WO2019101040A1 - 含有双环铂的组合产品、其制备方法及其用途 - Google Patents

含有双环铂的组合产品、其制备方法及其用途 Download PDF

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WO2019101040A1
WO2019101040A1 PCT/CN2018/116213 CN2018116213W WO2019101040A1 WO 2019101040 A1 WO2019101040 A1 WO 2019101040A1 CN 2018116213 W CN2018116213 W CN 2018116213W WO 2019101040 A1 WO2019101040 A1 WO 2019101040A1
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patient
acid
cancer
bicycloplatinum
pain
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PCT/CN2018/116213
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English (en)
French (fr)
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刘晓忠
李雄
靳奇峰
郑和校
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湖南湘源美东医药科技有限公司
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Priority to JP2020545427A priority Critical patent/JP7356438B2/ja
Priority to AU2018372753A priority patent/AU2018372753B2/en
Priority to CN201880074343.9A priority patent/CN111356454B/zh
Priority to EP18880461.1A priority patent/EP3714881A4/en
Priority to RU2020116704A priority patent/RU2784809C2/ru
Priority to US16/765,024 priority patent/US20200361973A1/en
Priority to CA3082295A priority patent/CA3082295A1/en
Priority to MX2020005310A priority patent/MX2020005310A/es
Priority to KR1020207015518A priority patent/KR20200090170A/ko
Publication of WO2019101040A1 publication Critical patent/WO2019101040A1/zh
Priority to IL274785A priority patent/IL274785A/en

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    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
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    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
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    • C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
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    • C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
    • C07C65/05—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring o-Hydroxy carboxylic acids
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Definitions

  • the present invention relates to a combination product comprising bicycloplatinum for use in the treatment and/or prevention of pain, inflammation and diseases associated with viral infection, and a process for the preparation of said combination product.
  • Bicycloplatinum is a eutectic compound formed by the bonding of carboplatin (CBP) and 1,1-cyclobutane (CBDCA) by hydrogen bonding.
  • CBP carboplatin
  • CBDCA 1,1-cyclobutane
  • bicycloplatinum has the characteristics of broad spectrum, high efficiency, low toxicity, low drug resistance, low cross-resistance and good penetrability.
  • Chinese patent application CN00124864.2 shows that bicyclo platinum has significant effects on head and neck cancer, nasopharyngeal cancer, breast cancer, lung cancer, liver cancer, pancreatic cancer, stomach cancer, intestinal cancer, lymphoma and the like. At the same time, it has a good effect on various indications such as benign prostatic hyperplasia, prostatic inflammation and rheumatoid arthritis (PCT/US2016/028720).
  • Persistent and breakthrough pain is a top concern for cancer patients. More than half of cancer patients experience severe, uncontrollable pain during the course of their illness, and pain management is a major challenge for cancer patients and oncologists (List MA, Stracks J, Colangelo L, et al. J. Clin. Oncol (2000) 18: 877–84 2.). Although cancer pain is a complex pathological process and a strong clinical problem, significant advances have been made in understanding the underlying neural mechanisms that cause cancer pain. Symptoms experienced by cancer patients are the result of cellular, tissue, and systemic changes that occur during proliferation, invasion, and metastasis. The immune system also has a significant effect on cancer pain. Cancer cells produce mediators that affect other cells in the cancer microenvironment, such as immune cells.
  • tumors growing near the peripheral nerves can compromise the integrity of the nerves, inducing conditions associated with persistent pain, hyperalgesia, or pain.
  • the effects of these two tumors on peripheral nerves may lead to central sensitization, which further enhances the nociceptive conduction of the spinal dorsal horn and the feeling of spontaneous breakthrough pain (Hamamoto DT, Khasabov SG, Cain DM, Simone DA.J Neurophysiol ( 2008) 100: 2300–11, Sabino MA, Luger NM, Mach DB, Rogers SD, Schwei MJ, Mantyh PW. Int. J. Cancer (2003) 104: 550-558).
  • a combination product comprising bicycloplatinum and an acidic material.
  • the acidic substance is selected from one or more of the following: 1,1-cyclobutanedicarboxylic acid, citric acid, chlorogenic acid, ferulic acid, maleic acid, salicylic acid, folic acid And gallic acid.
  • the ratio of the bicycloplatinum to the acidic substance is 1:0.01 to 1:99.
  • the combination product optionally comprises one or more additional additional components: coenzyme Q10, curcumin, glutathione, oryzanol, citric acid, vitamin C, and anthocyanin.
  • the combination product may be present in the form of a composition or a pharmaceutical composition or the bicycloplatinum, the acidic substance or the additional additional component in the combined product may each be present in a separate formulation.
  • a combination product comprising bicycloplatinum and one or more additional additional components: coenzyme Q10, curcumin, glutathione, oryzanol, citric acid, Vitamin C and anthocyanins.
  • the pain is selected from pain caused by cancer or other causes of non-cancer (eg, hepatitis B, hepatitis C, or rheumatoid arthritis) selected from cancer or other causes of cancer (eg, Inflammation caused by rheumatoid arthritis, the disease associated with viral infection is selected from diseases associated with hepatitis B virus, hepatitis C virus, Ebola virus or human immunodeficiency virus infection.
  • non-cancer eg, hepatitis B, hepatitis C, or rheumatoid arthritis
  • cancer or other causes of cancer eg, Inflammation caused by rheumatoid arthritis
  • the disease associated with viral infection is selected from diseases associated with hepatitis B virus, hepatitis C virus, Ebola virus or human immunodeficiency virus infection.
  • a method of treating and/or preventing pain, inflammation and a disease associated with a viral infection comprising using a combination product as described above for a patient in need thereof.
  • the pain is selected from pain caused by cancer or other causes of non-cancer (eg, hepatitis B, hepatitis C, or rheumatoid arthritis) selected from cancer or other causes of cancer (eg, Inflammation caused by rheumatoid arthritis, and the disease associated with viral infection is selected from diseases associated with hepatitis B virus, hepatitis C virus, Ebola virus or human immunodeficiency virus infection.
  • non-cancer eg, hepatitis B, hepatitis C, or rheumatoid arthritis
  • cancer or other causes of cancer eg, Inflammation caused by rheumatoid arthritis
  • the disease associated with viral infection is selected from diseases associated with hepatitis B virus, hepatitis C virus, Ebola virus or
  • the dose of bicycloplatin in the combination product is from 0.01 to 10 mg/kg of patient body weight, preferably from 0.01 to 5 mg/kg of patient body weight.
  • the combination product can be administered by oral, buccal, inhalation spray, sublingual, rectal, transdermal, vaginal mucosa, transmucosal, topical, nasal or enteral administration;
  • intramuscular injection, subcutaneous injection, intramedullary injection, as well as intrathecal direct administration of the brain, in situ administration, subcutaneous, intraperitoneal, intravenous, intra-articular synovium, sternum, internal, intrahepatic, intralesional, cranial Internal, intraperitoneal, nasal, or intraocular injection or other drug delivery methods.
  • the combination product may be present in the form of a composition or a pharmaceutical composition, or the bicycloplatinum, the acidic substance or the additional other component in the combined product may each be present in a separate formulation form, It can be administered simultaneously, continuously or at intervals.
  • the time interval includes, but is not limited to, an integer value in 1 to 24 hours, such as 1 hour, 2 hours, or 3 hours, etc.; an integer value in 1 to 30 days, such as 1 day, 2 days, or 3 days.
  • a process for the preparation of a combination product comprising: 1) adding bicycloplatin as the active substance or as the sole active substance; 2) optionally adding an acidic substance to form a mixture, wherein the bicyclic ring
  • the ratio of platinum to the acidic substance is: 1:0.01 to 1:99, preferably 1:3 to 1:10, and the acid is selected from one or more of the following: 1,1-cyclobutane Alkanedicarboxylic acid, citric acid, chlorogenic acid, ferulic acid, maleic acid, salicylic acid, folic acid, and gallic acid; and 3) optionally adding one or more additional groups selected from the group consisting of Points: Coenzyme Q10, curcumin, glutathione (GSH), oryzanol, citric acid, vitamin C and anthocyanins.
  • a process for the preparation of a bicyclic platinum or a combination of bicycloplatinum and 1,1-cyclobutanedicarboxylic acid comprising: 1) in a suitable solvent, at room temperature or Under heating, the carboplatin and the 1,1-cyclobutanedicarboxylic acid are stirred at a molar ratio of 1:1.05 to 1:99 for a suitable amount of time to obtain a mixture of bicycloplatinum containing 1,1-cyclobutanedicarboxylic acid.
  • the resulting mixture is directly lyophilized, concentrated, and then completely dissolved by adding an appropriate amount of water, lyophilized, or formulated into a desired aqueous solution to obtain a mixture containing bicycloplatinum and 1,1-cyclobutanedicarboxylic acid. combination.
  • bicyclic platinum as the sole active substance for the treatment and/or prevention of pain or inflammation, the pain being caused by cancer or other causes (eg by Pain caused by hepatitis B virus, hepatitis C virus or rheumatoid arthritis, and the inflammation is inflammation caused by cancer or other causes of non-cancer (for example, rheumatoid arthritis).
  • a combination product as described above for use in the treatment and/or prevention of pain, inflammation and diseases associated with viral infection is provided.
  • composition of bicycloplatin as the sole active substance and a method of preparing the mixture, the method comprising: adding bicycloplatin as the sole active substance.
  • a ninth aspect of the invention there is provided the use of bicyclic platinum as the sole active substance for the preparation of a medicament for the treatment and/or prevention of pain or inflammation.
  • the pain is pain caused by cancer or pain caused by other causes other than cancer
  • the inflammation is inflammation caused by cancer or other causes of non-cancer (for example, rheumatoid arthritis) .
  • a composition comprising bicycloplatin as the sole active substance for the treatment and/or prevention of pain or inflammation.
  • the pain is pain caused by cancer, or pain caused by other causes other than cancer (for example, hepatitis B, hepatitis C or rheumatoid arthritis), and the inflammation is inflammation caused by cancer Or inflammation caused by other causes of cancer (eg, rheumatoid arthritis).
  • Figure 1 shows the effect of bicycloplatin or ribavirin administered alone on hepatitis C virus (HCV).
  • FIG. 2 shows the effect of bicycloplatin alone on hepatitis B virus (HBV).
  • FIG. 3 shows the effect of bicycloplatin or zidovudine alone on HIV.
  • FIG. 4 shows the effect of administration of bicycloplatinum Ebola virus alone.
  • Figure 5 shows the effect of AA011 and VK021 and positive drugs on the virus.
  • Figure 6 shows the antiviral effect of the combination of MD36792 and AA011 (A in Figure 6) and VK021 (V in Figure 6).
  • Figure 7 shows the effect of MD36792 on analgesia.
  • subject is meant to include both humans and animals (eg, dogs, cats, rabbits, chickens, monkeys, etc.).
  • the term "dosage” refers to the weight (eg, milligrams (mg)) of active substance per kilogram (kg) of the subject's body weight.
  • ratio generally refers to a molar ratio.
  • the ratio (molar ratio) of the bicyclic platinum to the acidic substance is 1:0.01 to 1:99.
  • the bicyclic platinum content ratio % means weight percentage.
  • the term "disease associated with a viral infection” refers to a disease caused by a viral infection or a disease associated with a viral infection.
  • the viral infection includes, but is not limited to, a hepatitis virus (eg, hepatitis A virus, hepatitis B virus, hepatitis C virus), Ebola virus, or human immunodeficiency virus infection.
  • pain refers to pain caused by a tumor (eg, cancer), or pain caused by other causes (eg, hepatitis B, hepatitis C, or rheumatoid arthritis).
  • MD36792, AA011, and VK021 refer to bicyclic platinum, glutathione, and vitamin C, respectively.
  • room temperature refers to 25 °C ⁇ 1 °C. At the same time, if the experimental temperature is not specified, it is room temperature.
  • the term "about” refers to ⁇ 10% of the value modified by the term, more preferably ⁇ 5%, and most preferably ⁇ 2%, so that one of ordinary skill in the art can clearly modify The numerical value determines the scope of the term "about.”
  • the bicyclic platinum claimed herein as a main active substance exhibits a remarkable therapeutic effect in the treatment and/or prevention of pain, particularly pain caused by cancer patients.
  • cancer patients especially those with advanced liver cancer, kidney cancer patients, bone metastasis patients and bone cancer patients
  • the single choice of bicycloplatin injection or oral preparation is the only treatment.
  • the inventors found that a certain number of patients with advanced cancer showed no sensitivity to bicycloplatin and no effect on tumor suppression.
  • the effect of bicyclo platinum on cancer pain is still obvious, and even the pain disappears.
  • bicycloplatin has been shown to have a good effect on tumor-induced tissue edema and inflammation.
  • oral or injection of bicycloplatin was found.
  • tissue edema caused by cancer metastasis was substantially eliminated. This indicates that bicycloplatinum has a good anti-inflammatory effect on inflammation.
  • Hepatic tissue edema occurred in many patients with liver cancer, and tissue edema was significantly eliminated or reduced after a period of perfusion or oral administration with bicycloplatin.
  • a combination product comprising bicycloplatinum and an acidic material, or consisting of bicyclic platinum and an acidic material.
  • the acidic substance is selected from one or more of the following: 1,1-cyclobutanedicarboxylic acid, citric acid, chlorogenic acid, ferulic acid, maleic acid, salicylic acid, folic acid And gallic acid.
  • the ratio of the bicycloplatinum to the acidic substance is from about 1:0.01 to about 1:99, preferably about 1:1, about 1:1.08, about 1:2, about 1:3, about 1 :4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:20, about 1:30, about 1:40, about 1 : 50, about 1:60, about 1:70, about 1:80, about 1:90, and a range of ratios between the various ratios, including but not limited to: about 1:1 to about 1:2, about 1.08 Up to about 1:2, about 1:3 to about 1:10, and so on.
  • the combination product comprises one or more of the other additional components described below: Coenzyme Q10, curcumin, glutathione, oryzanol, citric acid, vitamin C, and anthocyanin.
  • the ratio of the bicycloplatinum to the additional other component is from about 0.1:1 to about 100:1, preferably about 0.1:1, about 0.2:1, about 0.3:1, about 0.4:1.
  • the ratio of bicycloplatinum to the additional other components is from about 0.1:1 to 10:1.
  • the ratio of bicycloplatinum:vitamin C is about 0.43:1
  • the ratio of bicycloplatinum:glutathione is about 1:1.25
  • the ratio of bicycloplatinum:coenzyme Q10 is about 1.02:1.
  • the percentage of the bicyclic platinum to the combined product is about 5%, about 10%, about 15%, about 16.64%, about 18.29%, about 19.11%, about 19.87%, about 20%, by weight. 25%, about 30%, about 35%, about 40%, about 44.46%, about 45%, about 50%, about 55%, about 60%, about 60.5%, about 65%, about 70%, about 75% , about 80%, about 85%, about 90%, about 95%, about 96.2%, about 99%, and ranges between the respective percentages, including but not limited to: about 5% to 99%, 16.64% to 60.5 %, about 18.29% to 44.46%, about 19.11% to about 35%.
  • the combination product may be present in the form of a composition or a pharmaceutical composition or the bicycloplatinum, the acidic substance or the additional additional component in the combined product may each be present in a separate formulation.
  • the combination product is an oral preparation such as a capsule, a tablet, a granule; a lyophilized preparation or an aqueous injection; an atomizing agent; or other preparation forms.
  • a combination product comprising bicycloplatinum and one or more additional additional components: coenzyme Q10, curcumin, glutathione, oryzanol, citric acid , vitamin C and anthocyanins.
  • the combined product optionally contains an acidic substance selected from one or more of the following: 1,1-cyclobutanedicarboxylic acid, citric acid, chlorogenic acid, awei Acid, maleic acid, salicylic acid, folic acid and gallic acid.
  • the ratio of the bicyclic platinum to the acidic substance is 1:0.01 to 1:99, preferably about 1:1, about 1:1.08, about 1:2, about 1:3, about 1: 4.
  • the ratio of the bicycloplatinum to the additional other component is from about 0.1:1 to about 100:1, preferably about 0.1:1, about 0.2:1, about 0.3:1, about 0.4:1.
  • the ratio of bicycloplatinum to the additional other components is from about 0.1:1 to 10:1.
  • the ratio of bicycloplatinum:vitamin C is about 0.43:1
  • the ratio of bicycloplatinum:glutathione is about 1:1.25
  • the ratio of bicycloplatinum:coenzyme Q10 is about 1.02:1.
  • the percentage of the bicyclic platinum to the combined product is about 5%, about 10%, about 15%, about 16.64%, about 18.29%, about 19.11%, about 19.87%, about 20%, by weight. 25%, about 30%, about 35%, about 40%, about 44.46%, about 45%, about 50%, about 55%, about 60%, about 60.5%, about 65%, about 70%, about 75% , about 80%, about 85%, about 90%, about 95%, about 96.2%, about 99%, and ranges between the respective percentages, including but not limited to: about 5% to 99%, 16.64% to 60.5 %, about 18.29% to 44.46%, about 19.11% to about 35%.
  • the combination product is an oral preparation such as a capsule, a tablet, a granule; a lyophilized preparation or an aqueous injection; an atomizing agent; or other preparation forms.
  • the pain is selected from pain caused by cancer or other causes of non-cancer (eg, hepatitis B, hepatitis C, or rheumatoid arthritis) selected from cancer or other causes of cancer (eg, Inflammation caused by rheumatoid arthritis, the disease associated with viral infection is selected from diseases associated with hepatitis B virus, hepatitis C virus, Ebola virus or human immunodeficiency virus infection.
  • non-cancer eg, hepatitis B, hepatitis C, or rheumatoid arthritis
  • cancer or other causes of cancer eg, Inflammation caused by rheumatoid arthritis
  • the disease associated with viral infection is selected from diseases associated with hepatitis B virus, hepatitis C virus, Ebola virus or human immunodeficiency virus infection.
  • a method of treating and/or preventing pain, inflammation and a disease associated with a viral infection comprising using a bicyclic platinum, such as the combination described above, for a patient in need thereof.
  • the pain is selected from pain caused by cancer or other causes of non-cancer (eg, hepatitis B, hepatitis C, or rheumatoid arthritis) selected from cancer or other causes of cancer (eg, The inflammation caused by rheumatoid arthritis and the disease associated with viral infection are selected from diseases associated with hepatitis B virus, hepatitis C virus, Ebola virus or human immunodeficiency virus infection.
  • the dose of bicycloplatin in the combination product is 0.01 to 10 mg/kg of patient body weight, preferably 0.01 to 5 mg/kg of patient body weight, 0.1 to 5 mg/kg of patient body weight, and 1 to 5 mg/kg of patient body weight.
  • the combination product can be administered by oral, buccal, inhalation spray, sublingual, rectal, transdermal, vaginal mucosa, transmucosal, topical, nasal or enteral administration;
  • intramuscular injection subcutaneous injection, intramedullary injection, as well as intrathecal, direct administration of the brain, in situ administration, subcutaneous, intraperitoneal, intravenous, intra-articular synovium, sternum, internal, intrahepatic, intralesional, cranial Internal, intraperitoneal, nasal, or intraocular injection or other drug delivery methods.
  • the combination product may be present in the form of a composition or a pharmaceutical composition, or the bicycloplatinum, optionally the acidic species or optionally the additional additional components in the combination product are each Separate formulations are present which can be administered simultaneously, continuously or at intervals.
  • the time interval includes, but is not limited to, an integer value in 1 to 24 hours, such as 1 hour, 2 hours, or 3 hours, etc.; an integer value in 1 to 30 days, such as 1 day, 2 days, or 3 days.
  • a process for the preparation of a combination product comprising: 1) adding bicycloplatin as the active substance or as the sole active substance; 2) optionally adding an acidic substance to form a mixture, wherein the bicyclic ring
  • the ratio of platinum to the acidic substance is: 1:0.01 to 1:99, preferably about 1:1, about 1:1.08, about 1:2, about 1:3, about 1:4, about 1:5, About 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:20, about 1:30, about 1:40, about 1:50, about 1:60, A ratio range between about 1:70, about 1:80, about 1:90, and the ratios, including but not limited to: about 1:1 to about 1:2, about 1.08 to about 1:2, about 1 : 3 to about 1:10, and the acid is selected from one or more of the group consisting of: 1,1-cyclobutanedicarboxylic acid, citric acid, chlorogenic acid, ferul
  • bicycloplatinum and the other additional components (coenzyme Q10, curcumin, glutathione, oryzanol, citric acid, vitamin C, and cyanine)
  • the ratio of:) is from about 0.1:1 to 10:1, from about 0.4:1 to about 8:1, from about 0.43:1 to about 5:1, from about 0.43:1 to about 1:1.25, about 0.43:1 to About 1:1.02; more preferably, the ratio of bicycloplatinum:vitamin C is about 0.43:1, the ratio of bicycloplatinum:glutathione is about 1:1.25, and the ratio of bicycloplatinum:coenzyme Q10 is about 1.02:1) .
  • a solution combination of bicycloplatinum with 1,1-cyclobutanedicarboxylic acid (1:1.2 to 1:20) was stable at 40 ° C for seven consecutive weeks.
  • the above acidic substance herein is 1,1-cyclobutanedicarboxylic acid, preferably wherein the ratio of bicycloplatinum to 1,1-cyclobutanedicarboxylic acid is from 1:1.2 to 1:20.
  • a process for the preparation of a bicyclic platinum or a combination of bicycloplatinum and 1,1-cyclobutanedicarboxylic acid comprising: 1) in a suitable solvent, preferably water , at room temperature or heating (preferably, 40 ° C), the molar ratio of carboplatin to 1,1-cyclobutanedicarboxylic acid in the range of 1:1.05 to 1:99 (for example, 1:1.2, 1:1.5, 1 : 3, 1:5, 1:10, 1:20 and any ratio between the ratios thereof, including but not limited to 1:1.2 to 1:20, or the ratio can be used according to specific actual needs, for example Mixing the above bicycloplatinum with the ratio described in the acidic substance) and stirring for a suitable amount of time, for example, 0.5 to 24 hours (preferably, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7) Hours, 8 hours, 9 hours, 10 hours, 11 hours
  • the present invention has many advantages over the methods reported in the prior art.
  • the method of the present invention is simple in operation, and greatly improves the yield of bicycloplatin, so that the raw material of carboplatin can be completely used.
  • the resulting lyophilized mixture was composed of bicycloplatinum and 1,1-cyclobutanedicarboxylic acid, and no carboplatin residue was observed.
  • bicycloplatin as an active substance or a sole active substance for the treatment and/or prevention of pain or inflammation
  • the pain caused by cancer or other causes Pain caused by (for example, hepatitis B, hepatitis C or rheumatoid arthritis)
  • the inflammation is inflammation caused by cancer or other causes of non-cancer (for example, rheumatoid arthritis).
  • a method for treating and/or preventing pain selected from pain caused by cancer or other causes of non-cancer eg, hepatitis B, hepatitis C or rheumatoid arthritis
  • Inflammation the inflammation is selected from inflammation caused by cancer or other causes other than cancer (for example, rheumatoid arthritis)
  • diseases associated with viral infections the diseases associated with viral infections are selected from hepatitis B virus
  • the acidic substance is selected from one or more of the following: 1,1-cyclobutanedicarboxylic acid, citric acid, chlorogenic acid, ferulic acid, maleic acid, salicylic acid, folic acid And gallic acid.
  • the combination product comprises one or more of the other additional components coenzyme Q10, curcumin, glutathione, oryzanol, citric acid, vitamin C and anthocyanin.
  • the combination product contains bicycloplatinum and one or more of the other additional components described below: Coenzyme Q10, curcumin, glutathione, oryzanol, citric acid, vitamin C and anthocyanins.
  • the combined product optionally contains an acidic substance selected from one or more of the following: 1,1-cyclobutanedicarboxylic acid, citric acid, chlorogenic acid, awei Acid, maleic acid, salicylic acid, folic acid and gallic acid.
  • the ratio of the bicycloplatinum to the acidic substance is from about 1:0.01 to about 1:99, preferably about 1:1, about 1:1.08, about 1:2, about 1:3, about 1 :4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:20, about 1:30, about 1:40, about 1 : 50, about 1:60, about 1:70, about 1:80, about 1:90, and a range of ratios between the various ratios, including but not limited to: about 1:1 to about 1:2, about 1.08 Up to about 1:2, about 1:3 to about 1:10, and so on.
  • the ratio of the bicycloplatinum to the additional other component is from about 0.1:1 to about 100:1, preferably about 0.1:1, about 0.2:1, about 0.3:1, about 0.4:1. , about 0.43:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 1:1, about 1:1.25, about 1.02:1, about 2:1 , about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1 , about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, and a range of ratios between the various ratios, including but not limited to: about 0.1:1 Up to 10:1, about 0.4:1 to about 8:1, about 0.43:1 to about 5:1, about 0.43:1 to about 1:1.25, about 0.43:1 to about 1:1.02, and the like.
  • the ratio of bicycloplatinum to the other additional components is about 0.1:1.
  • the ratio of bicycloplatinum:vitamin C is about 0.43:1, the ratio of bicycloplatinum:glutathione is about 1:1.25, and the ratio of bicycloplatinum:coenzyme Q10 is about 1.02:1.
  • the combination product may be present in the form of a composition or a pharmaceutical composition or the bicycloplatinum, the acidic substance or the additional additional component in the combined product may each be present in a separate formulation.
  • composition of bicycloplatin as the sole active substance comprising an excipient selected from the group consisting of magnesium stearate, hydroxypropyl cellulose, pregelatinized starch, chitosan , ⁇ -cyclodextrin, polyvinylpyrrolidone, and a process for preparing the mixture, the method comprising: adding bicycloplatin as the sole active material and optionally the excipient.
  • a ninth aspect of the invention there is provided the use of bicycloplatin as an active substance or a sole active substance for the preparation of a medicament for the treatment and/or prevention of pain or inflammation.
  • the pain is pain caused by cancer, or pain caused by other causes other than cancer (for example, hepatitis B, hepatitis C or rheumatoid arthritis), and the inflammation is inflammation caused by cancer Or inflammation caused by other causes of cancer (eg, rheumatoid arthritis).
  • a composition comprising bicycloplatin as an active substance or a sole active substance for the treatment and/or prevention of pain or inflammation.
  • the pain is pain caused by cancer, or pain caused by other causes other than cancer (for example, hepatitis B, hepatitis C or rheumatoid arthritis), and the inflammation is inflammation caused by cancer Or inflammation caused by other causes of cancer (eg, rheumatoid arthritis).
  • a method of treating and/or preventing pain comprising administering to a patient in need thereof an effective amount of bicycloplatinum.
  • the patient is a cancer patient, preferably a liver cancer patient, a renal cancer patient, a bone metastasis patient, a brain metastasis or a bone cancer patient, more preferably a late cancer patient or a patient who has developed resistance to a platinum anticancer drug. Most preferred is a patient with advanced liver cancer.
  • the effective dose of the bicyclic platinum may be lower than the effective anticancer dose of bicycloplatin in the cancer patient, or in some embodiments, the effective dose of the bicycloplatin may be equal to the effective antibiotic in the cancer patient.
  • the cancer dose for example, the cancer patient can use bicycloplatin as the sole drug to treat cancer and pain.
  • the bicyclic platinum may be the only active substance for treating and/or preventing pain.
  • the method further comprises administering to the patient one or more other active substances having an analgesic effect.
  • the method further comprises administering to the patient one or more active substances having an anti-cancer effect, wherein the active substance having an anti-cancer effect is preferably a non-platinum anticancer drug.
  • the bicyclic platinum is present in the form of a pharmaceutical composition. Further, wherein the bicyclic platinum is present in the combination product defined herein above.
  • the effective dose of bicycloplatin for the treatment and/or prevention of pain can be lower than the effective anticancer dose and has an analgesic effect in cancer patients who are resistant to platinum drugs.
  • the method and use of bicycloplatin for the treatment and/or prevention of pain is not limited to cancer patients, and bicycloplatin exhibits a significant analgesic effect comparable to the positive control drug, rotonidine, in the pain animal model experiments shown herein.
  • bicycloplatinum may have an analgesic effect on pain caused by cancer or non-cancer including, but not limited to, hepatitis B, hepatitis C, and rheumatoid arthritis.
  • the patient in the above methods and uses of treating and/or preventing pain, is not a cancer patient. In some embodiments, in the above methods and uses for treating and/or preventing pain, the patient is a cancer patient who has developed resistance to a platinum anticancer drug.
  • a method of treating and/or preventing tissue edema e.g., hepatic edema, brain edema, etc.
  • the method comprising administering to a patient in need thereof an effective amount of bicycloplatinum.
  • the patient is a cancer patient, preferably a liver cancer patient, a renal cancer patient, a bone metastasis patient, a brain metastasis or a bone cancer patient, more preferably a cancer advanced patient, most preferably a late liver cancer patient or a platinum anticancer drug.
  • a patient who has developed resistance preferably a liver cancer patient, a renal cancer patient, a bone metastasis patient, a brain metastasis or a bone cancer patient, more preferably a cancer advanced patient, most preferably a late liver cancer patient or a platinum anticancer drug.
  • the effective dose of the bicyclic platinum may be lower than the effective anticancer dose of bicycloplatin in the cancer patient, or in some embodiments, the effective dose of the bicycloplatin may be equal to the effective antibiotic in the cancer patient. Cancer dose. Further, it is further included that the patient is administered one or more active substances having an anticancer effect, wherein the active substance having an anticancer effect is preferably a non-platinum anticancer drug. Further, the patient is not a cancer patient. Further, the bicyclic platinum is present in the form of a pharmaceutical composition. Further, the bicyclic platinum is present in the combination product defined herein above.
  • a method of treating and/or preventing a disease associated with a viral infection such as a method of reducing a viral index in a patient, the method comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition, wherein the pharmaceutical composition comprises bicycloplatinum and glutathione.
  • the viral infection is hepatitis B virus, hepatitis C virus, Ebola virus, and/or human immunodeficiency virus infection.
  • the viral infection is a hepatitis B virus infection.
  • the viral infection is a hepatitis C virus infection.
  • the viral infection is an Ebola virus infection.
  • the viral infection is a human immunodeficiency virus infection.
  • it is included to administer an effective amount of the pharmaceutical composition to the patient 1-3 times a day. Further, comprising administering to the patient an effective amount of the pharmaceutical composition for at least 7 days, preferably from 1 month to 1 year, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 11, 12, 12 months, preferably, 1 month to 6 months, for example, 1, 2, 3, 4, 5, 6 months.
  • the patient does not receive any other antiviral medication, and/or does not receive any other antiviral medication. Further, it also includes administering to the patient other antiviral drugs.
  • the pharmaceutical composition optionally comprises one or more additional additional components: coenzyme Q10, curcumin, oryzanol, citric acid, vitamin C, and anthocyanin.
  • the ratio of bicycloplatinum to glutathione is from about 0.1:1 to about 100:1, preferably about 0.1:1, about 0.2:1, about 0.3:1, about 0.4:1, about 0.43:1 , about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 1:1, about 1:1.25, about 1.02:1, about 2:1, about 3:1 , about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1 , about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, and a range of ratios between the various ratios, including but not limited to: about 0.1:1 to 10:1.
  • bicycloplatin and glutathione are present in the same drug combination species in the treatment of a viral infection-associated disease.
  • the bicyclic platinum and glutathione may each be present in separate formulations, which may be administered simultaneously, continuously or at intervals.
  • the bicycloplatinum or pharmaceutical composition may be in the form of an oral preparation such as a capsule, a tablet, a granule; Dry preparation or water injection; atomizing agent; or other preparation form.
  • the bicycloplatinum or pharmaceutical composition can be administered by oral, buccal, inhalation spray, sublingual, rectal , transdermal, vaginal mucosa, transmucosal, topical, nasal or intestinal administration; injection, such as intramuscular, subcutaneous, intramedullary, and intrathecal, direct administration, in situ administration , subcutaneous, intraperitoneal, intravenous, intra-articular synovium, sternum, intrahepatic, intralesional, intracranial, intra-abdominal, nasal, or intraocular injection or other drug delivery methods.
  • the bicyclic platinum or pharmaceutical composition can be administered by oral or injection administration.
  • Bicyclic platinum as referred to in this embodiment may be commercially available or prepared by the methods described herein, and other compounds or acidic materials and additional components described herein are well known in the art and are commercially available or known in the art. The method of synthesis.
  • Analytical instrument Panalytical Empyrean. X-ray powder diffraction was carried out by mounting a sample of the crystalline material on a pedestal of a low background of Si single crystal and diffusing the sample into a sheet with the aid of a microscope slide. The position of 2-theta (2- ⁇ ) is calibrated by the standard position of the Panalytical 640 silicon powder.
  • the elongated focus copper tube operating at 45 KV and 40 mA produced X-ray radiation having a K ⁇ 1 wavelength of 1.540589 angstroms and a K ⁇ 2 wavelength of 1.544426 angstroms (K ⁇ 2/K ⁇ 1 intensity ratio of 0.50).
  • the collimated X-ray source is passed through a programmable divergence slit set at a length of 10 mm, and the reflected radiation passes through an anti-scatter slit having a length of 5.5 mm.
  • the sample in the range of 3°-40° in 2-theta was exposed in a continuous scanning mode (2-theta was increased at a rate of 16.3 sec / 0.013 °).
  • the running time is 3 minutes and 57 seconds.
  • the instrument is equipped with an RTMS detector. Control and acquire data with the Dell Optiplex 780 XP with data acquisition software.
  • the relative intensity of a peak is affected by factors such as the size of the particles being greater than 30 microns and the aspect ratio heterogeneity of the particles.
  • the position of the reflection is affected by the exact height of the sample in the diffractometer and the zero calibration of the diffractometer.
  • the surface flatness of the sample also has a certain influence. Therefore, the presented diffraction pattern data is not limited to an absolute value.
  • the DSC was used as a thermal analysis method to measure the amount of heat required to warm the sample, while also measuring the reference value as a function of temperature.
  • the general procedure for determining DSC is known, the specific instruments used in the described examples and the conditions employed are as follows:
  • Heating rate 10 ° C per minute
  • Purge gas nitrogen.
  • TGA is used to measure the change in physical and chemical properties of a sample as a function of elevated temperature (at a constant heating rate), or as a function of time (having a constant temperature and/or constant mass loss).
  • Heating rate 10 ° C per minute
  • Purge gas nitrogen.
  • the product was analyzed by XRPD, DSC and 1 H NMR as described above.
  • the product was analyzed by XRPD, DSC and 1 H NMR as described above.
  • Example 3 Preparation of a combination product comprising 1,1-cyclobutanedicarboxylic acid, citric acid and bicycloplatinum
  • citric acid acts as an acidic substance or as another component
  • the product was analyzed by XRPD, DSC and 1 H NMR as described above.
  • Example 4 Preparation of a combination product comprising 1,1-cyclobutanedicarboxylic acid, citric acid, GSH and bicycloplatinum
  • the product was analyzed by XRPD, DSC and 1 H NMR as described above.
  • Example 5 Preparation of a combination product comprising 1,1-cyclobutanedicarboxylic acid, chlorogenic acid, glutathione, vitamin C and bicycloplatin
  • the product was analyzed by XRPD, DSC and 1 H NMR as described above.
  • the product was analyzed by XRPD, DSC and 1 H NMR as described above.
  • the product was analyzed by XRPD, DSC and 1 H NMR as described above.
  • the product was analyzed by XRPD, DSC and 1 H NMR as described above.
  • the product was analyzed by XRPD, DSC and 1 H NMR as described above.
  • Example 10 Preparation of a combination product comprising coenzyme Q10, citric acid, chlorogenic acid, glutathione, vitamin C and bicycloplatinum
  • the product was analyzed by XRPD, DSC and 1 H NMR as described above.
  • the product was analyzed by XRPD, DSC and 1 H NMR as described above.
  • Virus Hepatitis C virus (HCV type 2a JFH1-Luc strain).
  • Experimental reagent DMEM medium, Kit (Invitrogen), Luciferase Assay System Kit (Promega) other experimental reagents.
  • the (Invitrogen) kit detects the toxic effects of drugs on cells. It is a redox indicator that produces absorbance changes and fluorescent signals based on cellular metabolic activity. Soluble in water, its oxidized form enters cells and is reduced by mitochondrial enzymes to produce measurable fluorescence and color changes for quantitative analysis of cell viability and cell proliferation as well as in vitro cytotoxicity studies.
  • This assay is based on the ability of metabolically active cells to convert reagents into fluorescent and colorimetric indicators. Damaged and inactive cells have lower natural metabolic activity, and the corresponding signals are lower, so the fluorescence signal is strong and can reflect the level of cell activity.
  • Huh7.5.1 cells were seeded in a 96-well cell culture plate, and the cells were allowed to adhere after use.
  • the drug was serially diluted with DMSO from a 3-fold gradient of 200-fold initial concentration to 6 gradients, and then diluted into complete drug-containing culture medium in DMEM complete medium, and tested for each concentration gradient. After the drug was cultured for 72 hours, the culture supernatant was discarded and added. The medium was incubated for 4 h at 37 ° C, and fluorescence readings were detected with excitation light 570 nm and emission light 595 nm.
  • the experiment set the ribavirin positive drug control group, the virus control group, and the cell control group.
  • Cells HepAD38 cells.
  • Virus Hepatitis B virus (HBV).
  • Experimental reagents DMEM/F12 medium, CellTiter-Glo detection kit (Promega), HBeAg antigen detection kit (Kehua), HBsAg antigen detection kit (Kehua), and other experimental reagents.
  • the toxic effect of the drug on cells was examined using the CellTiter-Glo kit (Promega).
  • the CellTiter-Glo kit detects the number of viable cells in culture by quantitatively measuring ATP.
  • the respiration of metabolically active cells and other life-live processes can produce ATP.
  • the kit uses a stable glow type generated by luciferase. Signaling, luciferase requires the involvement of ATP during luminescence.
  • An equal volume of CellTiter-Glo reagent was added to the cell culture medium, and the luminescence value was measured.
  • the light signal was proportional to the amount of ATP in the system, and ATP was positively correlated with the number of living cells. Thus the light signal value can reflect the number of living cells.
  • Method step HepAD38 cells were seeded in a 96-well cell culture plate, and the cells were attached to the cells for use.
  • the drug was diluted 9 gradients from 1 mM serially 3 folds with 2 replicate wells per gradient.
  • the drug was added to the cells and cultured in a CO2 incubator at 37 °C. After 3 days of drug administration, the drug-induced cytopathic effect (CPE) was observed under light microscope, and cell survival rate was measured by adding CellTiter-Glo. The toxicity of a drug to a cell is expressed as the activity of the cell.
  • CPE drug-induced cytopathic effect
  • HBeAg can only be expressed from cccDNA, and the expression level of HBeAg can reflect the synthesis amount of cccDNA. Therefore, we used ELISA to detect the content of HBeAg and detect the inhibitory effect of the drug on HBV. In this cell, HBsAg can be continuously translated from the integrated HBV DNA. We also detected the HBsAg content to determine the effect of the drug on HBV replication.
  • antigen inhibition rate (%) 100% - (drug group - blank control) / (cell control group - blank control) * 100%
  • Cells MT4 cells.
  • HIV Human immunodeficiency virus
  • Experimental reagents RPMI-1640 medium, CellTiter-Glo detection kit (Promega) and other experimental reagents.
  • the toxic effect of the drug on cells was examined using the CellTiter-Glo kit (Promega).
  • the CellTiter-Glo kit detects the number of viable cells in culture by quantitatively measuring ATP.
  • the respiration of metabolically active cells and other life-live processes can produce ATP.
  • the kit uses a stable glow type generated by luciferase. Signaling, luciferase requires the involvement of ATP during luminescence.
  • An equal volume of CellTiter-Glo reagent was added to the cell culture medium, and the luminescence value was measured.
  • the light signal was proportional to the amount of ATP in the system, and ATP was positively correlated with the number of living cells. Thus the light signal value can reflect the number of living cells.
  • Method step MT4 cells were seeded in a 96-well cell culture plate, and the cells were allowed to adhere after use.
  • the drug was diluted 9 gradients from 1 mM serially 3 folds with 2 replicate wells per gradient.
  • the drug was added to the cells and cultured in a CO2 incubator at 37 °C.
  • the cytopathic effect (CPE) caused by the drug was observed under light microscope, and cell survival rate was measured by adding CellTiter-Glo.
  • the toxicity of a drug to a cell is expressed as the activity of the cell.
  • the experiment was set up with cell control (uninfected cell control), virus control, positive drug control (Zidovudine, AZT).
  • Inhibition rate (%) (drug group - virus control) / (cell control - virus control) * 100%
  • MDCK cells MDCK cells.
  • Virus Ebola virus.
  • Experimental reagent DMEM medium, Kit (Invitrogen), Luciferase Assay System Kit (Promega) and other laboratory reagents.
  • the (Invitrogen) kit detects the toxic effects of drugs on cells. It is a redox indicator that produces absorbance changes and fluorescent signals based on metabolic activity. Soluble in water, its oxidized form enters cells and is reduced by mitochondrial enzymes to produce measurable fluorescence and color changes for quantitative analysis of cell viability and cell proliferation as well as in vitro cytotoxicity studies.
  • This assay is based on the ability of metabolically active cells to convert reagents into fluorescent and colorimetric indicators, with impaired and inactive cells having lower native metabolic activity and corresponding lower signals. Therefore, the fluorescence signal is strong and can reflect the level of cell activity.
  • MDCK cells were seeded in 96-well cell culture plates, and the cells were allowed to adhere after use.
  • the drug was diluted 9 gradients from 1 mM serially 3 folds with 2 replicate wells per gradient.
  • the drug was added to the cells and cultured in a CO2 incubator at 37 °C. After 2 days of drug-added culture, the drug-induced cytopathic effect (CPE) was observed under light microscope.
  • the medium was incubated at 37 ° C for 4 h, and the fluorescence reading was detected with excitation light of 570 nm and emission light of 595 nm.
  • the toxicity of a drug to a cell is expressed as the activity of the cell.
  • Method steps (1) Cell plating: MDCK cells were seeded in a 96-well cell culture plate, and the cells were allowed to adhere after being attached to the cells. (2) Dosing treatment: The drug was serially diluted 3 times into 9 drug concentration groups with maintenance medium (2% FBS), and configured into 2X drug-containing culture solution with 2 replicate wells per gradient. After the cells were grown into a single layer, 100 ⁇ l of a 2x drug-containing DMEM medium was added, and then 100 ⁇ l of DMEM diluted Ebola virus was added and cultured at 37 °C. (3) Detection: After the virus infection was continued for 48 hours, the Rluc reading was detected by Luciferase Assay Kit.
  • the experiment set the virus control group and the cell control group.
  • Example 16 Studies on the in vivo activity of bicycloplatin alone (oral or injection) against hepatitis B patients, hepatitis C patients, HIV infected persons, and Ebola virus infected individuals.
  • the double-ring platinum water injection injection was purchased from Beijing Xingda Technology System Co., Ltd., and the specification was 50mg/5mL.
  • the bicyclic platinum used in the oral preparation is prepared by reference to US2016/0297842, and the bicyclo platinum is dissolved in deionized water, and the specification is 50 mg/5 mL.
  • Virus index >>100000 IU/mL 1-3 months (four patients were injected orally, respectively), no case showed that the patient's virus index decreased, the virus index continued to rise, liver function did not improve; use double ring Platinum alone was administered to 20 patients with Ebola virus infection (Africa) for 1-3 weeks. None of the patients showed a downward trend in the virus index, and the virus index continued to rise, with no control or remission.
  • Example 17 A study of the in vivo activity of a bicyclic platinum-containing combination product against hepatitis B patients, hepatitis C patients, and HIV infected individuals.
  • the bicyclic platinum-containing combination product preparation disclosed in the present invention was used in 15 cases of hepatitis B patients (without any antiviral drug treatment), and after 1-3 months of treatment, the viral index was greatly decreased, and liver function was The index is basically normal; the bicyclo platinum-containing combination product disclosed in the present invention is used in 13 patients with hepatitis C (not treated with any antiviral drugs), and after 1-3 months of treatment, the viral index is greatly decreased, and 2 cases are The virus index falls below the detection limit, and the liver function index is basically normal; the bicyclo platinum-containing combination product disclosed in the present invention is used in 8 HIV-infected patients (without any antiviral drug treatment), after 1-3 months. Treatment, the viral index dropped significantly, the CD4 index increased significantly, and liver function indicators were basically normal.
  • Example 18 Study of the in vivo activity of a bicyclic platinum-containing combination product on hepatitis C patients and HIV-infected individuals.
  • the RNA virus index will be 1000 IU/mL or less, and the liver function is basically normal;
  • Female patients (28 years old), virological examination was HIV positive, with CD4 cells at 190, CD8 at 815, and CD4/CD8 0.23:1. After six months of oral administration of a bicyclic platinum-containing combination product, virological examination was not detected, CD4 was 563, CD8 was 575, and CD4/CD8 was 0.97:1.
  • the invention discloses a preparation combination of bicyclo platinum mixed with various acidic substances.
  • the present invention discloses a ratio of a mixture of bicyclic platinum and various acidic substances and a preparation method thereof.
  • the conventional preparation method may be a mixture of bicycloplatinum and a certain ratio of 1,1-cyclobutanedicarboxylic acid; or a bicyclic platinum and a certain ratio of 1,1-cyclobutanedicarboxylic acid completely dissolved in water. After lyophilization. The XRPD structure and H 1 -NMR showed no effect on the stability of the bicyclic platinum after mixing.
  • the preparation mixture can be prepared from carboplatin and a certain proportion of 1,1-cyclobutanedicarboxylic acid in water as a medium, after stirring at 0-40 ° C for 1 to 24 hours, or directly lyophilized and mixed uniformly. Into, or add an appropriate amount of water, all dissolved and freeze-dried.
  • the XRPD structure and H 1 -NMR showed that the mixed mixture was composed of bicyclo platinum and 1,1-cyclobutanedicarboxylic acid, and no carboplatin residue was observed.
  • This preparation method greatly increases the yield of the bicyclic platinum, so that the carboplatin raw material can be completely used.
  • the conventional preparation method may be bicyclo platinum and a certain ratio of 1,1-cyclobutanedicarboxylic acid, citric acid, chlorogenic acid, citric acid, gallic acid, ferulic acid, maleic acid, salicylic acid, etc.
  • One of the acid or a mixture of salicylic acid and the like is completely dissolved in water and then freeze-dried.
  • the XRPD structure and H 1 -NMR showed no effect on the stability of the bicyclic platinum after mixing.
  • Additional other components include: Coenzyme Q10, curcumin, glutathione (GSH), oryzanol, vitamin C, anthocyanins.
  • the preparation of a combination product in which bicycloplatinum is the main active material can be either a conventional preparation method or a specific preparation method for a specific case.
  • bicycloplatinum is prepared as a lyophilized powder or a water injection using water as a carrier. Stability studies showed that the formulation retained good stability. In various instances, the bicyclic platinum is compatible with the corresponding pharmaceutical excipients with good stability and is thus prepared into the corresponding oral preparation.
  • a solid combination product of a bicyclic platinum and 1,1-cyclobutanedicarboxylic acid (1:1.2 to 1:20), a solution combination product, is stable at 40 °C.
  • the above solid combination product was examined under light conditions for eight weeks and the results were shown to be stable.
  • MD36792 refers to bicyclic platinum
  • the ratio of the proportion of the ratio refers to the molar ratio of the bicyclic platinum to the 1,1-cyclobutanedicarboxylic acid
  • the illumination experiment conditions are illumination of 2000LX;
  • the solubility of the solution is: 1 mg/ml;
  • bicycloplatin as a main active substance for treating pain caused by cancer patients exhibits remarkable effects.
  • cancer patients especially those with advanced liver cancer, kidney cancer patients, bone metastasis patients, brain metastases and bone cancer patients, single use of bicycloplatin injection or oral preparations as the sole treatment (see Table 5).
  • the inventors found that a certain number of patients with advanced cancer showed no sensitivity to bicycloplatin and no effect on tumor suppression.
  • the effect of bicyclo platinum on cancer pain is still obvious, and even the pain disappears.
  • the above cancer patient dose once every two days, 150 mg / 5% aqueous dextrose intravenously.
  • the bicycloplatinum injection used was purchased from Beijing Xingda Technology System Co., Ltd., with a specification of 50 mg/5 mL.
  • bicycloplatin has been shown to have a good effect on tumor-induced tissue edema and inflammation.
  • oral or injection of bicycloplatin was found.
  • tissue edema caused by cancer metastasis was substantially eliminated. This indicates that bicycloplatinum has a good anti-inflammatory effect on inflammation.
  • Hepatic tissue edema occurred in many patients with liver cancer, and tissue edema was significantly eliminated or reduced after a period of perfusion or oral administration with bicycloplatin.
  • Example 22 Antiviral effect of additional other components AA011 and VK021 when used alone
  • the antiviral effects of AA011 and VK021 and positive drugs are shown in the figure below.
  • the positive drug 2'CMC has a good antiviral effect, and the antiviral effect is better as the drug dose is increased.
  • Additive AA011 had a certain antiviral effect at 1000 ⁇ M and 250 ⁇ M concentration, and had no obvious cytotoxicity at 1000 ⁇ M; additive VK021 also had some antiviral effects at 1000 ⁇ M and 250 ⁇ M concentrations, but weak cytotoxicity at 1000 ⁇ M.
  • Example 23 In vitro anti-HCV virus effect of a combination product of MD36792 and AA011, VK021
  • the anti-viral EC50 of MD36792 alone was 15.62 ⁇ g/ml, the toxicity CC50 for cells was 69.4, and the selection index SI for antiviral effect was 4.44.
  • the selection index is relatively low, and it can be considered that there is a certain antiviral effect, but the toxicity to the cells is relatively large.
  • the antiviral effect of 36792 in combination with AA011 and VK021 was EC50 of 4.43 ⁇ g/ml, CC50 of 24.82, and SI of 5.6.
  • the mixed use of the three samples was more toxic to the cells, and the selection index was not very large.
  • the antiviral effect of the combined use of MD36792 alone did not increase significantly at the cellular level.
  • Reagent Luo Tongding (Guangzhou Baiyunshan Pharmaceutical).
  • mice were fed for 5 days, and the body weight of the mice was weighed. Using stratified randomization method, 50 mice were randomly divided into a model group (ie, a blank control group (distilled water)) and a positive control group. Tongding, 100mg/kg, po), MD36792 low dose group (1mg/ml aqueous solution, 10mg/kg, ip), MD36792 medium dose group (2mg/ml aqueous solution, 20mg/kg, ip) and MD36792 high dose group (4mg /ml aqueous solution, 40mg/kg, ip), a total of 5 groups. The MD36792 group and the positive control group were given the corresponding drugs respectively. After 1 hr of administration, each group of mice was intraperitoneally injected with 0.8% acetic acid (0.2 mL/mouse). Observe and record the number of writhings within 15 minutes.
  • a model group ie, a blank control group (
  • MD36792 is dose-independent in analgesic action (see Figure 7).
  • MD36792 and the positive control drug Luotongding have significant analgesic effects in the model of evaluating the analgesic effect of the drug by the classical acetic acid-induced mouse writhing method.

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Abstract

本发明涉及含有双环铂的组合产品、所述组合产品在制备用于治疗和/或预防疼痛、炎症和与病毒相关的疾病的药物中的用途以及制备所述组合产品的方法。

Description

含有双环铂的组合产品、其制备方法及其用途 发明领域
本发明涉及含有双环铂的组合产品，所述组合产品用于治疗和/或预防疼痛、炎症和与病毒感染相关的疾病，以及所述组合产品的制备方法。
背景技术
自顺-二氯二胺配铂的抗肿瘤作用被发现后(Rosenberg et al.Nature,1965,205:698；Nature,1972,222:385)，顺铂作为一种抗肿瘤药物已经被广泛应用于临床医学中。这类药物虽然对例如泌尿生殖器癌、鼻咽癌、头孢圆形癌以及肺癌等癌症具有治疗效果，但药物具有毒性，会产生严重的副作用。从铂的类似物中寻找具有低毒性、抗肿瘤图谱广的高效抗肿瘤药物的研究过去几十年来是抗肿瘤药物领域的研究热点。
Figure PCTCN2018116213-appb-000001
双环铂(DCP)是由卡铂(CBP)与1,1-环丁烷(CBDCA)通过氢键连接形成的共晶化合物。根据专利CN1311183A报道及相应的学术报道，双环铂具有广谱、高效、低毒、低耐药、低交叉耐药以及穿透性好等特点。中国专利申请CN00124864.2表明，双环铂对头颈癌、鼻咽癌、乳腺癌、肺癌、肝癌、胰腺癌、胃癌、肠癌、淋巴癌等显著效果。同时对于前列腺增生、前列腺炎症、类风湿关节炎等多种适应症具有不错的疗效(PCT/US2016/028720)。
持续和突破性疼痛是癌症患者最关心的问题。超过半数的癌症患者在病程中会经历严重的、无法控制的疼痛，而疼痛的治疗是癌症患者和肿瘤治疗医师的主要挑战(List MA,Stracks J,Colangelo L,et al.J.Clin.Oncol(2000)18:877–84 2.)。虽然癌症疼痛是一个复杂的病理过程和一个强大的临床问题，但在理解导致癌症疼痛的基本神经机制方面已经取得了重大进展。癌症患者所经历的症状是在增殖、侵袭和转移过程中发生的细胞、组织和全身变化的结果。免疫系统对癌症疼痛也有明显的作用。癌细胞会产生影响 癌微环境中其他细胞的介质，如免疫细胞。
癌症和肿瘤区域免疫细胞释放一些神经免疫介质，具有多种外周伤害性神经末梢的兴奋性受体促进异常放电和互动。此外，在外周神经附近生长的肿瘤可以妥协的神经的完整性、诱导性条件伴有持续性疼痛，痛觉过敏，或痛。这两种肿瘤对周围神经的作用都可能导致中枢敏化，从而进一步增强脊髓背角伤害性传导的作用和自发突破性疼痛的感受(Hamamoto DT,Khasabov SG,Cain DM,Simone DA.J Neurophysiol(2008)100:2300–11，Sabino MA,Luger NM,Mach DB,Rogers SD,Schwei MJ,Mantyh PW.Int.J.Cancer(2003)104:550–558)。
铂类药物用于抗病毒的治疗比较罕见。US8247445B2报道新型结构的铂类配合物在预防或治疗病毒、细菌感染领域的活性。US5922689报道了顺铂衍生物的用于治疗AIDS。Jiajiu Shaw等人在专利文献(US6297245B1)中报道顺铂加入叶酸、辅酶Q10作为促进剂后用于治疗AIDS疾病。Jiajiu Shaw等人还公开了新型铂类药物用于治疗、阻断病毒、细菌、寄生虫引发的感染新疾病，以及用于治疗慢性、炎症疾病。杨旭清等人公开双环铂用于抗病毒或抗菌的用途。
但是，在本领域中仍然存在获得具有高效力地治疗和/或预防疼痛、炎症或与病毒感染相关疾病的具有良好稳定性的药物的需求。
发明内容
本发明的第一方面，提供一种组合产品，所述组合产品含有双环铂和酸性物质。进一步地，所述酸性物质选自下述中的一种或多种：1,1-环丁烷二羧酸、柠檬酸、绿原酸、阿魏酸、马来酸、水杨酸、叶酸和没食子酸。进一步地，所述双环铂与所述酸性物质的比例为：1:0.01至1:99。进一步地，所述组合产品任选地包含一种或多种下述另外的其它组分：辅酶Q10、姜黄素、谷胱甘肽、谷维素、柠檬酸、维生素C和花青素。进一步地，所述组合产品可以组合物或药物组合物的形式存在或者所述组合产品中的所述双环铂、所述酸性物质或所述另外的其它组分各自以单独的制剂形式存在。
在本发明的第二方面，提供一种组合产品，所述产品含有双环铂和一种或多种下述另外的其它组分：辅酶Q10、姜黄素、谷胱甘肽、谷维素、柠檬酸、维生素C和花青素。
在本发明的第三方面，提供如上所述的组合产品在制备药物中的用途，所述药物用于治疗和/或预防疼痛、炎症和与病毒感染相关的疾病。进一步地，所述疼痛选自由癌症或非癌症的其它原因(例如，乙型肝炎、丙型肝炎或类风湿关节炎)引起的疼痛，所述炎症 选自由癌症或非癌症的其它原因(例如，类风湿关节炎)引起的炎症，所述与病毒感染相关的疾病选自与乙型肝炎病毒、丙型肝炎病毒、埃博拉病毒或人类免疫缺陷病毒感染相关的疾病。
在本发明的第四方面，提供治疗和/或预防疼痛、炎症和与病毒感染相关的疾病的方法，所述方法包括对有此需要的患者使用如上所述的组合产品。进一步地，所述疼痛选自由癌症或非癌症的其它原因(例如，乙型肝炎、丙型肝炎或类风湿关节炎)引起的疼痛，所述炎症选自由癌症或非癌症的其它原因(例如，类风湿关节炎)引起的炎症，且所述与病毒感染相关的疾病选自与乙型肝炎病毒、丙型肝炎病毒、埃博拉病毒或人类免疫缺陷病毒感染相关的疾病。进一步地，所述组合产品中双环铂的剂量为0.01至10mg/kg患者体重，优选为0.01至5mg/kg患者体重。进一步地，所述组合产品可以通过下述方式施用：口服、口腔、吸入喷雾、舌下、直肠、透皮、阴道粘膜、透黏膜、局部给药，鼻或肠道给药；注射给药，如肌肉注射、皮下注射、髓内注射，以及鞘内、脑部直接给药、原位给药、皮下、腹腔内、静脉注射、关节内滑膜、胸骨、内、肝内、病灶内，颅内、腹腔、鼻腔、或眼内注射或其他药物递送方式。进一步地，所述组合产品可以组合物或药物组合物的形式存在，或所述组合产品中的所述双环铂、所述酸性物质或所述另外的其它组分各自以单独的制剂形式存在，其可以同时、连续或间隔一定时间施用。所述时间间隔包括但不限于1至24小时中的整数数值，例如1小时、2小时或3小时等；1至30天中的整数数值，例如1天、2天或3天。
在本发明的第五方面，提供制备组合产品的方法，所述方法包括：1)加入双环铂作为活性物质或者作为唯一活性物质；2)任选地加入酸性物质以形成混合物，其中所述双环铂与所述酸性物质的比例为：1:0.01至1:99，优选为1:3至1:10，且所述酸性物选自下述的一种或多种：1,1-环丁烷二羧酸、柠檬酸、绿原酸、阿魏酸、马来酸、水杨酸、叶酸和没食子酸；且3)任选地加入一种或多种选自下述的另外的其它组分：辅酶Q10、姜黄素、谷胱甘肽(GSH)、谷维素、柠檬酸、维生素C和花青素。
在本发明的第五方面，还提供了制备双环铂或双环铂与1,1-环丁烷二羧酸的组合物的方法，所述方法包括：1)在合适的溶剂中，在室温或加热下，将卡铂与1,1-环丁烷二羧酸以1:1.05至1:99的摩尔比，搅拌适量时间，得到含有1,1-环丁烷二羧酸的双环铂的混合物；且任选地2)将所得混合物直接冻干、浓缩后加入适量的水全部溶解后冻干，或者配制成所需的水溶液，得到含有双环铂和1,1-环丁烷二羧酸的组合物。
在本发明的第六方面，提供双环铂作为唯一活性物质在制备药物中的用途，所述药物 用于治疗和/或预防疼痛或炎症，所述疼痛是癌症引起的疼痛或其它原因(例如由乙肝病毒、丙肝病毒或、类风湿关节炎)引起的疼痛，且所述炎症是由癌症引起的炎症或非癌症的其它原因(例如，类风湿关节炎)引起的炎症。
在本发明的第七方面，提供用于治疗和/或预防疼痛、炎症和与病毒感染相关的疾病的如上所述的组合产品。
在本发明的第八方面，提供双环铂作为唯一活性物质的组合物以及制备该混合物的方法，所述方法包括：加入双环铂作为唯一活性物质。
在本发明的第九方面，提供双环铂作为唯一活性物质在制备药物中的用途，所述药物用于治疗和/或预防疼痛或炎症。进一步地，所述疼痛是由癌症引起的疼痛或由非癌症的其它原因引起的疼痛，且所述炎症是由癌症引起的炎症或非癌症的其它原因(例如，类风湿关节炎)引起的炎症。
在本发明的第十方面，提供用于治疗和/或预防疼痛或炎症的含有双环铂作为唯一活性物质的组合物。进一步地，所述疼痛是由癌症引起的疼痛，或由非癌症的其它原因(例如，乙型肝炎、丙型肝炎或类风湿关节炎)引起的疼痛，且所述炎症是由癌症引起的炎症或非癌症的其它原因(例如，类风湿关节炎)引起的炎症。
附图说明
图1显示单独给予双环铂或利巴韦林对丙肝病毒(HCV)的影响。
图2显示单独给予双环铂对乙肝病毒(HBV)的影响。
图3显示单独给予双环铂或齐多夫定对艾滋病病毒(HIV)的影响。
图4显示单独给予双环铂埃博拉病毒的影响。
图5显示AA011和VK021及阳性药物的对病毒的影响。
图6显示MD36792和AA011(图6中A)、VK021(图6中V)的组合产品的抗病毒效果。
图7显示MD36792在镇痛方面的作用。
定义
如本文所述的，术语“受试者”是指包括人和动物(例如，犬、猫、兔、鸡或猴等)。
如本文所述的，术语“剂量”是指每千克(kg)受试者体重的活性物质的重量(例如，毫克(mg))。
如本文所述的，术语“比例”通常是指摩尔比。例如，双环铂与所述酸性物质的比例(摩尔比)为：1:0.01至1:99。双环铂含量比例％，是指重量百分比。
如本文所述的，术语“与病毒感染相关的疾病”是指由病毒感染引起的疾病或者遭受病毒感染所伴随的疾病。所述病毒感染包括但不限于：肝炎病毒(例如，甲肝病毒、乙肝病毒、丙肝病毒)、埃博拉病毒或人类免疫缺陷病毒感染。
如本文所述的，术语“疼痛”是指由肿瘤(例如，癌症)引起的疼痛，或者其它原因引起的疼痛(例如，乙型肝炎、丙型肝炎或类风湿关节炎)引起的疼痛。
如本文所述，术语“MD36792、AA011和VK021”分别是指双环铂、谷胱甘肽和维生素C。
如本文所述的，术语“室温”是指25℃±1℃。同时，若没有具体指明实验温度，均为室温。
如本文所述的，术语“约”是指该术语所修饰的数值的±10％，更优选为±5％，最优选为±2％，因此本领域的普通技术人员能够清楚地根据所修饰的数值确定术语“约”的范围。
发明详述
本申请发明人发现，本申请要求保护的双环铂作为主要活性物质用于治疗和/或预防疼痛，特别是癌症患者引发的疼痛方面，展示了显著的疗效。在癌症患者中，尤其是肝癌晚期患者、肾癌患者、骨转移患者及骨癌患者，单一的选择了使用双环铂注射液或者口服制剂作为唯一的治疗手段。发明人发现，一定数量的癌症晚期患者对双环铂显示没有敏感性，对肿瘤的抑制没有出现疗效。但是双环铂对于癌痛出现明显的缓解效果依然明显，甚至疼痛消失。部分患者使用一定疗程后停止使用双环铂，疼痛也没有发生。
在治疗肿瘤患者的临床中发现，双环铂对于肿瘤引发的组织水肿、炎症显示良好的效果。在多例肺癌患者脑转移的患者采用口服或注射双环铂的过程中发现，在使用双环铂一周至两周后，脑部因癌转移引发的组织水肿基本消除。说明双环铂对于炎症由良好的抗炎症疗效。在多例肝癌患者发生的肝部组织水肿，在采用双环铂的灌注或口服一段时间后，组织水肿明显的消除或减少。
本发明的第一方面，提供一种组合产品，所述组合产品含有双环铂和酸性物质，或由双环铂和酸性物质组成。进一步地，所述酸性物质选自下述中的一种或多种：1,1-环丁烷二羧酸、柠檬酸、绿原酸、阿魏酸、马来酸、水杨酸、叶酸和没食子酸。进一步地，所述 双环铂与所述酸性物质的比例为：约1:0.01至约1:99，优选为约1:1、约1:1.08、约1:2、约1:3、约1:4、约1:5、约1:6、约1:7、约1:8、约1:9、约1:10、约1:20、约1:30、约1:40、约1:50、约1:60、约1:70、约1:80、约1:90以及所述各比例之间的比例范围，包括但不限于:约1:1至约1:2、约1.08至约1:2、约1:3至约1:10等。进一步地，所述组合产品包含一种或多种下述另外的其它组分：辅酶Q10、姜黄素、谷胱甘肽、谷维素、柠檬酸、维生素C和花青素。进一步地，所述双环铂与所述另外的其它组分的比例为：约0.1:1至约100:1，优选为约0.1:1、约0.2:1、约0.3:1、约0.4:1、约0.43:1、约0.5:1、约0.6:1、约0.7:1、约0.8:1、约0.9:1、约1:1、约1:1.25、约1.02:1、约2:1、约3:1、约4:1、约5:1、约6:1、约7:1、约8:1、约9:1、约10:1、约20:1、约30:1、约40:1、约50:1、约60:1、约70:1、约80:1、约90:1以及所述各比例之间的比例范围，包括但不限于:约0.1:1至10:1、约0.4:1至约8:1、约0.43:1至约5:1、约0.43:1至约1:1.25、约0.43:1至约1:1.02等。优选地，双环铂与所述另外的其它组分(辅酶Q10、姜黄素、谷胱甘肽、谷维素、柠檬酸、维生素C和花青素)的比例为：约0.1:1至10:1、约0.4:1至约8:1、约0.43:1至约5:1、约0.43:1至约1:1.25、约0.43:1至约1:1.02。更优选地，双环铂:维生素C的比例为约0.43:1、双环铂:谷胱甘肽的比例为约1:1.25、双环铂:辅酶Q10的比例为约1.02:1。进一步地，按重量计，所述双环铂占组合产品的百分比为约5％、约10％、约15％、约16.64％、约18.29％、约19.11％、约19.87％、约20％、约25％、约30％、约35％、约40％、约44.46％、约45％、约50％、约55％、约60％、约60.5％、约65％、约70％、约75％、约80％、约85％、约90％、约95％、约96.2％、约99％以及所述各百分比之间的范围，包括但不限于：约5％至99％、16.64％至60.5％、约18.29％至44.46％、约19.11％至约35％。
进一步地，所述组合产品可以组合物或药物组合物的形式存在或者所述组合产品中的所述双环铂、所述酸性物质或所述另外的其它组分各自以单独的制剂形式存在。进一步地，所述组合产品是口服制剂，如胶囊、片剂、颗粒剂；冻干制剂或水针剂；雾化剂；或其他制剂形式。
在本发明的第二方面，提供一种组合产品，所述组合产品含有双环铂和一种或多种下述另外的其它组分：辅酶Q10、姜黄素、谷胱甘肽、谷维素、柠檬酸、维生素C和花青素。进一步地，所述组合产品任选地含有酸性物质，所述酸性物质选自下述中的一种或多种：1,1-环丁烷二羧酸、柠檬酸、绿原酸、阿魏酸、马来酸、水杨酸、叶酸和没食子酸。进一步地，所述双环铂与所述酸性物质的比例为：1:0.01至1:99，，优选为约1:1、约1:1.08、 约1:2、约1:3、约1:4、约1:5、约1:6、约1:7、约1:8、约1:9、约1:10、约1:20、约1:30、约1:40、约1:50、约1:60、约1:70、约1:80、约1:90以及所述各比例之间的比例范围，包括但不限于:约1:1至约1:2、约1.08至约1:2、约1:3至约1:10等。进一步地，所述双环铂与所述另外的其它组分的比例为：约0.1:1至约100:1，优选为约0.1:1、约0.2:1、约0.3:1、约0.4:1、约0.43:1、约0.5:1、约0.6:1、约0.7:1、约0.8:1、约0.9:1、约1:1、约1:1.25、约1.02:1、约2:1、约3:1、约4:1、约5:1、约6:1、约7:1、约8:1、约9:1、约10:1、约20:1、约30:1、约40:1、约50:1、约60:1、约70:1、约80:1、约90:1以及所述各比例之间的比例范围，包括但不限于:约0.1:1至10:1、约0.4:1至约8:1、约0.43:1至约5:1、约0.43:1至约1:1.25、约0.43:1至约1:1.02等。优选地，双环铂与所述另外的其它组分(辅酶Q10、姜黄素、谷胱甘肽、谷维素、柠檬酸、维生素C和花青素)的比例为：约0.1:1至10:1、约0.4:1至约8:1、约0.43:1至约5:1、约0.43:1至约1:1.25、约0.43:1至约1:1.02。更优选地，双环铂:维生素C的比例为约0.43:1、双环铂:谷胱甘肽的比例为约1:1.25、双环铂:辅酶Q10的比例为约1.02:1。进一步地，按重量计，所述双环铂占组合产品的百分比为约5％、约10％、约15％、约16.64％、约18.29％、约19.11％、约19.87％、约20％、约25％、约30％、约35％、约40％、约44.46％、约45％、约50％、约55％、约60％、约60.5％、约65％、约70％、约75％、约80％、约85％、约90％、约95％、约96.2％、约99％以及所述各百分比之间的范围，包括但不限于：约5％至99％、16.64％至60.5％、约18.29％至44.46％、约19.11％至约35％。
进一步地，所述组合产品是口服制剂，如胶囊、片剂、颗粒剂；冻干制剂或水针剂；雾化剂；或其他制剂形式。
在本发明的第三方面，提供双环铂，例如上所述的组合产品，在制备药物中的用途，所述药物用于治疗和/或预防疼痛、炎症和与病毒感染相关的疾病。进一步地，所述疼痛选自由癌症或非癌症的其它原因(例如，乙型肝炎、丙型肝炎或类风湿关节炎)引起的疼痛，所述炎症选自由癌症或非癌症的其它原因(例如，类风湿关节炎)引起的炎症，所述与病毒感染相关的疾病选自与乙型肝炎病毒、丙型肝炎病毒、埃博拉病毒或人类免疫缺陷病毒感染相关的疾病。
在本发明的第四方面，提供治疗和/或预防疼痛、炎症和与病毒感染相关的疾病的方法，所述方法包括对有此需要的患者使用双环铂，例如上所述的组合产品。进一步地，所述疼痛选自由癌症或非癌症的其它原因(例如，乙型肝炎、丙型肝炎或类风湿关节炎)引起的疼痛，所述炎症选自由癌症或非癌症的其它原因(例如，类风湿关节炎)引起的炎症 且所述与病毒感染相关的疾病选自与乙型肝炎病毒、丙型肝炎病毒、埃博拉病毒或人类免疫缺陷病毒感染相关的疾病。进一步地，所述组合产品中双环铂的剂量为0.01至10mg/kg患者体重，优选为0.01至5mg/kg患者体重、0.1至5mg/kg患者体重、1至5mg/kg患者体重。进一步地，所述组合产品可以通过下述方式施用：口服、口腔、吸入喷雾、舌下、直肠、透皮、阴道粘膜、透黏膜、局部给药，鼻或肠道给药；注射给药，如肌肉注射、皮下注射、髓内注射，以及鞘内、脑部直接给药、原位给药、皮下、腹腔内、静脉注射、关节内滑膜、胸骨、内、肝内、病灶内，颅内、腹腔、鼻腔、或眼内注射或其他药物递送方式。进一步地，所述组合产品可以组合物或药物组合物的形式存在，或所述组合产品中的所述双环铂、任选的所述酸性物质或任选的所述另外的其它组分各自以单独的制剂形式存在，其可以同时、连续或间隔一定时间施用。所述时间间隔包括但不限于1至24小时中的整数数值，例如1小时、2小时或3小时等；1至30天中的整数数值，例如1天、2天或3天。
在本发明的第五方面，提供制备组合产品的方法，所述方法包括：1)加入双环铂作为活性物质或作为唯一活性物质；2)任选地加入酸性物质以形成混合物，其中所述双环铂与所述酸性物质的比例为：1:0.01至1:99，优选为约1:1、约1:1.08、约1:2、约1:3、约1:4、约1:5、约1:6、约1:7、约1:8、约1:9、约1:10、约1:20、约1:30、约1:40、约1:50、约1:60、约1:70、约1:80、约1:90以及所述各比例之间的比例范围，包括但不限于：约1:1至约1:2、约1.08至约1:2、约1:3至约1:10，且所述酸性物选自下述的一种或多种：1,1-环丁烷二羧酸、柠檬酸、绿原酸、阿魏酸、马来酸、水杨酸、叶酸和没食子酸；且3)任选地加入一种或多种选自下述的另外的其它组分：辅酶Q10、姜黄素、谷胱甘肽(GSH)、谷维素、柠檬酸、维生素C、花青素(所述双环铂与所述另外的其它组分的比例为：约0.1:1至约100:1，优选为约0.1:1、约0.2:1、约0.3:1、约0.4:1、约0.43:1、约0.5:1、约0.6:1、约0.7:1、约0.8:1、约0.9:1、约1:1、约1:1.25、约1.02:1、约2:1、约3:1、约4:1、约5:1、约6:1、约7:1、约8:1、约9:1、约10:1、约20:1、约30:1、约40:1、约50:1、约60:1、约70:1、约80:1、约90:1以及所述各比例之间的比例范围，包括但不限于:约0.1:1至10:1、约0.4:1至约8:1、约0.43:1至约5:1、约0.43:1至约1:1.25、约0.43:1至约1:1.02等；优选地，双环铂与所述另外的其它组分(辅酶Q10、姜黄素、谷胱甘肽、谷维素、柠檬酸、维生素C和花青素)的比例为：约0.1:1至10:1、约0.4:1至约8:1、约0.43:1至约5:1、约0.43:1至约1:1.25、约0.43:1至约1:1.02；更优选地，双环铂:维生素C的比例为约0.43:1、双环铂:谷胱甘肽的比例为 约1:1.25、双环铂:辅酶Q10的比例为约1.02:1)。
如本文所述，双环铂与1,1-环丁烷二羧酸(1:1.2至1:20)形成的溶液组合产品连续七周在40℃是稳定的。双环铂与没食子酸、水杨酸、柠檬酸、阿魏酸等形成的溶液组合产品在40℃条件下，虽然稳定，但在两周后开始分解。优选地，本文上述酸性物质为1,1-环丁烷二羧酸，优选地，其中双环铂与1,1-环丁烷二羧酸的比例为1:1.2至1:20。
在本发明的一些方面，还提供了制备双环铂或双环铂与1,1-环丁烷二羧酸的组合物的方法，所述方法包括：1)在合适溶剂(优选地，水)中，在室温或加热(优选地，40℃)，将卡铂与1,1-环丁烷二羧酸以1:1.05至1:99的摩尔比(例如，1:1.2、1:1.5、1:3、1:5、1:10、1:20以及其中各比例之间的任意比例，包括但不限于1:1.2至1:20，或者所述比例可依据具体实际需要配比使用，例如上述双环铂与酸性物质中所述的比例)混合，搅拌适量的时间，例如0.5至24小时(优选地，0.5小时、1小时、2小时、3小时、4小时、5小时、6小时、7小时、8小时、9小时、10小时、11小时、12小时、13小时、14小时、15小时、16小时、17小时、18小时、19小时、20小时、21小时、22小时、23小时、24小时或它们之间的任意范围)，得到含有1,1-环丁烷二羧酸的双环铂的混合物；且任选地2)将所得混合物直接冻干、浓缩后加入适量的水全部溶解后冻干，或者配制成所需的水溶液，得到含有双环铂和1,1-环丁烷二羧酸的组合物。相比现有技术所报道的方法，本发明具有很多优点，如，本发明的方法操作简单，而且大大提高了双环铂的收率，使卡铂的原料完全得以使用。而且所产生的冻干混合物是由双环铂和1,1-环丁烷二羧酸组成，没有检查到卡铂的残留。
在本发明的第六方面，提供双环铂作为活性物质或唯一活性物质在制备药物中的用途，所述药物用于治疗和/或预防疼痛或炎症，所述疼痛是癌症引起的疼痛或其它原因(例如，乙型肝炎、丙型肝炎或类风湿关节炎)引起的疼痛，且所述炎症是由癌症引起的炎症或非癌症的其它原因(例如，类风湿关节炎)引起的炎症。
在本发明的第七方面，提供用于治疗和/或预防疼痛(所述疼痛选自由癌症或非癌症的其它原因(例如，乙型肝炎、丙型肝炎或类风湿关节炎)引起的疼痛)、炎症(所述炎症选自由癌症或非癌症的其它原因(例如，类风湿关节炎)引起的炎症)和与病毒感染相关的疾病(所述与病毒感染相关的疾病选自与乙型肝炎病毒、丙型肝炎病毒、埃博拉病毒或人类免疫缺陷病毒感染相关的疾病)的组合产品，所述组合产品含有双环铂和酸性物质，或由双环铂和酸性物质组成。进一步地，所述酸性物质选自下述中的一种或多种：1,1-环丁烷二羧酸、柠檬酸、绿原酸、阿魏酸、马来酸、水杨酸、叶酸和没食子酸。进一步地， 所述组合产品包含一种或多种下述另外的其它组分辅酶Q10、姜黄素、谷胱甘肽、谷维素、柠檬酸、维生素C和花青素。
作为替代方案，所述组合产品含有双环铂和一种或多种下述另外的其它组分：辅酶Q10、姜黄素、谷胱甘肽、谷维素、柠檬酸、维生素C和花青素。进一步地，所述组合产品任选地含有酸性物质，所述酸性物质选自下述中的一种或多种：1,1-环丁烷二羧酸、柠檬酸、绿原酸、阿魏酸、马来酸、水杨酸、叶酸和没食子酸。
进一步地，所述双环铂与所述酸性物质的比例为：约1:0.01至约1:99，优选为约1:1、约1:1.08、约1:2、约1:3、约1:4、约1:5、约1:6、约1:7、约1:8、约1:9、约1:10、约1:20、约1:30、约1:40、约1:50、约1:60、约1:70、约1:80、约1:90以及所述各比例之间的比例范围，包括但不限于:约1:1至约1:2、约1.08至约1:2、约1:3至约1:10等。进一步地，所述双环铂与所述另外的其它组分的比例为：约0.1:1至约100:1，优选为约0.1:1、约0.2:1、约0.3:1、约0.4:1、约0.43:1、约0.5:1、约0.6:1、约0.7:1、约0.8:1、约0.9:1、约1:1、约1:1.25、约1.02:1、约2:1、约3:1、约4:1、约5:1、约6:1、约7:1、约8:1、约9:1、约10:1、约20:1、约30:1、约40:1、约50:1、约60:1、约70:1、约80:1、约90:1以及所述各比例之间的比例范围，包括但不限于:约0.1:1至10:1、约0.4:1至约8:1、约0.43:1至约5:1、约0.43:1至约1:1.25、约0.43:1至约1:1.02等。优选地，双环铂与所述另外的其它组分(叶酸、辅酶Q10、姜黄素、谷胱甘肽、谷维素、柠檬酸、没食子酸、维生素C和花青素)的比例为：约0.1:1至10:1、约0.4:1至约8:1、约0.43:1至约5:1、约0.43:1至约1:1.25、约0.43:1至约1:1.02。更优选地，双环铂:维生素C的比例为约0.43:1、双环铂:谷胱甘肽的比例为约1:1.25、双环铂:辅酶Q10的比例为约1.02:1。进一步地，所述组合产品可以组合物或药物组合物的形式存在或者所述组合产品中的所述双环铂、所述酸性物质或所述另外的其它组分各自以单独的制剂形式存在。
在本发明的第八方面，提供双环铂作为唯一活性物质的组合物，所述组合物含有选自下述的辅料：硬脂酸镁、羟丙基纤维素、预胶化淀粉、壳聚糖、β-环糊精、聚乙烯吡咯烷酮，以及制备该混合物的方法，所述方法包括：加入双环铂作为唯一活性物质和任选的所述辅料。
在本发明的第九方面，提供双环铂作为活性物质或唯一活性物质在制备药物中的用途，所述药物用于治疗和/或预防疼痛或炎症。进一步地，所述疼痛是由癌症引起的疼痛，或由非癌症的其它原因(例如，乙型肝炎、丙型肝炎或类风湿关节炎)引起的疼痛，且所 述炎症是由癌症引起的炎症或非癌症的其它原因(例如，类风湿关节炎)引起的炎症。
在本发明的第十方面，提供用于治疗和/或预防疼痛或炎症的含有双环铂作为活性物质或唯一活性物质的组合物。进一步地，所述疼痛是由癌症引起的疼痛，或由非癌症的其它原因(例如，乙型肝炎、丙型肝炎或类风湿关节炎)引起的疼痛，且所述炎症是由癌症引起的炎症或非癌症的其它原因(例如，类风湿关节炎)引起的炎症。
在本发明其它方面，提供一种治疗和/或预防疼痛的方法，所述方法包括对有此需要的患者使用有效剂量的双环铂。进一步地，所述患者是癌症患者，优选为肝癌患者、肾癌患者、骨转移患者、脑转移或骨癌患者，更优选为癌症晚期患者或对铂类抗癌药已经产生耐药性的患者，最优选为肝癌晚期患者。进一步地，所述双环铂的有效剂量可以低于双环铂在该癌症患者中的有效抗癌剂量，或者在有些实施方案中，所述双环铂的有效剂量可以等于在该癌症患者中的有效抗癌剂量，例如，所述癌症患者可以使用双环铂作为唯一药物来治疗癌症和疼痛。进一步地，所述双环铂可以作为唯一治疗和/或预防疼痛的活性物质。在有些实施方案中，所述方法还包括给所述患者使用一种或多种其他具有止痛效果的活性物质。在有些实施方案中，所述方法还包括给所述患者使用一种或多种具有抗癌效果的活性物质，其中所述具有抗癌效果的活性物质优选为非铂类抗癌药。进一步地，其中所述双环铂以药物组合物形式存在。进一步地，其中所述双环铂存在于本文上述所定义的组合产品中。
在本发明的其它方面，双环铂治疗和/或预防疼痛的有效剂量可以低于有效抗癌剂量，且在对铂类药物产生耐药性的癌症患者中具有镇痛作用。因此，双环铂治疗和/或预防疼痛的方法和用途不限于癌症患者，而且双环铂在本文所示的疼痛动物模型实验显示了与阳性对照药罗通定相当的显著镇痛作用。基于本文所示，双环铂对于癌症或非癌症(包括但不限于：乙型肝炎、丙型肝炎和类风湿关节炎)引起的疼痛均可以有镇痛作用。在有些实施方案中，在上述治疗和/或预防疼痛的方法和用途中，所述患者不是癌症患者。在有些实施方案中，在上述治疗和/或预防疼痛的方法和用途中，所述患者为对铂类抗癌药已经产生耐药性的癌症患者。
在本发明其它方面，提供一种治疗和/或预防组织水肿(例如肝部水肿，脑部水肿等)或炎症的方法，所述方法包括对有此需要的患者使用有效剂量的双环铂。进一步地，所述患者是癌症患者，优选为肝癌患者、肾癌患者、骨转移患者、脑转移或骨癌患者，更优选为癌症晚期患者，最优选为肝癌晚期患者或对铂类抗癌药已经产生耐药性的患者。进一步地，所述双环铂的有效剂量可以低于双环铂在该癌症患者中的有效抗癌剂量，或者在有些 实施方案中，所述双环铂的有效剂量可以等于在该癌症患者中的有效抗癌剂量。进一步地，还包括给所述患者使用一种或多种具有抗癌效果的活性物质，其中所述具有抗癌效果的活性物质优选为非铂类抗癌药。进一步地，所述患者不是癌症患者。进一步地，所述双环铂以药物组合物形式存在。进一步地，所述双环铂存在于本文上述所定义的组合产品中。
在本发明的其它方面，提供一种治疗和/或预防与病毒感染相关的疾病的方法，例如降低患者病毒指数的方法，所述方法包括对有此需要的患者使用有效剂量的药物组合物，其中所述药物组合物包含双环铂和谷胱甘肽。进一步地，所述病毒感染为乙型肝炎病毒，丙型肝炎病毒、埃博拉病毒，和/或人类免疫缺陷病毒感染。进一步地，所述病毒感染为乙型肝炎病毒感染。进一步地，所述病毒感染为丙型肝炎病毒感染。进一步地，其中所述病毒感染为埃博拉病毒感染。进一步地，所述病毒感染为人类免疫缺陷病毒感染。进一步地，包括给所述患者使用有效剂量的药物组合物，每天1-3次。进一步地，包括给所述患者使用有效剂量的药物组合物至少7天，优选地，1个月到1年，例如，1、2、3、4、5、6、7、8、9、10、11、12个月，优选地，1个月到6个月，例如，1、2、3、4、5、6个月。进一步地，所述患者不接受任何其他抗病毒药物治疗，和/或未接受任何其他抗病毒药物治疗。进一步地，还包括给所述患者施用其他抗病毒药物。进一步地，所述药物组合物任选地包含一种或多种下述另外的其它组分：辅酶Q10、姜黄素、谷维素、柠檬酸、维生素C和花青素。优选地，双环铂与谷胱甘肽的比例为：约0.1:1至约100:1，优选为约0.1:1、约0.2:1、约0.3:1、约0.4:1、约0.43:1、约0.5:1、约0.6:1、约0.7:1、约0.8:1、约0.9:1、约1:1、约1:1.25、约1.02:1、约2:1、约3:1、约4:1、约5:1、约6:1、约7:1、约8:1、约9:1、约10:1、约20:1、约30:1、约40:1、约50:1、约60:1、约70:1、约80:1、约90:1以及所述各比例之间的比例范围，包括但不限于:约0.1:1至10:1、约0.4:1至约8:1、约0.43:1至约5:1、约0.43:1至约1:1.25、约0.43:1至约1:1.02等。双环铂与谷胱甘肽的比例为：约0.1:1至10:1、约0.4:1至约8:1、约0.43:1至约5:1、约0.43:1至约1:1.25、约0.43:1至约1:1.02。更优选地，双环铂:谷胱甘肽的比例为约1:1.25。优选地，在治疗病毒感染相关的疾病时，双环铂和谷胱甘肽在同一药物组合物种存在。但在有些实施方案中，双环铂和谷胱甘肽也可以各自以单独的制剂形式存在，其可以同时、连续或间隔一定时间施用。
进一步地，在上述治疗和/或预防疼痛、炎症和与病毒感染相关的疾病的方法中，所述双环铂或药物组合物存在形式可以是：口服制剂，如胶囊、片剂、颗粒剂；冻干制剂或水针剂；雾化剂；或其他制剂形式。进一步地，在上述治疗和/或预防疼痛、炎症和与病 毒感染相关的疾病的方法中，所述双环铂或药物组合物可以通过下述方式施用：口服、口腔、吸入喷雾、舌下、直肠、透皮、阴道粘膜、透黏膜、局部给药，鼻或肠道给药；注射给药，如肌肉注射、皮下注射、髓内注射，以及鞘内、脑部直接给药、原位给药、皮下、腹腔内、静脉注射、关节内滑膜、胸骨、肝内、病灶内，颅内、腹腔、鼻腔、或眼内注射或其他药物递送方式。优选地，所述双环铂或药物组合物可以通过口服或注射给药的方式使用。
具体实施方式
以下结合附图和具体实施例，对本发明作进一步说明。应理解，以下实施例仅用于说明本发明而并非用于限定本发明权利要求中所涵盖的范围。
本实施例所提及的双环铂可以商购或通过本文所描述的方法制备，其它化合物或本文所述的酸性物质和另外的其它组分是本领域公知的，可以商购或者通过本领域公知的方法进行合成。
检测方法
本文实施例中所使用的检测方法如下:
(1)X-射线粉末衍射(XRPD)
分析仪器：Panalytical Empyrean。X射线粉末衍射通过将晶体材料样品安装于Si单晶低背景的台座上，并在显微镜载玻片的辅助下将样品扩散成薄片进行的。2-theta(2-θ)的位置通过Panalytical 640硅粉末标准位置进行校准。用在45KV和40mA的条件下运行的细长焦点铜管产生的Kα1波长为1.540589埃，Kα2波长为1.544426埃(Kα2/Kα1强度比为0.50)的X射线辐射。准直的X射线源通过一个长度设定在10毫米的可程序化的发散狭缝进行传递，被反射的辐射通过一长度为5.5毫米的抗散射狭缝。theta-theta模式中2-theta为3°-40°的范围内样品以连续扫描的模式(2-theta以16.3秒/0.013°的速率递增)进行曝光。运行时间为3分57秒。该仪器配备有RTMS检测器。通过配备数据采集软件的Dell Optiplex 780 XP控制与以及采集数据。
众所周知，峰的相对强度会受到如下因素的影响，例如微粒的尺寸大于30微米以及微粒的宽高比不均一性。此外，反射的位置会受到样品位于衍射仪中的准确高度以及衍射仪的零点校正所影响。样品的表面平整性也具有一定的影响。因此，呈现的衍射图案数据不局限于绝对值。
(2)差示扫描量热法(DSC)
DSC作为热分析法被用于测量样品升温所需要的热量，同时对作为温度函数的参考值也进行了测量。测定DSC的一般过程已知，在描述的实施例中使用的特定仪器与采用的条件如下:
分析仪器：TA Instruments Q2000 DSC；
升温速率：10℃每分钟；
吹扫气体：氮气。
热解重量分析(TGA)
TGA用来测量样品的物理与化学性质的变化与升高的温度(以恒定的加热速率)之间的函数关系，或者与时间的函数(具有恒定温度和/或恒定的质量损失)。测定TGA的一般过程已知，在描述的实施例中使用的特定仪器与采用的条件如下:
分析仪器：TA Instruments Q5000 TGA；
升温速率：10℃每分钟；
吹扫气体：氮气。
实施例1双环铂组合物的制备
1)将5.0g卡铂(13.47mmol)与2.232g 1,1-环丁烷二羧酸(15.50mmol)加入20mL的玻璃小瓶中。
2)在上述玻璃小瓶中加入15mL去离子水，并在室温下搅拌该混合物以形成均匀的悬浮液，同时保持小瓶远离光源。
3)冷却混合物至20℃，转移至500mL反应瓶，用50mL去离子水润洗。
4)加入175mL去离子水，搅拌均匀并在20℃恒温2小时以形成均一溶液。
5)过滤。滤液冷冻干燥，再真空干燥。
6)获得7.21g双环铂与1,1-环丁烷二羧酸混合物。
7)测定双环铂的含量，96.20％。DCP/1,1-环丁烷二羧酸比例:1:0.15。
产物通过如上所述的XRPD、DSC与 1H NMR分析。
实施例2双环铂组合物的制备
1)将5.0g卡铂(13.47mmol)与22.32g 1,1-环丁烷二羧酸(155.0mmol)加入200mL的玻璃瓶中。
2)在上述玻璃瓶中加入125mL去离子水，并在室温下搅拌该混合物以形成均匀的悬浮液，同时保持反应瓶远离光源。
3)冷却混合物至20℃，转移至5L反应瓶，用150mL去离子水润洗。
4)加入2.0L去离子水，搅拌均匀并在20℃恒温2小时以形成均一溶液。
5)过滤。滤液冷冻干燥，再真空干燥。
6)获得72.1g双环铂与1,1-环丁烷二羧酸混合物。
7)测定双环铂的含量，96.22％。DCP/1,1-环丁烷二羧酸比例:1:10.5。
产物通过如上所述的XRPD、DSC与 1H NMR分析。
实施例3含有1,1-环丁烷二羧酸、柠檬酸和双环铂的组合产品的制备
1)将5.0g卡铂(13.47mmol)与3.879g 1,1-环丁烷二羧酸(26.94mmol)加入50mL的反应瓶中。
2)在上述反应瓶中加入25mL去离子水，并在室温下搅拌该混合物以形成均匀的悬浮液，同时保持小瓶远离光源。
3)冷却混合物至20℃，转移至500mL反应瓶，用50mL去离子水润洗。
4)加入225mL去离子水，搅拌均匀并在20℃恒温2小时以形成均一溶液。
5)加入柠檬酸2.588g(13.47mmol)(柠檬酸是作为酸性物质还是作为另外的其它组分起作用)，继续搅拌，形成均一溶液。
6)过滤。滤液冷冻干燥，再真空干燥。
7)获得11.462g双环铂与1,1-环丁烷二羧酸、柠檬酸混合物。
8)测定双环铂的含量，60.50％。
DCP/1,1-环丁烷二羧酸/柠檬酸比例:1:1:1。
产物通过如上所述的XRPD、DSC与 1H NMR分析。
实施例4含有1,1-环丁烷二羧酸、柠檬酸、GSH和双环铂的组合产品的制备
1)将5.0g卡铂(13.47mmol)与3.879g 1,1-环丁烷二羧酸(26.94mmol)加入50mL的反应瓶中。
2)在上述反应瓶中加入25mL去离子水，并在室温下搅拌该混合物以形成均匀的悬浮液，同时保持小瓶远离光源。
3)冷却混合物至20℃，转移至500mL反应瓶，用50mL去离子水润洗。
4)加入225mL去离子水，搅拌均匀并在20℃恒温2小时以形成均一溶液。
5)加入柠檬酸2.588g(13.47mmol)、4.135g谷胱甘肽(GSH，13.47mmol)继续搅拌，形成均一溶液。过滤。
6)滤液经冷冻干燥，再真空干燥。
7)获得15.60g双环铂与1,1-环丁烷二羧酸、柠檬酸和谷胱甘肽形成的混合物。
8)测定双环铂的含量，44.46％。DCP/1,1-环丁烷二羧酸/柠檬酸/GSH比例:1:1:1:1。
产物通过如上所述的XRPD、DSC与 1H NMR分析。
实施例5含有1,1-环丁烷二羧酸、绿原酸、谷胱甘肽、维生素C和双环铂的组合产品的制备
1)将5.15g双环铂(13.47mmol)、2.232g 1,1-环丁烷二羧酸(15.50mmol)、4.77g绿原酸(13.47mmol)、4.135g谷胱甘肽(GSH，13.47mmol)、11.862g维生素C充分混合均匀。
2)获得28.15g双环铂组合产品。
7)测定双环铂的含量，18.29％。
产物通过如上所述的XRPD、DSC与 1H NMR分析。
实施例6含有绿原酸、谷胱甘肽、维生素C和双环铂的组合产品的制备
1)将5.15g双环铂(13.47mmol)、4.77g绿原酸(13.47mmol)、4.135g谷胱甘肽(GSH，13.47mmol)、11.862g维生素C充分混合均匀。
2)获得25.92g双环铂组合产品。
7)测定双环铂的含量，19.87％。
产物通过如上所述的XRPD、DSC与 1H NMR分析。
实施例7含有谷胱甘肽、维生素C和双环铂组合产品的制备
1)将5.15g双环铂(13.47mmol)、4.135g谷胱甘肽(GSH，13.47mmol)、11.862g维生素C充分混合均匀。
2)获得21.147g双环铂组合产品。
7)测定双环铂的含量，24.35％。
产物通过如上所述的XRPD、DSC与 1H NMR分析。
实施例8含有叶酸、绿原酸、谷胱甘肽、维生素C和双环铂的组合产品的制备
1)将5.15g双环铂(13.47mmol)、1.03g叶酸、4.77g绿原酸(13.47mmol)、4.135g谷胱甘肽(GSH，13.47mmol)、11.862g维生素C充分混合均匀。
2)获得26.95g双环铂组合产品。
7)测定双环铂的含量，19.11％。
产物通过如上所述的XRPD、DSC与 1H NMR分析。
实施例9含有辅酶Q10、绿原酸、谷胱甘肽、维生素C和双环铂的组合产品的制备
1)将5.15g双环铂(13.47mmol)、5.03g辅酶Q10、4.77g绿原酸(13.47mmol)、4.135g谷胱甘肽(GSH，13.47mmol)、11.862g维生素C充分混合均匀。
2)获得30.95g双环铂组合产品。
7)测定双环铂的含量，16.64％。
产物通过如上所述的XRPD、DSC与 1H NMR分析。
实施例10含有辅酶Q10、柠檬酸、绿原酸、谷胱甘肽、维生素C和双环铂的组合产品的制备
1)将5.15g双环铂(13.47mmol)、5.03g辅酶Q10、4.77g柠檬酸、4.135g谷胱甘肽(GSH，13.47mmol)、11.862g维生素C充分混合均匀。
2)获得30.95g双环铂组合产品。
7)测定双环铂的含量，16.64％。
产物通过如上所述的XRPD、DSC与 1H NMR分析。
实施例11含有谷维素、柠檬酸、谷胱甘肽、维生素C和双环铂组合产品的制备
1)将5.15g双环铂(13.47mmol)、5.03g谷维素、4.77g柠檬酸、4.135g谷胱甘肽(GSH，13.47mmol)、11.862g维生素C充分混合均匀。
2)获得30.95g双环铂组合产品。
7)测定双环铂的含量，16.64％。
产物通过如上所述的XRPD、DSC与 1H NMR分析。
实施例12 MD36792(双环铂)抗丙型肝炎病毒(HCV)体外活性的研究
(一)实验材料:
1.化合物：MD36792和利巴韦林(可商购获得)。
2.细胞：Huh7.5.1细胞。
3.病毒：丙型肝炎病毒(HCV 2a型JFH1-Luc病毒株)。
4.实验试剂：DMEM培养基、
Figure PCTCN2018116213-appb-000002
试剂盒(Invitrogen)、Luciferase Assay System试剂盒(Promega)其他实验试剂。
(二)实验方法
1.MD36792的细胞毒性检测
实验原理：实验采用
Figure PCTCN2018116213-appb-000003
(Invitrogen)试剂盒检测药物对细胞的毒性作用。
Figure PCTCN2018116213-appb-000004
是一种氧化还原指示剂，能根据细胞代谢活性产生吸光度变化和荧光信号。
Figure PCTCN2018116213-appb-000005
易溶于水，其氧化形式进入细胞后经线粒体酶还原产生可测量的荧光及颜色变化，用于细胞活性和细胞增殖的定量分析以及体外细胞毒性研究。这种测定是基于具有代谢活性的细胞能将试剂转换成荧光和比色指示剂的能力。受损和无活性细胞具有较低的天然代谢活性，对应的信号较低，因此荧光信号强弱，可以反映细胞活性的高低。
方法步骤：Huh7.5.1细胞接种于96孔细胞培养板中，细胞贴壁后备用。用DMSO将药物从200倍起始浓度3倍梯度连续稀释成6个梯度，然后用DMEM完全培养基稀释成含药物的培养液，每浓度梯度复孔检测。加药培养72h后，弃去培养上清，加入含有
Figure PCTCN2018116213-appb-000006
的培养基，37℃孵育4h后，以激发光570nm和发射光595nm检测荧光读值。
计算公式：细胞活性(％)＝(样品孔-空白对照)/(细胞对照-空白对照)*100％
2.MD36792抗丙型肝炎病毒(HCV)的实验
实验原理：含Rluc报告基因的HCV病毒株JFH1-Luc感染Huh7.5.1细胞后，Rluc随着病毒的复制得以表达，Rluc报告基因的表达水平可以反映HCV病毒的复制水平。
实验步骤:(1)细胞铺板:Huh7.5.1细胞接种于96孔细胞培养板中，细胞贴壁后备用。(2)病毒感染:用培养基将药物从2倍起始浓度3倍梯度连续稀释成9个梯度，每个浓度2个重复孔，将含药物的培养液100μL加入细胞孔中，之后感染JFH1-luc病毒培养液100μL。(3)检测:病毒感染后继续培养培养72h后，用Renilla Luciferase Assay Kit检测Rluc读值。
实验设定利巴韦林阳性药物对照组、病毒对照组、细胞对照组。
计算公式：抑制率(％)＝100％-(药物组-细胞对照组)/(病毒对照组-细胞对照组)*100％
实验结果：如图1所示，MD36792对HCV的EC50(50％的抑制作用)是121.1μM，因此MD36792的选择指数SI(SI＝CC50/EC50)为1.54。由于此模型中HCV的复制对细胞状态要求很高，当药物存在细胞毒性作用时，会严重影响病毒的复制，因此我们认为333μM和111μM对HCV的抑制作用是由于毒性作用造成。故MD36792对HCV无抑制作用。而对照药物利巴韦林对HCV有明显的抑制作用。
实施例13 MD36792(双环铂)抗乙型肝炎病毒(HBV)体外活性的研究
(一)实验材料:
1.化合物：MD36792。
2.细胞：HepAD38细胞。
3.病毒：乙型肝炎病毒(HBV)。
4.实验试剂：DMEM/F12培养基、CellTiter-Glo检测试剂盒(Promega)、HBeAg抗原检测试剂盒(科华)、HBsAg抗原检测试剂盒(科华)、及其他实验试剂。
(二)实验方法
1.MD36792的细胞毒性检测
实验原理：采用了CellTiter-Glo试剂盒(Promega)检测药物对细胞的毒性作用。CellTiter-Glo试剂盒通过对ATP进行定量测定来检测培养物中活细胞数目，有代谢活性细胞的呼吸作用和其他生命活动过程可以产生ATP，试剂盒中使用萤光素酶生成的稳定辉光型信号，发光过程中萤光素酶需要ATP的参与。向细胞培养基中加入等体积CellTiter-Glo试剂，测量发光值，光信号和体系中ATP量成正比，而ATP又和活细胞数正相关。因此光信号值可以反映活细胞的数目。
方法步骤：将HepAD38细胞接种于96孔细胞培养板中，细胞贴壁后备用。将药物从1mM连续3倍梯度稀释9个梯度，每梯度2个复孔。将药物加入到细胞中，于37℃的CO2培养箱中培养。加药培养3天后，光镜下观察药物引起的细胞病变效应(CPE)，加入CellTiter-Glo检测细胞存活率。药物对细胞的毒性以细胞的活性表示。
计算公式：细胞活性(％)＝(药物组-空白对照)/(细胞对照-空白对照)*100％
2.MD36792抗乙型肝炎病毒(HBV)的实验
实验原理：HepAD38细胞系中HBV的复制可被四环素调控。在撤去dox后，整合的HBV基因组可转录形成pgRNA,pgRNA继续逆转录成rc DNA,合成的rc DNA会重新进入细胞核内形成cccDNA。只从cccDNA上才能表达HBeAg，HBeAg的表达量可反应出cccDNA的合 成量，故我们采用ELISA方法检测HBeAg的含量，检测药物对HBV的抑制作用。在此细胞中HBsAg可以持续的从整合的HBV DNA上转录翻译而成，我们同时检测HBsAg的含量来确定药物对HBV复制的影响。
实验步骤:(1)细胞铺板:将撤去Dox 3天的HepAD38细胞接种于96孔板中，37℃的CO2培养箱中培养24h。(2)加药处理:将MD36792用DMEM/F12完全培养基(10％FBS)从333μM开始稀释，连续3倍梯度稀释9个梯度，每梯度2个复孔。将稀释好的药物加入到细胞中，37℃的CO2培养箱中培养72h。(3)检测:取上清用HBeAg抗原检测试剂盒、HBsAg抗原检测试剂盒分别检测HBeAg和HBsAg的表达量。
计算公式：抗原抑制率(％)＝100％-(药物组-空白对照)/(细胞对照组-空白对照)*100％
实验结果：如图2所示，MD36792对HBV的HBeAg(e抗原)和HBsAg(表面抗原)的表达无抑制作用。
实施例14 MD36792(双环铂)抗人类免疫缺陷病毒(HIV)体外活性研究
(一)实验材料:
1.化合物：MD36792和齐多夫定(AZT)(可商购获得)。
2.细胞：MT4细胞。
3.病毒：人类免疫缺陷病毒(HIV)。
4.实验试剂：RPMI-1640培养基、CellTiter-Glo检测试剂盒(Promega)及其他实验试剂。
(二)实验方法
1.MD36792的细胞毒性检测
实验原理：采用了CellTiter-Glo试剂盒(Promega)检测药物对细胞的毒性作用。CellTiter-Glo试剂盒通过对ATP进行定量测定来检测培养物中活细胞数目，有代谢活性细胞的呼吸作用和其他生命活动过程可以产生ATP，试剂盒中使用萤光素酶生成的稳定辉光型信号，发光过程中萤光素酶需要ATP的参与。向细胞培养基中加入等体积CellTiter-Glo试剂，测量发光值，光信号和体系中ATP量成正比，而ATP又和活细胞数正相关。因此光信号值可以反映活细胞的数目。
方法步骤：将MT4细胞接种于96孔细胞培养板中，细胞贴壁后备用。将药物从1mM连续3倍梯度稀释9个梯度，每梯度2个复孔。将药物加入到细胞中，于37℃的CO2培养箱中培养。光镜下观察药物引起的细胞病变效应(CPE)，加入CellTiter-Glo检测细胞 存活率。药物对细胞的毒性以细胞的活性表示。
计算公式：细胞活性(％)＝(药物组-空白对照)/(细胞对照-空白对照)*100
2.MD36792抗人类免疫缺陷病毒(HIV)的实验
实验原理：利用MT-4细胞保护实验对化合物进行抗病毒检测。
实验步骤：将3倍稀释的药物加入96孔板中，将LAI毒株病毒和MT-4细胞孵育后接种于孔板中，培养后，待病毒感染对照孔出现明显的CPE，加入CellTiter-Glo试剂，混匀后检测化学发光信号。
实验设细胞对照(未感染细胞对照)，病毒对照，阳性药物对照(齐多夫定，AZT)。
抑制率(％)＝(药物组-病毒对照)/(细胞对照–病毒对照)*100％
实验结果：如图3所示，MD36792对HIV的感染无抑制作用，而对照药物齐多夫定对HIV有明显的抑制作用。
实施例15 MD36792(双环铂)抗埃博拉病毒体外活性研究
(一)实验材料
1.化合物：MD36792。
2.细胞：MDCK细胞。
3.病毒：埃博拉病毒。
4.实验试剂：DMEM培养基、
Figure PCTCN2018116213-appb-000007
试剂盒(Invitrogen)、Luciferase Assay System试剂盒(Promega)及其他实验试剂。
(二)实验方法
1.MD36792的细胞毒性检测
实验原理：采用了
Figure PCTCN2018116213-appb-000008
(Invitrogen)试剂盒检测药物对细胞的毒性作用。
Figure PCTCN2018116213-appb-000009
是一种氧化还原指示剂，能根据代谢活性产生吸光度变化和荧光信号。
Figure PCTCN2018116213-appb-000010
易溶于水，其氧化形式进入细胞后经线粒体酶还原产生可测量的荧光及颜色变化，用于细胞活性和细胞增殖的定量分析以及体外细胞毒性研究。这种测定是基于具有代谢活性的细胞将试剂转换成荧光和比色指示剂的能力，受损和无活性细胞具有较低的天然代谢活性，对应的信号较低。因此荧光信号强弱，可以反映细胞活性的高低。
实验步骤：将MDCK细胞接种于96孔细胞培养板中，细胞贴壁后备用。将药物从1mM连续3倍梯度稀释9个梯度，每梯度2个复孔。将药物加入到细胞中，于37℃的CO2培养箱中培养。加药培养2天后，光镜下观察药物引起的细胞病变效应(CPE)，加入
Figure PCTCN2018116213-appb-000011
培养基，37℃孵育4h后，以激发光570nm和发射光595nm检测荧光读值。药物对细胞的毒性以细胞的活性表示。
计算公式：细胞活性(％)＝(药物组-空白对照)/(细胞对照-空白对照)*100％
2.MD36792抗埃博拉病毒的实验
实验原理：含Rluc报告基因的埃博拉病毒感染细胞后，Rluc随着病毒的复制得以表达，Rluc报告基因的表达水平可以反映腺病毒感染水平。
方法步骤:(1)细胞铺板:MDCK细胞接种于96孔细胞培养板中，待细胞贴壁后备用。(2)加药处理:用维持培养基(2％FBS)将药物连续3倍梯度稀释成9个药物浓度组，配置成2X含药培养液，每梯度2个复孔。待细胞长成单层后加入100μl含2x药物的DMEM培养液，然后加入100μl DMEM稀释的埃博拉病毒，37℃培养。(3)检测：病毒感染后继续培养培养48h后，用Luciferase Assay Kit检测Rluc读值。
实验设定病毒对照组、细胞对照组。
计算公式：抑制率(％)＝100％-(药物组-细胞对照组)/(病毒对照组-细胞对照组)*100％
实验结果：如图4所示，MD36792对埃博拉病毒的感染无抑制作用。
实施例16双环铂单独用药(口服或注射)对乙肝患者、丙肝患者者、HIV感染者和埃博拉病毒感染者的体内活性的研究。
其中双环铂水针剂注射剂，从北京兴大科技系统公司采购，规格为50mg/5mL。口服制剂所用双环铂参考专利US2016/0297842制备，将双环铂溶于去离子水中而得，规格为50mg/5mL。
实验方法：(1)使用双环铂单独给予12个乙肝患者使用1-3个月，观察病毒指数和肝功能。其中6例为点滴静脉注射，将150mg双环铂水溶液溶于250毫升5％葡萄糖水溶液，每两天一次；其中6例为口服，将150mg双环铂水溶液溶于250毫升5％葡萄糖水溶液，每两天一次。(2)使用双环铂单独给予9个丙肝患者使用1-3个月，观察病毒指数和肝功能其中6例为点滴静脉注射，将150mg双环铂水溶液溶于250毫升5％葡萄糖水溶液，每两天一次；其中6例为口服，将150mg双环铂水溶液溶于250毫升5％葡萄糖水溶液，每两天一次。(3)使用双环铂单独给予8个HIV感染者(病毒指数>>100000IU/mL)使用1-3个月(口服、注射分别四例患者)，观察病毒指数和肝功能；使用双环铂(参考上述方法，葡萄糖水溶液静脉注射)单独给予20例埃博拉病毒感染者(非洲)使用1-3 周，观察病毒指数和肝功能。
实验结果：(1)使用双环铂单独给予12个乙肝患者使用1-3个月，无一例显示患者的病毒指数有下降趋势，病毒指数持续上升，肝功能也未见改善；(2)使用双环铂单独给予9个丙肝患者使用1-3个月，无一例显示患者的病毒指数有下降趋势，病毒指数持续上升，肝功能也未见改善；(3)使用双环铂单独给予8个HIV感染者(病毒指数>>100000IU/mL)使用1-3个月(口服、注射分别四例患者)，无一例显示患者的病毒指数有下降趋势，病毒指数持续上升，肝功能也未见改善；使用双环铂单独给予20例埃博拉病毒感染者(非洲)使用1-3周，无一例显示患者的病毒指数有下降趋势，病毒指数持续上升，病情未见任何控制或者缓解。
实施例17含有双环铂的组合产品对乙肝患者、丙肝患者和HIV感染者的体内活性的研究。
实验方法：(1)采用组合产品在15例乙型肝炎患者(未经任何抗病毒药物治疗)中使用，经过1-3个月的治疗，观察病毒指数和肝功能指标；其中6例采用实验4制备的组合产品(所述组合产品以胶囊存在，所述胶囊可以根据本领域技术人员知晓的常规技术来制备)，用量参考双环铂用量，每两天一次，剂量为150毫克胶囊；其中9例采用实验10制备的组合产品，用量参考双环铂用量，每两天一次，剂量为150毫克胶囊；(2)采用组合产品在13例丙型肝炎患者(未经任何抗病毒药物治疗)中使用，经过1-3个月的治疗，观察病毒指数和肝功能指标；其中5例采用实验7制备的组合产品，用量参考双环铂用量，每天三次，剂量为50毫克胶囊；其中8例采用实验11制备的组合产品，用量参考双环铂用量，每天三次，剂量为50毫克胶囊；(3)采用组合产品在8例HIV感染者患者(未经任何抗病毒药物治疗)中使用，观察病毒指数和肝功能指标；其中2例采用实验4制备的组合物，用量参考双环铂用量，每天三次，剂量为50毫克胶囊；其中6例采用实验11制备的组合产品，用量参考双环铂用量，每天三次，剂量为50毫克胶囊。
实验结果：本发明公开的含有双环铂的组合产品制剂在15例乙型肝炎患者(未经任何抗病毒药物治疗)中使用，经过1-3个月的治疗，病毒指数大幅度下降，肝功能指标基本正常；本发明公开的含有双环铂的组合产品在13例丙型肝炎患者(未经任何抗病毒药物治疗)中使用，经过1-3个月的治疗，病毒指数大幅度下降，2例病毒指数下降到检测限以下，肝功能指标基本正常；本发明公开的含有双环铂的组合产品在8例HIV感染者患者(未经任何抗病毒药物治疗)中使用，经过1-3个月的治疗，病毒指数大幅度下降，CD4 指数大幅度上升，肝功能指标基本正常。
实施例18含有双环铂的组合产品对丙肝患者和HIV感染者的体内活性的研究。
下述案例(1)、(2)采用实验6制备的组合产品(所述组合产品以胶囊存在，所述胶囊可以根据本领域技术人员知晓的常规技术来制备)，用量参考双环铂用量，剂量为每天150毫克胶囊；下述案例(3)、(4)采用实验10制备的组合产品(所述组合产品以胶囊存在，所述胶囊可以根据本领域技术人员知晓的常规技术来制备)，用量参考双环铂用量，剂量为每天150毫克胶囊。
实验方法：(1)丙型肝炎患者贺先生(61岁)采用抗干扰素无效，服用其他抗病毒药物无效，RNA病毒指数持续上升，RNA病毒指数定量472000IU/mL，肝部出现典型的疼痛感，在口服含有双环铂的组合产品一个月后，检测RNA病毒指数和肝功能指标；(2)丙型肝炎患者王先生(51岁)，未经任何治疗，丙型肝炎III型患者，RNA病毒指数定量932000IU/mL，肝部出现典型的疼痛、压迫感。在口服含有双环铂的组合产品一个月后，观察疼痛和压迫感，继续两个月口服所述组合产品后，检测RNA病毒指数和肝功能指标；(3)女性患者(43岁)，病毒学检查确为HIV阳性，临床C2型。检查结果显示：CD4淋巴细胞计数为312，CD4细胞为319，CD4/CD8＝0.58:1。在口服含有双环铂的组合产品四个月后，检测CD4、CD8细胞及其比值；(4)女性患者(28岁)，病毒学检查确为HIV阳性，CD4细胞为190，CD8为815，CD4/CD8＝0.23:1。口服含有双环铂的组合产品六个月后，检测CD4、CD8细胞及其比值。
实验结果：(1)丙型肝炎患者贺先生(61岁)在口服含有双环铂的组合产品一个月后，RNA病毒指数定量下降到4520IU/mL。肝功能主要指标没有明显变化，患者疼痛感消失；(2)丙型肝炎患者王先生(51岁)，在口服含有双环铂的组合产品一个月后，疼痛、压迫感消失，继续两个月口服所述组合产品后，RNA病毒指数定量将为1000IU/mL以下，肝功能基本正常；(3)女性患者(43岁)，病毒学检查确为HIV阳性，临床C2型，检查结果显示:CD4淋巴细胞计数为312，CD4细胞为319，CD4/CD8＝0.58:1，在口服含有双环铂的组合产品四个月后，检查结果显示:CD4细胞为568，CD8为606，CD4/CD8＝0.92:1。(4)女性患者(28岁)，病毒学检查确为HIV阳性，CD4细胞为190，CD8为815，CD4/CD8＝0.23:1。经过口服含有双环铂的组合产品六个月后，病毒学检查已测不到，CD4为563，CD8为575，CD4/CD8＝0.97:1。
上述结果显示，双环铂直接抗病毒的活性很低，从多种病毒感染者单独使用双环铂或者双环铂组合产品的结果显示，双环铂单独使用对于患者体内抗病毒没有显示临床疗效。双环铂的组合产品用来治疗HCV、HBV、HIV病毒感染者，效果显著。
实施例19含有双环铂的组合产品的稳定性研究
本发明公开了双环铂与多种酸性物质混合后的制剂组合。为实现双环铂的更加稳定及尝试提高双环铂的溶解度，本发明公开了双环铂与多种酸性物质形成混合物的比例及制备方法。
(1)双环铂与1,1-环丁烷二羧酸形成混合物的方法
常规的制备方法，可以是双环铂与一定比例的1,1-环丁烷二羧酸混合而成；也可以是双环铂与一定比例的1,1-环丁烷二羧酸完全溶于水后冻干而成。XRPD结构、H 1-NMR显示混合后双环铂稳定性未见影响。
该制剂混合物的制备可以从卡铂与一定比例的1,1-环丁烷二羧酸在水作为介质，经过0-40℃条件下搅拌1至24小时后，或直接冻干、混合均匀而成，或加入适量的水全部溶解后冻干而成。XRPD结构、H 1-NMR显示混合后混合物是由双环铂和1,1-环丁烷二羧酸构成，没有检查到卡铂的残留。
这种制备方法大大提高了双环铂的收率，使卡铂的原料完全得以使用。
(2)双环铂与柠檬酸、绿原酸、柠檬酸、没食子酸等的混合物制备
常规的制备方法，可以是双环铂与一定比例的1,1-环丁烷二羧酸、柠檬酸、绿原酸、柠檬酸、没食子酸、阿魏酸、马来酸、水杨酸等其中一种酸或多种混合而成；也可以是双环铂与一定比例的1,1-环丁烷二羧酸、柠檬酸、绿原酸、柠檬酸、没食子酸、阿魏酸、马来酸、水杨酸等其中一种酸或多种混合完全溶于水后冻干而成。XRPD结构、H 1-NMR显示混合后双环铂稳定性未见影响。
(3)双环铂或者其混合物与另外的其它组分的组合产品的制备。
另外的其它组分包括:辅酶Q10、姜黄素、谷胱甘肽(GSH)、谷维素、维生素C、花青素。
如通过实施例5-10所示，以双环铂为主要活性物质的组合产品的制备，既可以采用常规的制备方法，也可以针对具体情况采用特殊的制备方法。
在多个实例中，双环铂以水作为载体，制备成冻干粉、水针剂。稳定性实验显示，该制剂保留良好的稳定性。多个实例中，双环铂与相应的药用辅料相容稳定性良好，由此制 备成相应的口服制剂。
实施例20双环铂与1,1-环丁烷二羧酸和辅料的稳定性研究
双环铂的组合产品连续八周的稳定性如下表1-4显示：
1、双环铂与1,1-环丁烷二羧酸(1:1.2至1:20)形成的固体组合产品、溶液组合产品在40℃是稳定的。上述固体组合产品在光照条件下连续八周的考察，结果显示是稳定的。
表1
Figure PCTCN2018116213-appb-000012
Figure PCTCN2018116213-appb-000013
Figure PCTCN2018116213-appb-000014
2、双环铂与维生素C、没食子酸、水杨酸、柠檬酸(即，VC，下同)、阿魏酸等形成的固体组合产品在40℃是稳定的。
表2
Figure PCTCN2018116213-appb-000015
Figure PCTCN2018116213-appb-000016
3、双环铂与没食子酸、水杨酸、柠檬酸、阿魏酸等形成的溶液组合产品在40℃条件下，基本上在两周后开始分解。
表3
Figure PCTCN2018116213-appb-000017
Figure PCTCN2018116213-appb-000018
4、双环铂与相应的辅料的稳定性实验证明：双环铂与硬脂酸镁、羟丙基纤维素、预胶化淀粉、维生素C、壳聚糖、β-环糊精、聚乙烯吡咯烷酮的单一或多个混合后在40℃条件下连续8周的考察是稳定的。
表4
Figure PCTCN2018116213-appb-000019
备注：
1、MD36792是指双环铂；
2、配比物的比例是指双环铂与1,1-环丁烷二羧酸的摩尔比例；
3、高温实验条件为T＝40℃；
4、光照实验条件为照度为2000LX；
5、溶液溶度为：1mg/ml；
6、误差在上下2％。
实施例21双环铂对疼痛和炎症的影响
本申请发明人发现，本专利公开双环铂作为主要活性物质用于治疗癌症患者引发的疼痛方面，展示了显著的疗效。在癌症患者中，尤其是肝癌晚期患者、肾癌患者、骨转移患者、脑转移及骨癌患者，单一的选择了使用双环铂注射液或者口服制剂作为唯一的治疗手段(请参考表5)。发明人发现，一定数量的癌症晚期患者对双环铂显示没有敏感性，对肿瘤的抑制没有出现疗效。但是双环铂对于癌痛出现明显的缓解效果依然明显，甚至疼痛消失。部分患者使用一定疗程后停止使用双环铂，疼痛也没有发生。
表5双环铂作为主要活性物质对由癌症引起的疼痛的效果
Figure PCTCN2018116213-appb-000020
上述癌症患者剂量：每两天使用一次，150毫克/5％葡萄糖水溶液静脉点滴。所用双环铂注射液从北京兴大科技系统公司采购，规格为50mg/5mL。
在治疗肿瘤患者的临床中发现，双环铂对于肿瘤引发的组织水肿、炎症显示良好的效果。在多例肺癌患者脑转移的患者采用口服或注射双环铂的过程中发现，在使用双环铂一周至两周后，脑部因癌转移引发的组织水肿基本消除。说明双环铂对于炎症由良好的抗炎症疗效。在多例肝癌患者发生的肝部组织水肿，在采用双环铂的灌注或口服一段时间后，组织水肿明显的消除或减少。
实施例22.另外的其它组分AA011和VK021单独使用时的抗病毒效果
AA011(谷胱甘肽)和VK021(维生素C)样品信息如下表6所示:
Figure PCTCN2018116213-appb-000021
如图5所示，AA011和VK021及阳性药物的抗病毒效果如下图所示。阳性药物2’CMC具有良好的抗病毒效果，随着药物剂量的增大抗病毒效果越好。添加剂AA011在1000μM和250μM浓度时有一定的抗病毒效果，并且在1000μM时没有明显的细胞毒性；添加剂VK021在1000μM和250μM浓度时也有一定的抗病毒效果，但在1000μM时有微弱的细胞毒性。
实施例23 MD36792和AA011、VK021的组合产品的体外抗HCV病毒的效果
MD36792和AA011、VK021样品信息及检测结果如下表7所示:
Figure PCTCN2018116213-appb-000022
MD36792和AA011(图6中A)、VK021(图6中V)的组合产品的抗病毒效果如图6所示。
MD36792单独使用抗病毒的EC50为15.62μg/ml，对细胞的毒性CC50为69.4，抗病毒效果的选择指数SI为4.44。选择指数比较低，可以认为有一定的抗病毒效果，但是对细胞的毒性比较大。36792和AA011、VK021联合使用的抗病毒效果为EC50为4.43μg/ml、CC50为24.82、SI为5.6。三个样品混合使用对细胞的毒性更大，选择指数也不是很大，联合使用比MD36792单独使用的抗病毒效果在细胞水平上并没有明显提高。
实施例24 MD36792的镇痛作用的研究
(一)、实验材料、动物及设备
1.动物：ICR小鼠，50只，18-22g(长沙斯莱克景达实验动物公司)
2.试剂：罗通定(广州白云山制药)。
3.仪器：玻璃罩。
4.药物：MD36792
(二)、实验方法及实验结果
实验方法：动物适应性喂养5天，称取小鼠体质量，采用分层随机分组法，将50只小鼠随机分为模型组(即，空白对照组(蒸馏水))、阳性对照组(罗通定，100mg/kg，p.o)、MD36792低剂量组(1mg/ml水溶液，10mg/kg，i.p.)、MD36792中剂量组(2mg/ml水溶液，20mg/kg，i.p.)和MD36792高剂量组(4mg/ml水溶液，40mg/kg，i.p.)，共5组。MD36792组及阳性对照组分别给予相应药物，给药1hr后，各组小鼠腹腔注射0.8％醋酸(0.2mL/只)。观察并记录15min内扭体次数。
实验结果：
实验结果如下表8所示：
Figure PCTCN2018116213-appb-000023
*与模型组(即，空白对照组)相比，在统计学上具有显著差异，P<0.05
**与模型组(即，空白对照组)相比，在统计学上具有显著差异，P<0.01
腹腔注射0.8％醋酸后15min内，模型组小鼠平均扭体次数达到19次。与模型组比较，MD36792高剂量组(40mg/kg)与阳性对照组(罗通定，100mg/kg)在统计学上显著抑制 小鼠扭体次数(分别为，P＝0.009或P＝0.000)。MD36792在镇痛作用方面呈剂量非依赖性的(请参考图7)。
因此，由以上数据表明，在采用经典的醋酸致小鼠扭体法评价药物的镇痛作用的模型中，MD36792与阳性对照药罗通定均具有显著镇痛作用。

Claims (51)

  1. 一种组合产品，所述组合产品含有双环铂和酸性物质。
  2. 根据权利要求1的组合产品，其中所述酸性物质选自下述中的一种或多种：1,1-环丁烷二羧酸、柠檬酸、绿原酸、阿魏酸、马来酸、水杨酸、叶酸和没食子酸。
  3. 根据权利要求2的组合产品，其中所述双环铂与所述酸性物质的比例为：1:0.01至1:99，优选为1:3至1:10。
  4. 根据权利要求1-3中任一项的组合产品，所述组合产品任选地包含一种或多种下述另外的其它组分：辅酶Q10、姜黄素、谷胱甘肽、谷维素、柠檬酸、维生素C和花青素。
  5. 根据权利要求1-4中任一项的组合产品，所述组合产品可以组合物或药物组合物的形式存在，所述组合产品是口服制剂，如胶囊、片剂、颗粒剂；冻干制剂或水针剂；雾化剂；或其他制剂形式。
  6. 根据权利要求1-4中任一项的组合产品，所述双环铂、所述酸性物质或所述另外的其它组分各自以单独的制剂形式存在，所述组合产品是口服制剂，如胶囊、片剂、颗粒剂；冻干制剂或水针剂；雾化剂；或其他制剂形式。
  7. 一种组合产品，所述组合产品含有双环铂和一种或多种下述另外的其它组分：辅酶Q10、姜黄素、谷胱甘肽、谷维素、柠檬酸、维生素C和花青素。
  8. 根据权利要求7的组合产品，其中所述组合产品任选地含有酸性物质，所述酸性物质选自下述中的一种或多种：1,1-环丁烷二羧酸、柠檬酸、绿原酸、阿魏酸、马来酸、水杨酸、叶酸和没食子酸，所述组合产品是口服制剂，如胶囊、片剂、颗粒剂；冻干制剂或水针剂；雾化剂；或其他制剂形式。
  9. 根据权利要求8的组合产品，其中所述双环铂与所述酸性物质的比例为：1:0.01至1:99，优选为1:3至1:10。
  10. 根据权利要求1-9中任一项的组合产品在制备药物中的用途，所述药物用于治疗和/或预防疼痛、炎症和与病毒感染相关的疾病。
  11. 根据权利要求10的用途，其中所述疼痛选自由癌症或其它原因引起的疼痛，所述炎症选自由癌症或其它原因引起的炎症，所述与病毒感染相关的疾病选自与乙型肝炎病毒、丙型肝炎病毒、埃博拉病毒或人类免疫缺陷病毒感染相关的疾病。
  12. 一种治疗和/或预防疼痛、炎症和与病毒感染相关的疾病的方法，所述方法包括对有此需要的患者使用根据权利要求1-9中任一项的组合产品。
  13. 根据权利要求12的方法，其中所述疼痛选自由癌症或其它原因引起的疼痛，所述炎症选自由癌症或其它原因引起的炎症且所述与病毒感染相关的疾病选自与乙型肝炎病毒、丙型肝炎病毒、埃博拉病毒或人类免疫缺陷病毒感染相关的疾病。
  14. 根据权利要求12-13中任一项的方法，其中所述组合产品中双环铂的剂量为0.01至10mg/kg患者体重，优选为0.01至5mg/kg患者体重。
  15. 根据权利要求12-14中任一项的方法，所述组合产品可以通过下述方式施用：口服、口腔、吸入喷雾、舌下、直肠、透皮、阴道粘膜、透黏膜、局部给药，鼻或肠道给药；注射给药，如肌肉注射、皮下注射、髓内注射，以及鞘内、脑部直接给药、原位给药、皮下、腹腔内、静脉注射、关节内滑膜、胸骨、内、肝内、病灶内，颅内、腹腔、鼻腔、或眼内注射或其他药物递送方式。
  16. 根据权利要求12-15中任一项的方法，所述组合产品可以组合物或药物组合物的形式存在，或所述组合产品中的所述双环铂、所述酸性物质或所述另外的其它组分各自以单独的制剂形式存在，其可以同时、连续或间隔一定时间施用。
  17. 一种制备权利要求1-9中任一项的组合产品的方法，所述方法包括：
    1)加入双环铂作为活性物质；
    2)任选地加入酸性物质以形成混合物，其中所述双环铂与所述酸性物质的比例为：1:0.01至1:99，优选为1:3至1:10，且所述酸性物选自下述的一种或多种：1,1-环丁烷二羧酸、柠檬酸、绿原酸、阿魏酸、马来酸、水杨酸、叶酸和没食子酸；且
    3)任选地加入一种或多种选自下述的另外的其它组分：辅酶Q10、姜黄素、谷胱甘肽(GSH)、谷维素、柠檬酸、维生素C和花青素。
  18. 用于治疗和/或预防疼痛、炎症和与病毒感染相关的疾病的根据权利要求1-9中任一项的组合产品。
  19. 双环铂作为唯一活性物质在制备药物中的用途，所述药物用于治疗和/或预防疼痛或炎症。
  20. 根据权利要求19的用途，所述疼痛是癌症引起的疼痛，且所述炎症是由癌症引起的炎症。
  21. 根据权利要求19的用途，所述疼痛是由非癌症的其它原因引起的疼痛，且所述炎症是由非癌症的其它原因引起的炎症。
  22. 一种治疗和/或预防疼痛的方法，所述方法包括对有此需要的患者使用有效剂量的双环铂。
  23. 根据权利要求22所述的方法，其中所述患者是癌症患者，优选为肝癌患者、肾癌患者、骨转移患者、脑转移或骨癌患者，更优选为癌症晚期患者或对铂类抗癌药已经产生耐药性的患者，最优选为肝癌晚期患者。
  24. 根据权利要求23所述的方法，其中所述双环铂的有效剂量可以低于双环铂在该癌症患者中的有效抗癌剂量。
  25. 根据权利要求22-24中任一项的方法，其中所述双环铂为唯一治疗和/或预防疼痛的活性物质。
  26. 根据权利要求22-24中任一项的方法，进一步包括给所述患者使用一种或多种其他具有止痛效果的活性物质。
  27. 根据权利要求22-26中任一项的方法，进一步包括给所述患者使用一种或多种具有抗癌效果的活性物质，其中所述具有抗癌效果的活性物质优选为非铂类抗癌药。
  28. 根据权利要求22、25和26中任一项的方法，其中所述患者不是癌症患者。
  29. 根据权利要求22-28中任一项的方法，其中所述双环铂以药物组合物形式存在。
  30. 根据权利要求22-28中任一项的方法，其中所述双环铂存在于权利要求1-9中任一项的组合产品中。
  31. 一种治疗和/或预防组织水肿，例如肝部水肿，脑部水肿等，或炎症的方法，所述方法包括对有此需要的患者使用有效剂量的双环铂。
  32. 根据权利要求31所述的方法，其中患者是癌症患者，优选为肝癌患者、肾癌患者、骨转移患者、脑转移或骨癌患者，更优选为癌症晚期患者或对铂类抗癌药已经产生耐药性的患者，最优选为肝癌晚期患者。
  33. 根据权利要求32所述的方法，其中所述双环铂的有效剂量可以低于双环铂在该癌症患者中的有效抗癌剂量。
  34. 根据权利要求32-33中任一项的方法，进一步包括给所述患者使用一种或多种具有抗癌效果的活性物质，其中所述具有抗癌效果的活性物质优选为非铂类抗癌药。
  35. 根据权利要求31中的方法，其中所述患者不是癌症患者。
  36. 根据权利要求31-35中任一项的方法，其中所述双环铂以药物组合物形式存在。
  37. 根据权利要求31-35中任一项的方法，其中所述双环铂存在于权利要求1-9中任一项的组合产品中。
  38. 一种治疗和/或预防与病毒感染相关的疾病的方法，例如降低患者病毒指数的 方法，所述方法包括对有此需要的患者使用有效剂量的药物组合物，其中所述药物组合物包含双环铂和谷胱甘肽。
  39. 根据权利要求38所述的方法，其中所述病毒感染为乙型肝炎病毒，丙型肝炎病毒、埃博拉病毒，和/或人类免疫缺陷病毒感染。
  40. 根据权利要求38所述的方法，其中所述病毒感染为乙型肝炎病毒感染。
  41. 根据权利要求38所述的方法，其中所述病毒感染为丙型肝炎病毒感染。
  42. 根据权利要求38所述的方法，其中所述病毒感染为埃博拉病毒感染。
  43. 根据权利要求38所述的方法，其中所述病毒感染为人类免疫缺陷病毒感染。
  44. 根据权利要求38-43中任一项的方法，包括给所述患者使用有效剂量的药物组合物，每天1-3次。
  45. 根据权利要求44中的方法，包括给所述患者使用有效剂量的药物组合物至少7天，优选地，1个月到1年，优选地，1个月到6个月，例如，1、2、3、4、5、6个月。
  46. 根据权利要求38-45中任一项的方法，其中所述患者不接受任何其他抗病毒药物治疗，和/或未接受任何其他抗病毒药物治疗。
  47. 根据权利要求38-45中任一项的方法，进一步包括给所述患者施用其他抗病毒药物。
  48. 根据权利要求38-47中任一项的方法，其中所述药物组合物任选地包含一种或多种下述另外的其它组分：辅酶Q10、姜黄素、谷维素、柠檬酸、维生素C和花青素。
  49. 根据权利要求22-48中任一项的方法，其中所述双环铂或药物组合物存在形式是：口服制剂，如胶囊、片剂、颗粒剂；冻干制剂或水针剂；雾化剂；或其他制剂形式。
  50. 根据权利要求22-48中任一项的方法，其中所述双环铂或药物组合物可以通过下述方式施用：口服、口腔、吸入喷雾、舌下、直肠、透皮、阴道粘膜、透黏膜、局部给药，鼻或肠道给药；注射给药，如肌肉注射、皮下注射、髓内注射，以及鞘内、脑部直接给药、原位给药、皮下、腹腔内、静脉注射、关节内滑膜、胸骨、肝内、病灶内，颅内、腹腔、鼻腔、或眼内注射或其他药物递送方式。
  51. 一种制备双环铂或双环铂与1,1-环丁烷二羧酸的组合物的方法，所述方法包括：
    1)在合适的溶剂中，在室温或加热下，将卡铂与1,1-环丁烷二羧酸以1:1.05至1:99的摩尔比，搅拌适量时间，得到含有1,1-环丁烷二羧酸的双环铂的混合物；且任选地
    2)将所得混合物直接冻干、浓缩后加入适量的水全部溶解后冻干，或者配制成所需的水溶液，得到含有双环铂和1,1-环丁烷二羧酸的组合物。
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US20200361973A1 (en) 2020-11-19
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