Pharmaceutical solution having anti-tumor effect-enhancing and toxicity-reducing effect, and pharmaceutical composition comprising same

Abstract

The present disclosure relates to a pharmaceutical solution having an anti-tumor efficacy-enhancing and toxicity-reducing effect, and a pharmaceutical composition comprising the solution as well as a method for using them. The pharmaceutical solution uses deuterium oxide as a solvent.

1 . A pharmaceutical solution, comprising deuterium oxide as a solvent, wherein in the deuterium oxide, the isotope abundance of deuterium is 50.0% to 99.9%. 
     
     
         2 . The pharmaceutical solution according to  claim 1 , wherein the isotope abundance of deuterium is 99.0% to 99.9%. 
     
     
         3 . The pharmaceutical solution according to  claim 1 , further comprising sodium chloride, the pharmaceutical solution containing 0.1 g to 5 g sodium chloride per 100 ml solution. 
     
     
         4 . The pharmaceutical solution according to  claim 1 , further comprising glucose, the pharmaceutical solution comprising 0.1 g to 50 g glucose per 100 ml solution. 
     
     
         5 . The pharmaceutical solution according to  claim 1 , further comprising sodium bicarbonate, the pharmaceutical solution comprising 1 g to 10 g sodium bicarbonate per 100 ml solution. 
     
     
         6 . The pharmaceutical solution according to  claim 1 , further comprising glucose and sodium chloride, the pharmaceutical solution comprising 5 g glucose and 0.9 g sodium chloride per 100 ml solution and having a pH adjusted to 3.5 to 5.5. 
     
     
         7 . The pharmaceutical solution according to  claim 1 , wherein the pharmaceutical solution is a Ringer's deuterium oxide solution comprising 0.9 g sodium chloride, 0.012 g potassium chloride and 0.024 g calcium chloride per 100 ml solution and having a pH adjusted to 4.5 to 7.5. 
     
     
         8 . The pharmaceutical solution according to  claim 1 , further comprising sodium hyaluronate, the pharmaceutical solution comprising 0.04 g to 3 g sodium hyaluronate per 100 ml solution. 
     
     
         9 . The pharmaceutical solution according to  claim 1 , further comprising hydroxyethyl starch, the pharmaceutical solution comprising 3 g to 8 g hydroxyethyl starch per 100 ml solution. 
     
     
         10 . The pharmaceutical solution according to  claim 1 , further comprising hydroxypropyl-β-cyclodextrin (HP-β-CD), the pharmaceutical solution comprising 0.4 g to 10 g HP-β-CD per 100 ml solution. 
     
     
         11 . The pharmaceutical solution according to  claim 1 , wherein the pharmaceutical solution is a solution for lavage and perfusion, a solution for injection, a suspension, an emulsion, or a solution for embolization. 
     
     
         12 . An anti-tumor medicament for combinational administration, characterized in that the medicament comprises the pharmaceutical solution according to  claim 1 , and at least one anti-tumor drug, and optionally one or more pharmaceutically acceptable excipients. 
     
     
         13 . The medicament for combinational administration according to  claim 12 , wherein the anti-tumor drug includes antimetabolites, phytogenic anti-tumor drugs, tumor antibiotics, alkylating agents, platinum preparations, monoclonal antibody anti-tumor drugs, or mixtures thereof. 
     
     
         14 . The medicament for combinational administration according to  claim 13 , wherein the antimetabolites include 5-fluorouracil, gemcitabine, floxuridine, pemetrexed, raltitrexed, fludarabine, cytarabine, or mixtures thereof; the tumor antibiotics include mitomycin, epirubicin, peplomycin, daunorubicin, adriamycin, pirarubicin, aclarubicin, or mixtures thereof; the platinum preparations include cisplatin, oxaliplatin, carboplatin, nedaplatin, or mixtures thereof; the phytogenic anti-tumor drugs include paclitaxel, paclitaxel liposomes, paclitaxel albumin, docetaxel, etoposide, hydroxycamptothecin, or mixtures thereof; the alkylating agents include thiotepa, carmustine, nimustine, fotemustine, estramustine, cyclophosphamide, myleran, or mixtures thereof; the monoclonal antibody anti-tumor drugs include bevacizumab, cetuximab, trastuzumab, panitumumab, nimotuzumab, recombinant human endostatin, or mixtures thereof. 
     
     
         15 . An anti-tumor pharmaceutical composition, wherein the pharmaceutical composition comprises the pharmaceutical solution according to  claim 1 , at least one anti-tumor drug, and optionally one or more pharmaceutically excipients. 
     
     
         16 . The pharmaceutical composition according to  claim 15 , wherein the anti-tumor drug includes antimetabolites, phytogenic anti-tumor drugs, tumor antibiotics, alkylating agents, platinum preparations, monoclonal antibody anti-tumor drugs, or mixtures thereof. 
     
     
         17 . The pharmaceutical composition according to  claim 16 , wherein the antimetabolites include 5-fluorouracil, gemcitabine, floxuridine, pemetrexed, raltitrexed, fludarabine, cytarabine, or mixtures thereof; the tumor antibiotics include mitomycin, epirubicin, peplomycin, daunorubicin, adriamycin, pirarubicin, aclarubicin, or mixtures thereof; the platinum preparations include cisplatin, oxaliplatin, carboplatin, nedaplatin, or mixtures thereof; the phytogenic anti-tumor drugs include paclitaxel, paclitaxel liposomes, paclitaxel albumin, docetaxel, etoposide, hydroxycamptothecin, or mixtures thereof; the alkylating agents include thiotepa, carmustine, nimustine, fotemustine, estramustine, cyclophosphamide, myleran, or mixtures thereof; the monoclonal antibody anti-tumor drugs include bevacizumab, cetuximab, trastuzumab, panitumumab, nimotuzumab, recombinant human endostatin, or mixtures thereof. 
     
     
         18 . A method for treating tumors, comprising administering a therapeutically effective amount of the pharmaceutical solution according to  claim 1 , to a mammal having a tumor. 
     
     
         19 . The method according to  claim 18 , wherein the pharmaceutical solution is administered by perfusion and lavage, hyperthermic perfusion and lavage, intravenous injection, intra-arterial injection, topical intrathecal injection, or intratumoral and peritumoral injection. 
     
     
         20 . The method according to  claim 18 , wherein the pharmaceutical solution is a solution for lavage and perfusion, a solution for injection, a solution for suspension, an solution for emulsion, or a solution for embolization. 
     
     
         21 . The method according to  claim 20 , wherein the administration by perfusion and lavage or by hyperthermic perfusion and lavage is performed by perfusing and lavaging thoracic cavity, peritoneal cavity, pelvic cavity, bladder cavity, buccal cavity, nasal cavity, enteric cavity, uterine cavity, or skin of the mammal having a tumor, with a solution for lavage and perfusion. 
     
     
         22 . The method according to  claim 21 , wherein in the administration by hyperthermic perfusion and lavage, the temperature of the solution for lavage and perfusion is 40° C. to 48±1° C. 
     
     
         23 . The method according to  claim 21 , wherein in the administration by perfusion and lavage or by hyperthermic perfusion and lavage, the dose of a solution for lavage and perfusion is 5 to 6,000 ml/administration. 
     
     
         24 . The method according to  claim 20 , wherein in the administration by intravenous injection, intra-arterial injection, intrathecal injection, or intratumoral and peritumoral injection, the dose of a solution for injection is 1 ml/kg to 20 ml/kg. 
     
     
         25 . The method according to  claim 18 , wherein the tumor is selected from 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, and complications and recurrence of various malignant tumors, such as thoracic, peritoneal and/or pelvic cavity metastasis and implantation of tumor cells, and malignant effusion in thoracic, peritoneal and/or pelvic cavity. 
     
     
         26 . The method according to  claim 25 , wherein the lung cancer includes small cell lung cancer (SCLC) and non-small cell lung cancer; the colorectal cancer includes early stage colorectal cancer and advanced stage colorectal cancer; the primary liver cancer includes a hepatic cell type, a hepatic duct cell type, and a mixed type; the esophageal cancer includes adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, and small cell carcinoma; the gastric cancer and cardiac cancer include adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, small cell carcinoma, and malignant gastrointestinal stromal tumor; the pancreatic cancer includes ductal cell carcinoma and osteoclast-like giant cell carcinoma; the renal cell carcinoma includes clear cell carcinoma and papillary renal cell carcinoma; the bladder cancer includes urothelial carcinoma, squamous cell carcinoma, and adenocarcinoma; the prostate cancer includes adenocarcinoma, ductal adenocarcinoma, urothelial carcinoma, and squamous cell carcinoma; the head and neck cancer includes squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinoma; the nasopharyngeal carcinoma includes squamous cell carcinoma and adenocarcinoma; the cervical cancer includes squamous cell carcinoma, adenocarcinoma, and sarcoma; the ovarian cancer includes ovarian epithelial cancer, germ cell tumors, and ovarian sex cord-stromal tumors; the breast cancer includes epithelial tumors, mesenchymal tumors, and myoepitheliomas; the brain tumors include primary brain tumors and brain tumor metastases; the bone and joint sarcomas includes chondrosarcoma, osteosarcoma, Ewing's sarcoma, and soft tissue sarcoma; the thyroid cancer includes papillary carcinoma, follicular carcinoma, and medullary carcinoma; the skin cancer includes basal cell carcinoma and squamous cell carcinoma; the malignant melanoma includes superficial diffusive melanoma, nodular melanoma, and acral-lentiginous melanoma; the malignant lymphomas include Hodgkin's lymphoma and non-Hodgkin's lymphoma; and the leukemia includes acute leukemia and chronic leukemia. 
     
     
         27 . The method according to  claim 18 , wherein the mammal is selected from a rodent and a human.