.
- 35-FU high-dose positive control group 5% glucose injection diluted 5-FU (30 mg / kg).
- 45-FU low-dose control group 5% glucose injection diluted 5-FU (12 mg/kg).
- Test group 1 A heavy aqueous solution of glucose (5 ml/kg) was diluted with 5-FU (12 mg/kg).
- Test group 2 A heavy aqueous solution of glucose (10 ml/kg) was diluted with 5-FU (12 mg/kg).
- Test group 3 A heavy aqueous solution of glucose (20 ml/kg) was diluted with 5-FU (12 mg/kg).
- the formula for calculating tumor volume (TV) is:
- TV 1/2 ⁇ a ⁇ b 2
- a and b represent the length and width, respectively.
- V 0 is the measured tumor volume at the time of sub-cage administration (i.e., d 0 )
- V t is the tumor volume at each measurement.
- Tumor growth inhibition rate (%), the formula is as follows:
- the bone marrow DNA content was observed to observe the inhibitory effect of the drug on the bone marrow, and the toxicity of the drug was monitored.
- the mean value was expressed by X ⁇ SD, and the inter-group analysis was statistically processed by t-test.
- the results were statistically analyzed using SPSS (Staffstical Package for the Social Science) 17.0.
- the anti-tumor activity was evaluated by the volume of transplanted tumor: the results showed that heavy water combined with low-dose 5-FU had a good anti-tumor effect on the transplanted tumor. After 21 days of administration, it was a heavy glucose solution (5 ml/kg) combined with 5-FU group. : tumor volume 1.22 ⁇ 0.15cm 3; weight glucose solution (10ml / kg) combined 5-FU group: tumor volume 1.45 ⁇ 0.25cm 3; weight glucose solution (20ml / kg) combined 5-FU group: tumor volume 1.27 ⁇ 0.24 Cm 3 , T/C was ⁇ 40% compared with the negative control group.
- the tumor volume was reduced to 2.27 ⁇ 0.30 cm 3 , and the T/C was 80.91%, >40%, which did not reach the pharmaceutically effective standard. It can be seen that the use of heavy water combined with 5-FU, heavy water significantly improved the anti-tumor effect of 5-FU, as shown in Figure 5.
- the anti-tumor activity was evaluated by transplanted tumors.
- the results showed that heavy water combined with low-dose 5-FU had a good anti-tumor effect on transplanted tumors.
- the inhibition rate was 56.32%; the inhibition rate was 53.70% when the heavy glucose solution (10ml/kg) was combined with 5-FU, and the inhibition rate was 54.22% when the heavy glucose solution (20ml/kg) was combined with 5-FU;
- T/C was >40%, P ⁇ 0.001; all reached the pharmaceutically effective standard.
- the low-dose 5-FU group was used alone, the inhibition rate was 23.64%, which did not reach the pharmaceutically effective standard. quasi. It can be seen that the use of heavy water combined with 5-FU, heavy water significantly improved the anti-tumor effect of 5-FU, see Table 19. and Figure 6.
- the tumor growth inhibition rate is >40%, which is pharmaceutically effective.
- mice BALB/c nude mice, 6-7 weeks, body weight: 18-20 g, gender: female, supplied by Shanghai Slack Laboratory Animal Co., Ltd.
- Cell line Human breast cancer MCF-7 cells were provided by Nanjing Kaiji Biotechnology Development Co., Ltd.
- Test drug Gemcitabine (GEM), a heavy aqueous solution of sodium chloride prepared in Example 1.
- tumors were taken, cultured in resuscitation, and cultured MCF-7 cell suspension was collected, and sterile physiological saline was added to prepare a concentration of 1 ⁇ 10 7 cells/ml, and each 0.1 ml was inoculated into the right axillary subcutaneous space of nude mice. .
- Nude mice were transplanted with vernier calipers to measure the diameter of the transplanted tumor. After 10 days of inoculation, the animals were randomly divided into groups of 8 animals each growing to 100-110 mm 3 . At the same time, administration was started, and administration was carried out by tail vein injection once every 3 days for 21 consecutive days. The anti-tumor effect of the test sample was dynamically observed using a method of measuring the tumor diameter. The animal's body weight was also recorded to observe the toxicity of the test sample. The nude mice were sacrificed 21 days after the administration, and the tumor pieces were surgically removed and weighed and photographed.
- the bone marrow nucleated cells were routinely isolated, the cell DNA was extracted, the OD value was determined by UV-260 ultraviolet spectrophotometer, and the OD value was used as a representative value of the DNA content to observe the effect of the test sample on inhibiting DNA synthesis.
- Negative control group normal saline 10 ml/kg.
- Paclitaxel positive control group Paclitaxel (8 mg/kg) was diluted with physiological saline.
- Gemcitabine positive control group Gemcitabine (20 mg/kg) was diluted with physiological saline.
- 4 gemcitabine low-dose control group diluted gemcitabine (10 mg / kg) in saline.
- Test group 1 Gemcitabine (10 mg/kg) was diluted with a sodium chloride heavy aqueous solution (5 ml/kg).
- Test group 2 Gemcitabine (10 mg/kg) was diluted with a sodium chloride heavy aqueous solution (10 ml/kg).
- Test group 3 Gemcitabine (10 mg/kg) was diluted with a sodium chloride heavy aqueous solution (20 ml/kg).
- the antitumor activity was evaluated by the volume of transplanted tumor: the sodium chloride aqueous solution combined with the low-dose gemcitabine had a good anti-tumor effect on the transplanted tumor.
- the sodium chloride heavy aqueous solution 5 ml/kg was combined with the gemcitabine group: Tumor volume 1.949 ⁇ 0.491 cm 3 ; sodium chloride heavy aqueous solution (10 ml/kg) combined with gemcitabine group: tumor volume 1.743 ⁇ 0.503 cm 3 ; sodium chloride heavy aqueous solution (20 ml/kg) combined with gemcitabine group: tumor volume 1.671 ⁇ 0.386 cm 3 , compared with the negative control group, T / C are ⁇ 40%, reaching the pharmacy effective standard.
- the tumor volume of the single-dose low-dose gemcitabine group was only a small decrease, which was 2.757 ⁇ 0.342 cm 3 , and the T/C was 60.39%, >40%, which did not reach the pharmaceutically effective standard.
- the use of heavy water in combination with gemcitabine significantly increased the anti-tumor effect of gemcitabine, as shown in Figure 8.
- the antitumor activity was evaluated by transplanted tumor: the sodium chloride heavy aqueous solution combined with low-dose gemcitabine had a good anti-tumor effect on the transplanted tumor. After 21 days of administration, it was inhibited by sodium chloride heavy aqueous solution (5 ml/kg) combined with gemcitabine. The rate was 48.82%; the inhibition rate of sodium chloride heavy aqueous solution (10ml/kg) combined with gemcitabine was 57.78%; the inhibition rate of sodium chloride heavy aqueous solution (20ml/kg) combined with gemcitabine was 60.70%; compared with the negative control group, P ⁇ 0.001; T/C are >40%, reaching the pharmaceutically effective standard.
- the tumor growth inhibition rate is >40%, which is pharmaceutically effective.
- the sodium chloride heavy aqueous solution combined with a half dose of gemcitabine (10 mg/kg) can achieve the same efficacy (equivalent) of paclitaxel (8 mg/kg) and high dose gemcitabine (20 mg/kg), but tumor-bearing
- the weight gain of the mice was similar to that of the negative control group, and the DNA content of the bone marrow was also increased.
- 5-FU and gemcitabine are antimetabolites in cytotoxic antineoplastic agents. It can be seen from Example 23 and Example 24 that heavy water can be used in combination with antimetabolite antineoplastic agents to inhibit the growth of different tumors with universal applicability.
- Cell line Human lung cancer A549 cells were provided by Nanjing Kaiji Biotechnology Development Co., Ltd.
- Test drug Gemcitabine (GEM), a heavy aqueous solution of sodium chloride prepared in Example 1.
- the tumor was resuscitated and inoculated, and the cell suspension was prepared by adding sterile physiological saline, and inoculated into the axilla of the right upper limb of the animal.
- the number of tumor cells inoculated was approximately 5 ⁇ 10 6 /piece.
- the diameter of the transplanted tumor was measured with a vernier caliper in nude mice. After 10 days of inoculation, the animals were randomly divided into groups of 8 animals each growing to 100-110 mm 3 . At the same time, administration was started, and administration was carried out by tail vein injection once every 3 days for 21 consecutive days. The anti-tumor effect of the test sample was dynamically observed using a method of measuring the tumor diameter. The animal's body weight was also recorded and the toxicity of the test sample was observed. The nude mice were sacrificed 21 days after the administration, and the tumor pieces were surgically removed and weighed and photographed.
- 1 saline control group physiological saline 10ml / kg.
- Paclitaxel positive control group Paclitaxel (8 mg/kg) was diluted with physiological saline.
- Gemcitabine positive control group Gemcitabine (20 mg/kg) was diluted with physiological saline.
- 4 gemcitabine low-dose control group diluted gemcitabine (10 mg / kg) in saline.
- Test group 1 Gemcitabine (10 mg/kg) was diluted with a sodium chloride heavy aqueous solution (5 ml/kg).
- Test group 2 Gemcitabine (10 mg/kg) was diluted with a sodium chloride heavy aqueous solution (10 ml/kg).
- Test group 3 Gemcitabine (10 mg/kg) was diluted with a sodium chloride heavy aqueous solution (20 ml/kg).
- the antitumor activity was evaluated by the volume and tumor weight of the transplanted tumor: the results showed that after 21 days of administration, the tumor weight was reduced by 2.23 ⁇ 0.2 g and the inhibition rate was 23.6%, compared with the control group of the gemcitabine alone.
- the pharmacy effective standard has not been reached.
- the tumor weight inhibition rate is greater than 40% of the drug, which is effective.
- the tumor weight decreased significantly, the tumor weight was 0.94 ⁇ 0.25 and 1.04 ⁇ 0.13 g, respectively, and the tumor proliferation rates were 67.97 and 64.54%, respectively; There was almost no increase, indicating that paclitaxel and gemcitabine were significantly toxic to animals.
- the combination of heavy water and low-dose gemcitabine can achieve the same equivalence of high-dose paclitaxel and gemcitabine, and has no corresponding toxicity.
- the weight-bearing mice have increased body weight during the administration period. The results are shown in Table 21 and Figure 13.
- mice BALB/c nude mice, age: 6-7 weeks, body weight: 18-20 g, sex: female, supplied by Shanghai Slack Laboratory Animal Co., Ltd.
- Test drug paclitaxel, a heavy aqueous solution of sodium chloride prepared in Example 1.
- the tumor was resuscitated and inoculated, and the cell suspension was prepared by adding sterile physiological saline, and inoculated into the axilla of the right upper limb of the animal.
- the number of tumor cells inoculated was approximately 5 ⁇ 10 6 /piece.
- Nude mice were transplanted with vernier calipers to measure the diameter of the transplanted tumor. After 10 days of inoculation, the animals were randomly grouped when the tumor grew to 100-110 mm 3 . At the same time, administration was started, and administration was carried out by tail vein injection once every 3 days for 21 consecutive days. The animal's body weight was recorded and the toxicity of the test sample was observed. The nude mice were sacrificed 21 days after the administration, and the tumor pieces were surgically removed and weighed.
- 1 saline control group physiological saline 10ml / kg.
- Paclitaxel positive control group Paclitaxel (8 mg/kg) was diluted with physiological saline.
- Test group 1 Paclitaxel (8 mg/kg) was diluted with a sodium chloride heavy aqueous solution (5 ml/kg).
- Test group 2 Paclitaxel (8 mg/kg) was diluted with a sodium chloride heavy aqueous solution (10 ml/kg).
- Test group 3 Paclitaxel (8 mg/kg) was diluted with a sodium chloride heavy aqueous solution (20 ml/kg).
- Paclitaxel is an important anti-tumor botanical drug. There are different types, including paclitaxel, paclitaxel liposome, paclitaxel albumin, and docetaxel. The mechanism of action is similar. The results showed that after 21 days of administration, the sodium chloride heavy aqueous solution 10 ml/kg and 20 ml/kg were combined with the paclitaxel 8 mg/kg group and the model group (normal saline), and the tumor-bearing nude mouse human ovarian cancer SKOV3 cells were transplanted.
- mice BALB/c nude mice, age: 6-7 weeks, body weight: 18-20 g, sex: female, supplied by Shanghai Slack Laboratory Animal Co., Ltd.
- Cell line Human bladder cancer 5637 cells were provided by Nanjing Kaiji Biotechnology Development Co., Ltd.
- Test drug thiotepa, a heavy aqueous solution of sodium chloride prepared in Example 1.
- the tumor was resuscitated and inoculated, and the cell suspension was prepared by adding sterile physiological saline, and inoculated into the axilla of the right upper limb of the animal.
- the number of tumor cells inoculated was approximately 5 ⁇ 10 6 /piece.
- Nude mice were transplanted with vernier calipers to measure the diameter of the transplanted tumor. After 10 days of inoculation, the animals were randomly grouped when the tumor grew to 100-110 mm 3 . At the same time, administration was started, and administration was carried out by tail vein injection once every 3 days for 21 consecutive days. The animal's body weight was recorded and the toxicity of the test sample was observed. The nude mice were sacrificed 21 days after the administration, and the tumor pieces were surgically removed and weighed.
- 1 saline control group physiological saline 10ml / kg.
- Paclitaxel positive control group Satiepa (0.2 mg/kg) was diluted with physiological saline.
- Test group 1 Sodium chloride (1 ml/kg) was diluted with thiotepa (0.2 mg/kg).
- Test group 2 Sodium chloride (10 ml/kg) was diluted with thiotepa (0.2 mg/kg).
- Test group 3 Sodium chloride (20 ml/kg) was diluted with thiotepa (0.2 mg/kg).
- ethyleneimine alkylating agent that participates in guanine binding, affects DNA synthesis, and is effective against a variety of tumor cells, especially for bladder cancer cells, heavy water combined with thiotepa, showing synergistic increase in thiotepa
- the effect of anti-bladder cancer 56373 cells increased the growth inhibition rate of cancer cells from 39% to 54%-63.4%, confirming the function of heavy water as a broad-spectrum anti-tumor synergist, but heavy water at a small dose (1ml/ When kg), the effect is not obvious.
- mice BALB/c nude mice, age: 6-7 weeks, body weight: 18-20 g, sex: female. Provided by Shanghai Slack Laboratory Animal Co., Ltd.
- Test drug Bevacizumab (Avastin, Roche), a heavy aqueous solution of sodium chloride prepared in Example 1.
- the diameter of the xenograft tumors was measured using a vernier caliper. After 10 days of inoculation, the animals were randomly grouped when the tumors grew to 100-110 mm 3 . At the same time, administration was started, and administration was carried out by tail vein injection once every 3 days for 14 consecutive days. The animal's body weight was recorded to observe the toxicity of the test sample. After 14 days of drug administration, the drug was stopped for 1 week, and the nude mice were sacrificed. The tumors were surgically removed and weighed and examined for microvessel density (MVD). The staining was performed by the standard EnVisionTM method, and the microvessel volume was counted by the Weidner microvascular method. Field of view, the highest microvessel density in the tumor was selected, and the number of microvessels in the three high power fields was counted at 400 times, and the average value was taken as the MVD value.
- MMD microvessel density
- Negative control group 0.9% sodium chloride injection 10 ml/kg.
- Bevacizumab positive control group Bevacizumab (5 mg/kg) was diluted with 0.9% sodium chloride injection.
- Test group 1 Bevacizumab (5 mg/kg) was diluted with a sodium chloride heavy aqueous solution (10 ml/kg).
- Test group 2 Bevacizumab (5 mg/kg) was diluted with a sodium chloride heavy aqueous solution (20 ml/kg).
- Negative control group 1.97 ⁇ 0.29 Bevacizumab positive control group 1.12 ⁇ 0.17* 43.1 Diluted bevacizumab (5mg/kg) in a heavy aqueous solution of sodium chloride (10ml/kg) 1.04 ⁇ 0.13* 47.2 Diluted bevacizumab (5mg/kg) in a heavy aqueous solution of sodium chloride (20ml/kg) 0.93 ⁇ 0.2* 53.7
- Bevacizumab is a microvascular growth inhibitor. When microvascular growth is inhibited in tumor tissues, microvessels are reduced and blood supply is reduced. The results showed that heavy water as a broad-spectrum anti-tumor synergist can also enhance the effect of bevacizumab on reducing tumor microvessel density (MVD), reduce the blood supply of pancreatic cancer PANC-1 cells, and thus inhibit tumor growth.
- MMD tumor microvessel density
- Test article A heavy aqueous solution of sodium chloride prepared in Example 1.
- Test 1 Single dose to observe toxicity
- Dosing using the maximum dose method, using the sodium chloride heavy aqueous solution prepared in Example 1 2ml / 100g, intravenous bolus injection rate of 2ml / min, a total of 20 rats, male and female.
- the control group was given the same volume of 0.9% sodium chloride injection, a total of 10 rats, half male and half female.
- a single intravenous administration toxicity test was carried out on a single intravenous administration test of rat sodium chloride heavy aqueous solution, and the test substance was administered at a maximum administration volume of 20 ml/kg. After the administration, there was a decrease in activity and shortness of breath after the administration. The other symptoms were not found to be related to the administration of the test article. After 2 weeks of continuous observation, the normal growth of the animal body did not cause death. According to the results of this test, the minimum lethal dose (MLD) of single intravenous administration of the test sample sodium chloride heavy aqueous solution was greater than 20 ml/kg.
- MLD minimum lethal dose
- Dosing using the method of repeating the maximum dose for multiple times, using the sodium chloride heavy aqueous solution prepared in Example 1 2 ml/100 g, intravenous bolus injection rate, 2 ml/min, once a day for five consecutive days. A total of 20 rats, half male and half female. The control group was given the same volume of 0.9% sodium chloride injection, a total of 10 rats, half male and half female.
- the rat sodium chloride heavy aqueous solution was repeatedly administered intravenously for toxicity test, and the test substance was administered at a maximum administration volume of 20 ml/kg once a day for five consecutive days. Immediately after each administration, the animals in the test group showed symptoms of decreased activity, shortness of breath, and increased urination. The above symptoms were recovered within 1 hour after administration, and no abnormalities were found.
- the test article sodium chloride heavy aqueous solution was repeatedly administered intravenously to the rats to give a sodium chloride heavy aqueous solution, and the test substance was administered at a maximum administration volume of 20 ml/kg. After the administration, there was a decrease in activity and shortness of breath after the administration. The other symptoms were not found to be related to the administration of the test article. After continuous observation for 3 months, the normal growth of the animal body did not cause death. According to the results of this test, the minimum lethal dose (MLD) of repeated intravenous administration of the test sample sodium chloride heavy aqueous solution was greater than 20 ml/kg.
- MLD minimum lethal dose
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Abstract
Description
组别 | 细胞数 |
对照 | 76.0±4.6 |
5-FU(0.195ug/ml) | 66.0±2.6 |
5-FU(0.39ug/ml) | 47.3±4.0 |
5-FU(0.78ug/ml) | 31.3±1.5 |
5-FU(1.56ug/ml) | 23.0±4.6 |
5-FU(3.125ug/ml) | 12.0±2.0 |
5-FU(6.25ug/ml) | 10.7±1.5 |
5-FU(12.5ug/ml) | 6.3±0.6 |
组别 | 细胞数 |
对照 | 178.3±13.8 |
GEM(1.95nM) | 160.0±6.6 |
GEM(3.9nM) | 112.7±3.5 |
GEM(7.8nM) | 59.0±2.0 |
GEM(15.6nM) | 51.7±3.1 |
GEM(31.2nM) | 37.3±2.3 |
GEM(62.5nM) | 22.3±0.6 |
GEM(125nM) | 16.0±1.0 |
GEM(250nM) | 9.7±2.1 |
组别 | G1期 | S期 | G2期 |
对照(生理盐水) | 82.53±1.76 | 9.40±1.83 | 8.06±1.89 |
重水(30%,v/v) | 89.19±3.81 | 6.61±1.41 | 4.21±0.95 |
5-FU(12.5ug/ml,生理盐水为溶媒) | 32.69±8.66 | 26.07±11.32 | 41.24±2.97 |
重水(30%,v/v)+5-FU(12.5ug/ml) | 49.16±4.47 | 0.30±0.26 | 50.53±4.26 |
组别 | G1期 | S期 | G2期 |
对照(生理盐水) | 80.29±5.02 | 13.50±1.33 | 6.21±4.52 |
重水(30%,v/v) | 86.23±3.69 | 0.31±0.28 | 13.47±3.94 |
GM(250nM,生理盐水为溶媒) | 73.73±3.73 | 15.55±5.51 | 10.71±2.39 |
重水(30%,v/v)+GM(250nM) | 87.32±1.60 | 0.08±0.01 | 12.6±1.46 |
组别 | MST(天) | T/C(%) |
生理盐水(0.4ml/只) | 14.1±1.9 | |
5-FU(20mg/kg)(生理盐水为溶媒) | 21.8±2.9* | 154.6% |
5-FU(30mg/kg)(生理盐水为溶媒) | 22.3±4.9* | 158.1% |
氯化钠重水溶液(0.4ml/只) | 17.2±3.2** | 121.9% |
氯化钠重水溶液(0.1ml/只)+5-FU(20mg/kg) | 21.4±3.1* | 151.7% |
氯化钠重水溶液(0.2ml/只)+5-FU(20mg/kg) | 24.1±2.7* | 170.9% |
氯化钠重水溶液(0.4ml/只)+5-FU(20mg/kg) | 25.7±2.6* | 182.2% |
组别 | MST(天) | T/C(%) |
生理盐水(0.4ml/只) | 15.3±1.9 | |
氯化钠重水溶液(0.1ml/只)+5-FU(20mg/kg) | 26.1±3.7* | 170.5% |
氯化钠重水溶液(0.2ml/只)+5-FU(20mg/kg) | 29.1±3.1* | 190.1% |
氯化钠重水溶液(0.4ml/只)+5-FU(20mg/kg) | 34.5±3.3* | 225.4% |
组别 | 腹水量(ml) |
生理盐水(0.4ml/只) | 14.3±1.4 |
5-FU(20mg/kg)(生理盐水为溶媒) | 6.9±0.9* |
5-FU(30mg/kg)(生理盐水为溶媒) | 4.9±0.5* |
氯化钠重水溶液(0.4ml/只) | 9.9±0.3** |
氯化钠重水溶液(0.1ml/只)+5-FU(20mg/kg) | 7.0±1.3* |
氯化钠重水溶液(0.2ml/只)+5-FU(20mg/kg) | 5.9±0.5* |
氯化钠重水溶液(0.4ml/只)+5-FU(20mg/kg) | 4.7±0.3* |
组别 | 腹水量(ml) |
生理盐水(0.4ml/只) | 12.2±0.7 |
氯化钠重水溶液(0.1ml/只)+5-FU(20mg/kg) | 5.8±0.7* |
氯化钠重水溶液(0.2ml/只)+5-FU(20mg/kg) | 3.3±0.1* |
氯化钠重水溶液(0.4ml/只)+5-FU(20mg/kg) | 2.6±0.1* |
组别 | 瘤重(g) | 生长抑制率(%) |
阴性对照组 | 1.97±0.29 | |
贝伐单抗阳性对照组 | 1.12±0.17* | 43.1 |
氯化钠重水溶液(10ml/kg)稀释贝伐单抗(5mg/kg) | 1.04±0.13* | 47.2 |
氯化钠重水溶液(20ml/kg)稀释贝伐单抗(5mg/kg) | 0.93±0.2* | 53.7 |
组别 | MVD |
阴性对照组 | 31.10±4.47 |
贝伐单抗阳性对照组 | 22.40±3.22* |
氯化钠重水溶液(10ml/kg)稀释贝伐单抗(5mg/kg) | 18.80±1.58* |
氯化钠重水溶液(20ml/kg)稀释贝伐单抗(5mg/kg) | 16.60±1.92* |
组别 | 给药后0天 | 给药后7天 | 给药后14天 |
氯化钠重水溶液 | 304.40±21.10 | 333.00±21.47 | 360.50±16.30 |
对照组 | 309.40±10.09 | 334.80±9.58 | 364.40±11.19 |
组别 | 给药后0天 | 给药后7天 | 给药后14天 |
氯化钠重水溶液 | 248.80±17.08 | 264.20±19.58 | 275.80±19.45 |
对照组 | 250.20±6.22 | 267.60±10.97 | 278.40±11.72 |
组别 | 给药后0天 | 给药后30天 | 给药后90天 |
氯化钠重水溶液 | 305.20±20.90 | 352.00±31.72 | 452.40±30.14 |
对照组 | 303.20±11.10 | 361.01±29.65 | 461.91±31.19 |
组别 | 给药后0天 | 给药后30天 | 给药后90天 |
氯化钠重水溶液 | 243.52±14.88 | 293.20±18.83 | 395.63±29.54 |
对照组 | 251.28±11.22 | 298.12±14.67 | 405.42±26.12 |
Claims (32)
- 一种药用溶液,特征在于,其使用重水作为溶剂。
- 根据权利要求1的药用溶液,特征在于,重水中氘元素的同位素丰度为1-99.9%,更优选为50-99.9%,最优选为90-99.9%。
- 权利要求1所述的药用溶液,其适合于胃肠外给药。
- 权利要求1所述的药用溶液,特征在于,所述药用溶液包含氯化钠,其中100ml药用溶液包含0.1克-5克氯化钠,优选0.5克-2.5克氯化钠的氯化钠重水溶液。
- 权利要求1所述的药用溶液,特征在于,所述药用溶液为由重水和氯化钠配制的氯化钠浓度为每100ml药用溶液包含0.9克氯化钠且pH为4.5-7.0的氯化钠重水溶液。
- 权利要求1所述的药用溶液,特征在于,所述药用溶液包含葡萄糖,其中每100ml药用溶液包含0.1克-50克葡萄糖,优选5克-50克葡萄糖的葡萄糖重水溶液。
- 权利要求1所述的药用溶液,特征在于,所述药用溶液为由重水和葡萄糖配制的葡萄糖浓度为每100ml药用溶液包含5克或者10克葡萄糖且pH为3.2-6.5的葡萄糖重水溶液。
- 权利要求1所述的药用溶液,特征在于,所述药用溶液为由重水、氯化钠和葡萄糖配制的每100ml药用溶液包含0.9克氯化钠和5克葡萄糖且pH为3.5-5.5的葡萄糖氯化钠重水溶液。
- 权利要求1所述的药用溶液,特征在于,所述药用溶液为由重水、氯化钠、氯化钾和氯化钙配制的每100ml药用溶液包含0.9克氯化钠、0.012克氯化钾和0.024克氯化钙(CaCI2·2H2O)且pH为4.5-7.5的林格重水溶液。
- 权利要求1所述的药用溶液,特征在于,所述药用溶液为由重水、乳酸钠、氯化钠、氯化钾和氯化钙配制的每100ml药用溶液包含0.31克乳酸钠、0.6克氯化钠、0.03克氯化钾和0.02克氯化钙(CaCI2·2H2O)且pH为6.0-7.5的乳酸钠林格重水溶液。
- 权利要求1所述的药用溶液,特征在于,所述药用溶液为由重水、 乳酸钠、葡萄糖、氯化钠、氯化钾和氯化钙配制的每100ml药用溶液包含0.31克乳酸钠、0.6克氯化钠、0.03克氯化钾、0.02克氯化钙和5克葡萄糖且pH为3.6-6.5的复方乳酸钠葡萄糖重水溶液。
- 权利要求1所述的药用溶液,特征在于,所述药用溶液为由重水和果糖配制的每500ml药用溶液包含25克-50克果糖且pH为7.0-7.4的果糖重水溶液。
- 权利要求1所述的药用溶液,特征在于,所述药用溶液为由重水、果糖和氯化钠配制的每1000ml药用溶液包含50克果糖与9克氯化钠且pH为4.0-6.5的果糖氯化钠重水溶液。
- 权利要求1所述的药用溶液,特征在于,所述药用溶液为由重水、甘油、果糖和氯化钠配制的每1000ml药用溶液包含100克甘油、50克果糖与9克氯化钠且pH为3.0-6.0的甘油果糖氯化钠重水溶液。
- 权利要求1所述的药用溶液,特征在于,所述药用溶液为由重水、醋酸钠、氯化钠、氯化钾和氯化钙配制的每500ml药用溶液包含1.9克醋酸钠、3.0克氯化钠、0.15克氯化钾和0.1克氯化钙(CaCI2·2H2O)且pH为6.0-7.4的醋酸钠林格重水溶液。
- 权利要求1所述的药用溶液,特征在于,所述药用溶液为重水和碳酸氢钠配制的每100ml药用溶液包含1-50克碳酸氢钠,优选5克-10克碳酸氢钠,最优选5克碳酸氢钠且pH为7.5-8.5的碳酸氢钠重水溶液。
- 权利要求1所述的药用溶液,特征在于,所述药用溶液为由重水、氯化钠、氯化钾、葡萄糖、磷酸二氢钾、磷酸氢二钠和碳酸氢钠配制的每100ml药用溶液包含0.8克氯化钠、0.04克氯化钾、0.1克葡萄糖、0.006克磷酸二氢钾、0.00475克磷酸氢二钠和0.035克碳酸氢钠且pH为6.0-7.5的Hank氏平衡盐重水溶液。
- 权利要求1所述的药用溶液,特征在于,所述药用溶液为由重水、氯化钠、氯化钾、葡萄糖、磷酸二氢钾、磷酸氢二钠和碳酸氢钠配制的每100ml药用溶液包含0.8克氯化钠、0.04克氯化钾、0.1克葡萄糖、0.006克磷酸二氢钾、0.00475克磷酸氢二钠和0.22克碳酸氢钠且pH为6.0-7.5的Eagles平衡盐重水溶液。
- 权利要求1所述的药用溶液,特征在于,所述药用溶液为由重水、氯化钠、氯化钾、氯化钙、氯化镁、醋酸钠和柠檬酸钠配制的每100ml药用溶液包含0.64克氯化钠、0.075克氯化钾、0.048克氯化钙、0.03克氯化镁、0.39克醋酸钠、0.17克柠檬酸钠且pH为6.0-7.4的平衡盐重水溶液。
- 一种药用组合物,特征在于,所述药用组合物包含权利要求1-19中任一项的药用溶液、至少一种抗肿瘤药和任选的药学上可用的辅料。
- 权利要求20的药用组合物,其中所述抗肿瘤药选自抗肿瘤细胞毒类药物和单克隆抗体抗肿瘤药物。
- 权利要求21的药用组合物,其中所述抗肿瘤细胞毒类药物包括抗代谢物、植物抗肿瘤药、肿瘤抗生素、烷基化剂和铂制剂。
- 权利要求22的药用组合物,其中抗代谢物包括5-氟尿嘧啶、吉西他滨、氟尿苷、培美曲塞、雷替曲塞、氟达拉滨、阿糖胞苷,所述肿瘤抗生素包括丝裂霉素、表柔比星、平阳霉素、柔红霉素、阿霉素、吡柔比星、阿柔比星,所述铂制剂包括顺铂、奥沙利铂、卡铂、奈达铂,所述植物抗肿瘤药包括紫杉醇、紫杉醇脂质体、紫杉醇白蛋白型、多西紫杉醇、依托泊苷、羟基喜树碱,所述烷基化剂包括塞替派、卡莫司汀、尼莫司汀、福莫司汀、雌莫司汀、环磷酰胺、马利兰。
- 权利要求21的药用组合物,其中单克隆抗体抗肿瘤药包括贝伐单抗、西妥昔单抗、曲妥珠单抗、帕尼妥单抗、尼妥珠单抗、重组人血管内皮抑素。
- 权利要求1-19中任一项的药用溶液或权利要求20-24中任一项的药用组合物在制备抗肿瘤药物中的用途。
- 权利要求1-19中任一项的药用溶液或权利要求20-24中任一项的药用组合物,其用于治疗或预防恶性肿瘤。
- 一种联用药物,其特征在于,包含重水和至少一种抗肿瘤药物,其中重水和抗肿瘤药物可分开给药、相继给药或同时给药。
- 一种治疗或预防恶性肿瘤的方法,其包括给予肿瘤患者治疗有效量的权利要求1-19中任一项的药用溶液或权利要求20-24中任一项的药用组合物或权利要求27的联用药物。
- 权利要求28的方法,其中所述恶性肿瘤选自:肺癌、结直肠癌、原发性肝癌、食道癌、胃癌及贲门癌、胰腺癌、肾细胞癌、膀胱癌、前列腺癌、头颈癌、鼻咽癌、宫颈癌、卵巢癌、乳腺癌、脑瘤、骨及关节肉瘤、甲状腺癌、皮肤癌、恶性黑色素瘤、恶性淋巴瘤、白血病、各种恶性肿瘤的并发症和复发如肿瘤细胞胸腹盆腔转移和种植、恶性胸腹盆腔积液。
- 权利要求29的方法,其中肺癌包括小细胞肺癌(SCLC)、非小细胞肺癌(NSCLC);结直肠癌包括早期结直肠癌、进展期结直肠癌;原发性肝癌包括肝细胞型、肝管细胞型、混合型;食道癌包括腺癌、鳞癌、腺鳞癌、小细胞癌;胃癌及贲门癌包括腺癌、鳞癌、腺鳞癌、小细胞癌、恶性胃肠间质瘤;胰腺癌包括导管细胞癌、破骨细胞样巨癌细胞;肾细胞癌包括透明细胞癌、乳头状肾细胞癌;膀胱癌包括尿路上皮癌、鳞状细胞癌、腺癌;前列腺癌包括腺癌、导管腺癌、尿路上皮癌、鳞状细胞癌;头颈癌包括鳞癌、腺癌、腺鳞癌;鼻咽癌包括鳞状细胞癌、腺癌;宫颈癌包括鳞癌、腺癌、肉瘤;卵巢癌包括卵巢上皮癌、生殖细胞肿瘤、卵巢性索间质肿瘤;乳腺癌包括上皮性肿瘤、间叶性肿瘤、肌上皮瘤;脑瘤包括原发性脑瘤和脑转移瘤、骨及关节肉瘤包括软骨肉瘤、成骨肉瘤、尤文肉瘤、软组织肉瘤;甲状腺癌包括乳头状癌、滤泡癌、髓样癌;皮肤癌包括基底细胞癌和鳞状细胞癌;恶性黑色素瘤包括表浅扩散性黑色素瘤、结节性黑色素瘤、肢端雀班黑色素瘤;恶性淋巴瘤包括霍奇金淋巴瘤和非霍奇金淋巴瘤;白血病包括急性白血病、慢性白血病。
- 重水在制备权利要求1-19中任一项的药用溶液中用途。
- 权利要求31的用途,其中所述药用溶液能作为广谱抗肿瘤增效剂协同增效抗肿瘤药效果。
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CN201580027908.4A CN106659735A (zh) | 2014-05-26 | 2015-05-25 | 一种具有抗肿瘤增效减毒效果的药用溶液及包含其的药用组合物 |
CN202210348700.4A CN114831931B (zh) | 2014-05-26 | 2015-05-25 | 一种具有抗肿瘤增效减毒效果的药用溶液及包含其的药用组合物 |
AU2015267897A AU2015267897A1 (en) | 2014-05-26 | 2015-05-25 | Pharmaceutical solution having anti-tumor effect-enhancing and toxicity-reducing effect, and pharmaceutical composition comprising same |
JP2017514768A JP2017516854A (ja) | 2014-05-26 | 2015-05-25 | 抗腫瘍相乗減毒効果を有する薬用溶液及びそれを含む薬用組成物 |
CN202210349337.8A CN114848589A (zh) | 2014-05-26 | 2015-05-25 | 一种具有抗肿瘤增效减毒效果的药用溶液及包含其的药用组合物 |
EP15799410.4A EP3150212B1 (en) | 2014-05-26 | 2015-05-25 | Pharmaceutical solution having anti-tumor effect-enhancing and toxicity-reducing effect, and pharmaceutical composition comprising same |
US15/360,065 US20170071976A1 (en) | 2014-05-26 | 2016-11-23 | Pharmaceutical solution having anti-tumor effect-enhancing and toxicity-reducing effect, and pharmaceutical composition comprising same |
US16/407,736 US11090330B2 (en) | 2014-05-26 | 2019-05-09 | Pharmaceutical solution having a toxicity-reducing effect for antitumor drugs, and pharmaceutical composition comprising same |
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CN201410227737.7 | 2014-05-26 | ||
CN201410227737.7A CN105311051A (zh) | 2014-05-26 | 2014-05-26 | 具有增加抗肿瘤药物疗效的载体溶媒、制备方法及其给药途径 |
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JP (1) | JP2017516854A (zh) |
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Cited By (2)
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US10525022B2 (en) | 2014-12-29 | 2020-01-07 | Metimedi Pharmaceuticals Co., Ltd. | Pharmaceutical composition for treating cancer, containing lactate metal salt |
CN115369091A (zh) * | 2022-09-29 | 2022-11-22 | 成都赛诺联创生物科技有限公司 | 一种Caco-2细胞倒置模型及其制备方法 |
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CN106913868A (zh) * | 2017-03-10 | 2017-07-04 | 上海景峰制药有限公司 | 一种免疫脂质体及其制备方法和应用 |
CN110870869A (zh) * | 2018-08-31 | 2020-03-10 | 成都夸常奥普医疗科技有限公司 | 包含糖类营养素和常规无效化合物的药物组合物及其应用 |
WO2020092815A1 (en) * | 2018-11-01 | 2020-05-07 | Memorial Sloan Kettering Cancer Center | Improved intra-arterial tumor targeting for diagnosis and/or treatment |
CN114306342B (zh) * | 2020-09-30 | 2024-06-28 | 江苏先声药业有限公司 | 一种注射用伊马替尼盐的药物组合物及其制备方法 |
CN113559058A (zh) * | 2021-07-30 | 2021-10-29 | 石家庄学院 | 吉西他滨氨基酸注射液 |
WO2024002147A1 (zh) * | 2022-06-29 | 2024-01-04 | 正大天晴药业集团股份有限公司 | 喹啉衍生物或其盐环糊精包合物 |
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CN115369091A (zh) * | 2022-09-29 | 2022-11-22 | 成都赛诺联创生物科技有限公司 | 一种Caco-2细胞倒置模型及其制备方法 |
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CN106659735A (zh) | 2017-05-10 |
EP3150212B1 (en) | 2020-12-16 |
AU2015267897A1 (en) | 2017-01-19 |
CN114831931B (zh) | 2024-05-24 |
CN105311051A (zh) | 2016-02-10 |
US11090330B2 (en) | 2021-08-17 |
US20170071976A1 (en) | 2017-03-16 |
US20190262267A1 (en) | 2019-08-29 |
CN114848589A (zh) | 2022-08-05 |
EP3150212A4 (en) | 2017-11-22 |
EP3150212A1 (en) | 2017-04-05 |
JP2017516854A (ja) | 2017-06-22 |
CN114831931A (zh) | 2022-08-02 |
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