WO2022100535A1 - 一种抗肿瘤药物组合物及其应用 - Google Patents

一种抗肿瘤药物组合物及其应用 Download PDF

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WO2022100535A1
WO2022100535A1 PCT/CN2021/129184 CN2021129184W WO2022100535A1 WO 2022100535 A1 WO2022100535 A1 WO 2022100535A1 CN 2021129184 W CN2021129184 W CN 2021129184W WO 2022100535 A1 WO2022100535 A1 WO 2022100535A1
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pharmaceutical composition
polyethylene glycol
tumor
peg
camptothecin derivatives
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French (fr)
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王庆彬
石娟
胡静云
赵宣
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Tianjin Jenkem Technology Co Ltd
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Tianjin Jenkem Technology Co Ltd
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Priority to EP21891060.2A priority Critical patent/EP4230205B1/en
Priority to US18/252,424 priority patent/US20230405132A1/en
Publication of WO2022100535A1 publication Critical patent/WO2022100535A1/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to the technical field of medicine, in particular to an anti-tumor pharmaceutical composition (the active ingredients of which include polyethylene glycol-modified camptothecin derivatives (especially polyethylene glycol-modified irinotecan) and temozolomide) and its application.
  • the active ingredients of which include polyethylene glycol-modified camptothecin derivatives (especially polyethylene glycol-modified irinotecan) and temozolomide) and its application.
  • Tumor is one of the common diseases that threaten human health, second only to cardiovascular disease.
  • the research on tumor has made great progress, and a variety of radiotherapy, chemotherapy and other methods have been developed to treat tumors. All have limitations, it is difficult to achieve a radical effect, and drug resistance and side effects are prone to occur. Cancer mortality still ranks first among all diseases. Statistics show that 3 million people died of cancer in my country in 2006, and the incidence of cancer is still on the rise, with a younger trend. According to statistics, in less than 20 years, the incidence of cancer in my country has increased by 69%, and the mortality rate has increased by 29.4%. Therefore, researching new and effective tumor therapeutic drugs is still the main direction of current tumor therapy.
  • Camptothecin a pyrroloquinoline cytotoxic alkaloid
  • CPT a pyrroloquinoline cytotoxic alkaloid
  • camptothecin derivatives So far, a series of semi-synthetic and fully synthetic camptothecin derivatives have appeared and entered the clinical application or clinical trial stage, for example, hydroxycamptothecin, irinotecan, topotecan, 9-aminocamptothecin, 9- Nitrocamptothecin, Gematecan, etc. It has been reported that camptothecin derivatives are used in the treatment of neuroblastoma, especially relapsed and refractory neuroblastoma, but the effect is not satisfactory.
  • the present invention provides a pharmaceutical composition, the active ingredients of which include:
  • Temozolomide or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof.
  • the above-mentioned active ingredient consists of the above-mentioned (1) and (2).
  • the above-mentioned active ingredients may be composed of polyethylene glycol-modified camptothecin derivatives and temozolomide.
  • the mass ratio of active ingredient (2) to (1) may be 0.1-10:0.1-10 (specifically Such as 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:4, 1:5, 1 :6, 1:7, 1:8, 1:9, 1:10), especially 1:1-10, such as 1:1-5.
  • the molar ratio of the camptothecin derivative part to temozolomide can be 0.01-100:0.01-100 (specifically, such as 1:0.1, 1:1, 1:10, 1:20, 1 :30, 1:40, 1:50, 1:70, 1:80, 1:90, 1:100).
  • polyethylene glycol-modified camptothecin derivatives of the present invention have the structure of general formula (I):
  • PEG represents a polyethylene glycol residue, and the molecular weight of PEG is 300-60000 Daltons (specifically, 300, 500, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 16000, 17000, 18000, 19000, 20000, 21000, 22000, 23000, 24000, 25000, 26000, 28000, 30000, 40000, 50000, 60000);
  • a 1 and A 2 represent the same or different amino acid residues
  • n is an integer of 2-12 (specifically, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12);
  • n is an integer of 0-6 (specifically such as 0, 1, 2, 3, 4, 5, 6);
  • CPT is the residue of a camptothecin derivative.
  • n is an integer of 2-6, eg, 2 or 3.
  • n is an integer from 0 to 3, eg, 0, 1, 2, or 3.
  • the above-mentioned camptothecin derivatives are selected from: 10-hydroxycamptothecin, 7-ethyl-10-hydroxycamptothecin, 9-nitrocamptothecin, 9-aminocamptothecin, irinotecan (irinotecan), topotecan (topotecan) and belonotecan (belotecan), ixatecan (exatecan), lurtotecan (lurtotecan), diflomotecan (diflomotecan), gimatecan (gimatecan) or karenitecin; in one embodiment of the present invention, the above-mentioned camptothecin derivatives are 7-ethyl-10-hydroxycamptothecin or irinotecan.
  • CPT can be selected from the following structures:
  • the CPT is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-N-phenyl
  • the molecular weight of the above PEG can be 10000-40000 Daltons, such as 15000-30000, such as 18000-25000, specifically 21000-23000.
  • the above-mentioned PEG may be a straight-chain, Y-shaped or multi-branched polyethylene glycol residue.
  • the above-mentioned PEG has the structure of general formula (II):
  • i is an integer from 10 to 1500 (specifically, such as 10, 20, 30, 40, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500).
  • the above-mentioned PEG has the structure of general formula (III):
  • h is an integer from 5 to 700 (specifically, such as 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700) .
  • the above-mentioned PEG has the structure of general formula (IV):
  • k is an integer from 1 to 500 (specifically, such as 1, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500);
  • j is an integer of 3-12 (specifically such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12);
  • R is the core molecule of multi-branched polyethylene glycol, which can be selected from the group consisting of: pentaerythritol, methyl glucoside, sucrose, diethylene glycol, propylene glycol, glycerol, or the residue of polyglycerol.
  • the above-mentioned PEG has the structure of general formula (V):
  • q, s, t and z are independently selected from integers from 2 to 340,
  • y is an integer of 1-5 (specifically, 1, 2, 3, 4, 5).
  • the above-mentioned PEG has the structure of general formula (VI):
  • u, v and w are independently selected from integers from 2 to 460,
  • x is an integer of 1-5 (specifically, 1, 2, 3, 4, 5).
  • a 1 and A 2 are independently selected from: aspartic acid, glutamic acid, glycine, alanine, leucine, isoleucine, valine, phenylalanine amino acid or methionine residue; more specifically, A 1 is selected from aspartic acid or glutamic acid residues, and A 2 is selected from glycine, alanine, leucine, isoleucine, valine, benzene Alanine or methionine residue; in one embodiment of the present invention, A 1 is a glutamic acid residue, and A 2 is a glycine residue.
  • A1 is
  • a 2 is selected from
  • m is 2, and n is 1, and the polyethylene glycol-modified camptothecin derivatives have the structure of the general formula (V):
  • PEG, CPT, A 1 and A 2 have the corresponding definitions above in the present invention.
  • PEG, CPT, A 1 and A 2 have the corresponding definitions above in the present invention.
  • polyethylene glycol-modified camptothecin derivatives have the following structure:
  • the molecular weight of PEG can be 10000-40000 Daltons, such as 15000-30000, such as 18000-25000, specifically 21000-23000.
  • the above-mentioned pharmaceutical composition further comprises one or more pharmaceutically acceptable adjuvants.
  • the above-mentioned pharmaceutically acceptable excipients refer to conventional pharmaceutical excipients in the pharmaceutical field, for example, diluents, excipients such as water, etc., fillers such as starch, sucrose, etc.; binders such as cellulose derivatives, alginate , gelatin and polyvinylpyrrolidone, etc.; wetting agents such as glycerin, etc.; disintegrating agents such as agar, calcium carbonate and sodium bicarbonate, etc.; absorption enhancers such as quaternary ammonium compounds, etc.; surfactants such as cetyl alcohol, etc.; adsorption carriers such as Kaolin and bentonite, etc.; lubricants such as talc, calcium and magnesium stearate, polyethylene glycol, etc.
  • other adjuvants such as flavoring agents, sweetening agents and the like can also be added to the pharmaceutical composition.
  • the above-mentioned pharmaceutical compositions can be tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (including soft capsules, microcapsules), lozenges, syrups, liquids, emulsions, suspensions, controlled release formulations (eg, immediate release formulations, sustained release formulations, sustained release microcapsules), aerosols, films (eg , oral disintegrating film, oral mucosa-adhesive film), injection (for example, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), intravenous drip, transdermal absorption preparation, ointment, lotion , adhesive formulations, suppositories (eg, rectal suppositories, vaginal suppositories), pellets, nasal formulations, pulmonary formulations (inhalants), eye drops, and the like.
  • tablets including sugar-coated tablets, film-
  • compositions can be administered parenterally or parenterally, such as by intravenous, intramuscular, intradermal, subcutaneous, intraperitoneal routes.
  • the above two active ingredients can be administered by the same or different routes of administration, for example, polyethylene glycol-modified camptothecin derivatives or pharmaceutically acceptable salts thereof, Esters, prodrugs, solvates can be administered parenterally (eg, intravenous, intramuscular, intradermal, subcutaneous, intraperitoneal routes), while temozolomide or a pharmaceutically acceptable salt, ester, pro- Drugs, solvates are administered by the gastrointestinal route (eg, oral administration).
  • the above two active ingredients polyethylene glycol modified camptothecin derivatives or their pharmaceutically acceptable salts, esters, prodrugs, solvates, and temozolomide or its pharmaceutical
  • the above acceptable salts, esters, prodrugs, solvates can be administered by the same or different routes of administration, for example, polyethylene glycol-modified camptothecin derivatives or pharmaceutically acceptable salts thereof, Esters, prodrugs, solvates can be administered parenterally (eg, intravenous, intramuscular, intraderma
  • the above two active ingredients can be formulated for simultaneous, separate or sequential administration.
  • the above-mentioned pharmaceutically acceptable adjuvant is a pharmaceutically acceptable injection adjuvant, such as isotonic sterile saline solution (sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium chloride, chloride potassium, calcium chloride, magnesium chloride, etc., or mixtures of the foregoing salts), or a dry, eg, freeze-dried composition, which is suitably formed into an injectable solute by the addition of sterile water or physiological saline.
  • sterile saline solution sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium chloride, chloride potassium, calcium chloride, magnesium chloride, etc., or mixtures of the foregoing salts
  • a dry, eg, freeze-dried composition which is suitably formed into an injectable solute by the addition of sterile water or physiological saline.
  • compositions of the present invention can be prepared according to conventional production methods in the pharmaceutical field.
  • the active ingredient is mixed with one or more pharmaceutically acceptable excipients and then formulated into the desired dosage form.
  • the pharmaceutical composition of the present invention can contain 0.1-99.5% by weight (specifically, such as 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% , 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.5%) of the active ingredient.
  • the present invention also provides an application of the above-mentioned pharmaceutical composition in the preparation of a medicament for treating tumors.
  • the tumor is a malignant tumor, including but not limited to: lymphoma, blastoma, sarcoma, liposarcoma, synovial cell sarcoma, neuroendocrine tumor, carcinoid tumor, gastrinoma, pancreatic islet cell Carcinoma, mesothelioma, schwannoma, acoustic neuroma, meningioma, adenocarcinoma, melanoma, leukemia, squamous cell carcinoma, epithelial squamous cell carcinoma, lung cancer (eg, small cell lung cancer, non-small cell lung cancer), adenocarcinoma Cancer Lung cancer, lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, gastric cancer, colon cancer, pancreatic cancer, glioma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver cancer, breast cancer, colon cancer, rectal cancer, colon cancer Rec
  • the above-mentioned tumors can be selected from intermediate and advanced tumors, relapsed and/or refractory tumors, failed and/or recurrent tumors treated with chemotherapeutic drugs, failed and/or recurrent tumors treated with radiotherapy, failed treatment with targeted drugs and/or Recurrent tumor, failed immunotherapy and/or recurrent tumor.
  • the tumor is a brain tumor, such as a glioma
  • the glioma can include: astrocytoma, glioblastoma multiforme, ependymoma, ependymoblastoma, medulloblastoma, oligodendroglioma, and oligodendroglioma, especially adult refractory glioblastoma multiforme and recurrent or progressive glioblastoma multiforme cell tumor, anaplastic astrocytoma.
  • the tumor is a blastoma, including but not limited to: glioblastoma, medulloblastoma, neuroblastoma, hemangioblastoma, hepatoblastoma, Retinoblastoma, etc.
  • the tumor is neuroblastoma, especially relapsed or refractory neuroblastoma.
  • the present invention also provides an application of the above pharmaceutical composition in enhancing the efficacy of polyethylene glycol-modified camptothecin derivatives (eg, polyethylene glycol-modified irinotecan) or temozolomide.
  • polyethylene glycol-modified camptothecin derivatives eg, polyethylene glycol-modified irinotecan
  • temozolomide e.g, polyethylene glycol-modified irinotecan
  • the present invention also provides a polyethylene glycol-modified camptothecin derivative (such as polyethylene glycol-modified irinotecan) or a pharmaceutically acceptable salt, ester, prodrug and solvate thereof in enhancing the effect of temozolomide. application in medicinal efficacy.
  • a polyethylene glycol-modified camptothecin derivative such as polyethylene glycol-modified irinotecan
  • a pharmaceutically acceptable salt, ester, prodrug and solvate thereof in enhancing the effect of temozolomide. application in medicinal efficacy.
  • the present invention also provides a kind of temozolomide or its pharmaceutically acceptable salt, ester, prodrug, solvate in enhancing polyethylene glycol modified camptothecin derivatives (eg polyethylene glycol modified irinotecan) application in medicinal efficacy.
  • polyethylene glycol modified camptothecin derivatives eg polyethylene glycol modified irinotecan
  • the drug effect is an anti-tumor effect, such as inhibiting tumor growth (eg, reducing tumor volume).
  • the above-mentioned enhancement may be to increase the anti-tumor effect by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200% , 300%, 400%, 500%, etc.
  • polyethylene glycol-modified camptothecin derivatives and tumors have the above corresponding definitions of the present invention.
  • the present invention also provides a method for treating tumors, comprising administering to a subject in need thereof a therapeutically effective amount of a polyethylene glycol-modified camptothecin derivative or a pharmaceutically acceptable salt, ester, pro- Drugs, solvates, and temozolomide or a pharmaceutically acceptable salt, ester, prodrug, solvate, or steps of the above-mentioned pharmaceutical compositions of the present invention.
  • the tumor the polyethylene glycol-modified camptothecin derivative, and the pharmaceutical composition have the above corresponding definitions of the present invention.
  • polyethylene glycol-modified camptothecin derivatives or pharmaceutically acceptable salts, esters, prodrugs, solvates thereof, and temozolomide or pharmaceutically acceptable salts, esters, Prodrugs and solvates can be administered in the same or different routes of administration, for example, polyethylene glycol-modified camptothecin derivatives or their pharmaceutically acceptable salts, esters, prodrugs, and solvates can be administered with parenteral routes of administration (eg, intravenous, intramuscular, intradermal, subcutaneous, intraperitoneal routes), while temozolomide or a pharmaceutically acceptable salt, ester, prodrug, solvate thereof is administered by the gastrointestinal route Administration (eg, oral administration).
  • parenteral routes of administration eg, intravenous, intramuscular, intradermal, subcutaneous, intraperitoneal routes
  • temozolomide or a pharmaceutically acceptable salt, ester, prodrug, solvate thereof is administered by the gastrointestinal route Administration (eg, oral administration).
  • polyethylene glycol-modified camptothecin derivatives or pharmaceutically acceptable salts, esters, prodrugs, solvates thereof, and temozolomide or pharmaceutically acceptable salts, esters, Prodrugs, solvates can be formulated for simultaneous, separate or sequential administration.
  • the above-mentioned subject is a mammal, such as a human.
  • the tumor is neuroblastoma, especially relapsed or refractory neuroblastoma.
  • the above-mentioned therapeutically effective amount may vary according to the route of administration, the age, body weight of the patient, the type and severity of the disease to be treated, and the like, and may be administered one or more times.
  • the combination of polyethylene glycol-modified camptothecin derivatives (especially polyethylene glycol-modified irinotecan) and temozolomide showed extremely strong treatment for tumors (such as neuroblastoma).
  • the tumor inhibition rate can be as high as 98%, which is significantly better than that of the monotherapy group. Therefore, the pharmaceutical composition provided by the present invention has a better application prospect for tumor treatment.
  • Figure 1 shows the changes in the body weight of mice in each group, wherein the data points represent the average body weight of the group, and the error bars represent the standard error of the mean (SEM).
  • Figure 2 shows the changes in tumor volume of mice in each group, wherein the data points represent the group mean, and the error bars represent the standard error of the mean (SEM).
  • Figure 3 shows the survival rate of mice in each group, there are 10 animals in each treatment group, and the death of animals after administration is related to the tumor inhibition rate.
  • polymers such as polyethylene glycol are preferably characterized by molecular weight due to the potential heterogeneity of PEG compounds, which are generally defined by their average molecular weight rather than repeating units.
  • salt is to be understood as any form of the corresponding compound of the invention, wherein the compound is in ionic form or charged and coupled to an oppositely charged ion (cation or anion) or in solution.
  • the definition also includes quaternary ammonium salts and complexes of this molecule with other molecules and ions, especially complexes formed by ionic interactions.
  • esters is to be understood as a compound formed by the reaction of an acid with the hydroxyl group of the corresponding compound of the present invention.
  • solvate is understood to refer to any form of the corresponding compound of the present invention in which the compound is attached to another molecule (usually a polar solvent) via a non-covalent bond, including in particular hydrates and alcoholates, such as methanol matter.
  • prodrug is used in its broadest sense and encompasses derivatives that are convertible into the compounds of the present invention in vivo.
  • examples of prodrugs include, but are not limited to, derivatives and metabolites of the corresponding compounds of the present invention, including biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable Hydrolyzed carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs.
  • the prodrugs with carboxyl functional groups are lower alkyl esters of carboxylic acids.
  • carboxylic acid esters are readily obtained by esterification of any carboxylic acid moieties present in the molecule.
  • Prodrugs can generally be prepared by known methods, as described in Burger's "Medicinal Chemistry and Drug Discovery Sixth Edition (Donald J. Abraham ed., 2001, Wiley) and “Design and Applications of Prodrugs” (H. Bundgaard ed., 1985) , Harwood Academic Publishers).
  • tumor refers to a new organism formed by the proliferation of local tissue cells under the action of various tumorigenic factors. According to the cell characteristics of the new organism and the degree of harm to the body, tumors are classified into benign tumors and malignant tumors.
  • Malignant tumor refers to a disease that is characterized by uncontrollable growth and spread of malignant cells and tissue infiltration, and which is determined by pathological examination to meet the criteria of "Classification of Diseases and Causes of Death" published by the Ministry of Health of the People's Republic of China.
  • anti-tumor effect refers to a biological effect that can be manifested by a reduction in tumor volume, a reduction in the number of tumor cells, a reduction in the number of metastases, an increase in life expectancy, or amelioration of various physiological symptoms associated with cancerous conditions express.
  • brain tumor refers to a new organism that grows in the cranial cavity, also known as intracranial tumor, brain cancer, which can originate in the brain, meninges, nerves, blood vessels and brain appendages, or invade the skull by metastases from other tissues or organs of the body. formed within.
  • the most common brain tumor is glioma, accounting for more than 1/3 to 1/2; its tissue origin is ectodermal tumor, and more than half are malignant.
  • Glioma can be divided into: astrocytoma, glioblastoma multiforme, ependymoma, ependymoblastoma, medulloblastoma, oligodendroglioma and oligodendroglioma according to pathology and clinical Glioblastoma.
  • meningioma schwannoma (90% of acoustic neuroma), pituitary adenoma and craniopharyngioma (the most common intracranial congenital tumors) and so on.
  • neuroblastoma is a disease in which malignant (cancer) cells form in the nervous tissue of the adrenal glands, neck, thorax or spinal cord, which is an embryonal form of the sympathetic nervous system arising from neuroblasts (pluripotent sympathetic nerve cells) tumor.
  • cancer malignant cells form in the nervous tissue of the adrenal glands, neck, thorax or spinal cord, which is an embryonal form of the sympathetic nervous system arising from neuroblasts (pluripotent sympathetic nerve cells) tumor.
  • neuroblastoma When neuroblastoma is diagnosed, the cancer has usually metastasized (spread), most commonly to the lymph nodes, bone, bone marrow, liver, and skin.
  • treating refers to preventing, curing, reversing, attenuating, alleviating, minimizing, inhibiting, arresting and/or stopping one or more clinical symptoms of a disease after the onset of the disease.
  • prevention refers to the prevention, minimization, or refractory to the onset or progression of a disease by treatment prior to the onset of the disease.
  • patient or “subject” and the like are used interchangeably herein to refer to any animal or cells thereof, whether in vitro or in situ, to be treated according to the methods described herein.
  • the aforementioned animals include mammals, eg, rats, mice, guinea pigs, rabbits, dogs, monkeys or humans, especially humans.
  • animal room staff Upon arrival of the animals, animal room staff transferred the animals from the shipping packaging to the cages and inspected each animal.
  • the scope of inspection includes appearance, limbs and cavities, etc., and whether there is any abnormal performance when the animal is stationary or moving. Adaptation period of 7 days.
  • mice will be housed in transparent resin plastic cages (300mm x 180mm x 120mm) in the animal room, 5 mice per cage. Cage litter was autoclaved sawdust and corncob litter, which was changed twice a week. The room number in which the animal was housed throughout the experiment will be recorded in the experiment log. The animal room is equipped with a high-efficiency air filter with a ventilation rate of 15-25 air changes per hour. The temperature will be maintained between 20-26°C (68-79°F) and the relative humidity will be 40-70%. Continuously observe and record temperature and humidity. The lighting conditions are 12 hours (08:00-20:00) of fluorescent lighting and 12 hours of no lighting per day.
  • the experimental mice can obtain unlimited access to special mouse chow (sterilized by irradiation, Shanghai Slack Laboratory Animal Co., Ltd., China). The experimental mice had unlimited access to drinking water treated by the CRO.
  • Cage and Animal Identification Each animal is assigned a unique number. Item number, species/strain, sex, cage number, and animal number should be indicated on the cage label before animals are grouped.
  • the rat cages were layered with cage racks to mitigate the influence of environmental factors on the experiment.
  • the molecular weight of the PEG moiety is 21000-23000.
  • SK-N-SH cells were cultured in EMEM medium supplemented with 10% heat-inactivated fetal bovine serum, 100 ⁇ g/ml penicillin and 100 ⁇ g/ml streptomycin (incubator environment: 37° C., 5% CO 2 ). Passage routinely twice a week. Cells in exponential growth phase were harvested and inoculated tumors were counted.
  • the dosing groups are shown in the table below.
  • Tumor inhibition rate TGI% (1-T/C) ⁇ 100%
  • Body weight and tumor volume were compared using two-way ANOVA analysis. All data were analyzed using GraphPad Prism 5. p ⁇ 0.05 was statistically significant.
  • the body weight changes of the animals in each group are shown in Table 3 and Figure 1 .
  • Table 4 and Figure 2 show tumor volumes (mm 3 ) at different time points for all dosing groups.
  • the tumor growth inhibitory effect of each group is shown in Table 5.
  • the body weights of each group at different time points after tumor inoculation are shown in Table 3 and Figure 1. During the study period, the body weights of each group were stable and did not differ significantly, indicating that the various treatment regimens in this study did not have significant toxic side effects on the test mice.
  • the 4th and 6th groups had extremely significant therapeutic effects, and the tumor inhibition rates in the groups were 96.1% and 98.0%, respectively (P ⁇ 0.001).
  • Groups 2, 3, and 5 had a slight tumor inhibitory effect, and their inhibition rates were 25.0%, 31.0%, and 50.5%, respectively (P ⁇ 0.001). The data of these groups showed that the combination therapy had enhanced tumor suppressive effect compared with the single drug.
  • the combination therapy group showed a strong therapeutic effect in the SK-N-SH in vivo subcutaneous tumor model in this study.

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Abstract

一种抗肿瘤药物组合物及其应用，该抗肿瘤药物组合物的活性成分包括聚乙二醇修饰的喜树碱类衍生物(特别是聚乙二醇修饰的伊立替康)和替莫唑胺，通过动物实验证实，聚乙二醇修饰的喜树碱类衍生物(特别是聚乙二醇修饰的伊立替康)与替莫唑胺联合给药对肿瘤(例如神经母细胞瘤)表现出极强的治疗效果，肿瘤抑制率可高达98％，显著优于单药治疗组，因此提供的抗肿瘤药物组合物对于肿瘤治疗具有较佳的应用前景。

Description

一种抗肿瘤药物组合物及其应用 技术领域
本发明涉及医药技术领域，具体涉及一种抗肿瘤药物组合物(其活性成分包括聚乙二醇修饰的喜树碱类衍生物(特别是聚乙二醇修饰的伊立替康)和替莫唑胺)及其应用。
背景技术
肿瘤是威胁人类健康的常见疾病之一，仅次于心血管疾病，关于肿瘤的研究已取得较大进展，已发展了多种治疗肿瘤的各种放疗、化疗等方法，但各种药物及疗法均存在局限性，很难达到根治的效果，且易出现耐药性和副作用。肿瘤死亡率仍居于各种疾病之首。数据显示，2006年我国有300万人死于癌症，而且肿瘤发病率仍处于上升趋势，并有年轻化趋势。据资料统计在不到20年的时间里，我国肿瘤发病率上升了69％，死亡率上升了29.4％。因此，研究新的有效的肿瘤治疗药物仍是目前肿瘤治疗的主要方向。
喜树碱(CPT)为一种吡咯喹啉细胞毒性生物碱，是除紫杉醇之外，研究最多的天然抗肿瘤药物之一。1967-1970年，研究者发现该生物碱在体外对Hela细胞、L1210细胞及啮齿类动物显示出较强的抗肿瘤活性，引起人们的极大关注。1985年，Hsiang等人发现喜树碱及衍生物是以拓朴异构酶(topoⅠ)为作用靶点抑制DNA的合成而发挥抗癌作用的机理后，许多衍生物应运而生，成为抗癌领域研究的新热点。至今，已经有一系列半合成和全合成的喜树碱衍生物出现并进入临床应用或临床试验阶段，例如，羟基喜树碱、伊立替康、拓扑替康、9-氨基喜树碱、9-硝基喜树碱、吉马替康等。有报道将喜树碱衍生物用于神经母细胞瘤，特别是复发和难治性神经母细胞 瘤，的治疗，但其效果并不理想。
发明内容
为克服现有技术的不足，本发明提供一种药物组合物，其活性成分包括：
(1)聚乙二醇修饰的喜树碱类衍生物或其药学上可接受的盐、酯、前药、溶剂化物；以及
(2)替莫唑胺或其药学上可接受的盐、酯、前药、溶剂化物。
在本发明的一个实施方式中，上述活性成分由上述(1)和(2)组成。
具体地，上述活性成分可以由聚乙二醇修饰的喜树碱类衍生物和替莫唑胺组成。
具体地，上述药物组合物中，活性成分(2)与(1)(例如，替莫唑胺与聚乙二醇修饰的喜树碱类衍生物)的质量比可以为0.1-10:0.1-10(具体如1:0.1、1:0.2、1:0.3、1:0.4、1:0.5、1:1、1:1.5、1:2、1:2.5、1:3、1:4、1:5、1:6、1:7、1:8、1:9、1:10)，特别是1:1-10，如1:1-5。
具体地，上述药物组合物中，喜树碱类衍生物部分与替莫唑胺的摩尔比可以为0.01-100:0.01-100(具体如1:0.1、1:1、1:10、1:20、1:30、1:40、1:50、1:70、1:80、1:90、1:100)。
具体地，本发明上述聚乙二醇修饰的喜树碱类衍生物，具有通式(Ⅰ)的结构：
Figure PCTCN2021129184-appb-000001
其中：
PEG表示聚乙二醇残基，PEG的分子量为300-60000道尔顿(具体如300、 500、1000、2000、3000、4000、5000、6000、7000、8000、9000、10000、16000、17000、18000、19000、20000、21000、22000、23000、24000、25000、26000、28000、30000、40000、50000、60000)；
A 1和A 2表示相同或不同的氨基酸残基；
m是2-12的整数(具体如2、3、4、5、6、7、8、9、10、11、12)；
n是0-6的整数(具体如0、1、2、3、4、5、6)；
CPT为喜树碱类衍生物的残基。
具体地，m为2-6的整数，例如，2或3。
具体地，n为0-3的整数，例如，0、1、2或3。
具体地，上述喜树碱类衍生物选自：10-羟基喜树碱、7-乙基-10-羟基喜树碱、9-硝基喜树碱、9-氨基喜树碱、伊立替康(irinotecan)、拓扑替康(topotecan)和贝洛替康(belotecan)、依沙替康(exatecan)、卢托替康(lurtotecan)、二氟替康(diflomotecan)、吉马替康(gimatecan)或卡尼替康(karenitecin)；在本发明的一个实施例中，上述喜树碱类衍生物为7-乙基-10-羟基喜树碱或伊立替康。
具体地，通式(Ⅰ)中，CPT可以选自如下结构：
Figure PCTCN2021129184-appb-000002
Figure PCTCN2021129184-appb-000003
在本发明的一个实施例中，CPT为
Figure PCTCN2021129184-appb-000004
具体地，上述PEG的分子量可以为10000-40000道尔顿，如15000-30000，如18000-25000，具体如21000-23000。
具体地，上述PEG可以为直链、Y型或多分支型聚乙二醇残基。
在本发明的一个实施方式中，上述PEG具有通式(Ⅱ)的结构：
Figure PCTCN2021129184-appb-000005
其中，i为10-1500的整数(具体如10、20、30、40、50、100、200、300、400、500、600、700、800、900、1000、1100、1200、1300、1400、1500)。
在本发明另一个实施方式中，上述PEG具有通式(Ⅲ)的结构：
Figure PCTCN2021129184-appb-000006
其中，h为5-700的整数(具体如5、10、20、30、40、50、100、150、200、250、300、350、400、450、500、550、600、650、700)。
在本发明另一个实施方式中，上述PEG具有通式(Ⅳ)的结构：
Figure PCTCN2021129184-appb-000007
其中：
k是1-500的整数(具体如1、5、10、20、30、40、50、100、150、200、250、300、350、400、450、500)；
j是3-12的整数(具体如3、4、5、6、7、8、9、10、11、12)；
R是多分支聚乙二醇的核心分子，其可选自：季戊四醇、甲基葡萄糖苷、蔗糖、二甘醇、丙二醇、甘油或聚甘油的残基。
在本发明的一个实施方式中，上述PEG具有通式(Ⅴ)的结构：
Figure PCTCN2021129184-appb-000008
其中，q、s、t和z独立地选自2-340的整数，
y为1-5的整数(具体如1、2、3、4、5)。
在本发明的一个实施方式中，上述PEG具有通式(Ⅵ)的结构：
Figure PCTCN2021129184-appb-000009
其中，u、v和w独立地选自2-460的整数，
x为1-5的整数(具体如1、2、3、4、5)。
具体地，通式(Ⅰ)中，A 1和A 2独立地选自：天冬氨酸、谷氨酸、甘氨酸、丙氨酸、亮氨酸、异亮氨酸、缬氨酸、苯丙氨酸或蛋氨酸残基；更具体地，A 1选自天冬氨酸或谷氨酸残基，A 2选自甘氨酸、丙氨酸、亮氨酸、异亮氨酸、缬氨酸、苯丙氨酸或蛋氨酸残基；在本发明的一个实施例中，A 1为谷氨酸残基，A 2为甘氨酸残基。
具体地，A 1为
Figure PCTCN2021129184-appb-000010
具体地，A 2选自
Figure PCTCN2021129184-appb-000011
Figure PCTCN2021129184-appb-000012
在本发明的一个实施例中，
Figure PCTCN2021129184-appb-000013
为
Figure PCTCN2021129184-appb-000014
在本发明的一个实施方式中，通式(Ⅰ)的结构中，m为2，n为1，所述的聚乙二醇修饰的喜树碱类衍生物具有通式(Ⅴ)的结构：
Figure PCTCN2021129184-appb-000015
其中，PEG、CPT、A 1和A 2具有本发明上述相应定义。
在本发明另一实施方式中，通式(Ⅰ)的结构中，m为3，n为1，本发明所述的聚乙二醇修饰的喜树碱类衍生物具有通式(Ⅵ)的结构：
Figure PCTCN2021129184-appb-000016
Figure PCTCN2021129184-appb-000017
其中，PEG、CPT、A 1和A 2具有本发明上述相应定义。
在本发明一个实施例中，上述聚乙二醇修饰的喜树碱类衍生物具有如下结构：
Figure PCTCN2021129184-appb-000018
具体地，上式Ⅶ中，PEG的分子量可以为10000-40000道尔顿，如15000-30000，如18000-25000，具体如21000-23000。
具体地，上述药物组合物中还包含一种或多种药物上可接受的辅料。
具体地，上述药学上可接受的辅料是指药学领域常规的药物辅料，例如，稀释剂、赋形剂如水等，填充剂如淀粉、蔗糖等；粘合剂如纤维素衍生物、藻酸盐、明胶和聚乙烯吡咯烷酮等；湿润剂如甘油等；崩解剂如琼脂、碳酸钙和碳酸氢钠等；吸收促进剂如季铵化合物等；表面活性剂如十六烷醇等；吸附载体如高岭土和皂粘土等；润滑剂如滑石粉、硬脂酸钙和镁、聚乙二醇等。另外，还可以在药物组合物中加入其它辅剂如香味剂、甜味剂等。
具体地，上述药物组合物可以为片剂(包括糖衣片剂、膜包衣片剂、舌下片剂、口腔崩解片、口腔片剂等等)、丸剂、粉剂、颗粒剂、胶囊剂(包括软胶囊、微胶囊)、锭剂、糖浆剂、液体、乳剂、混悬剂、控制释放制剂(例如，瞬时释放制剂、缓释制剂、缓释微囊)、气雾剂、膜剂(例如，口 服崩解膜剂、口腔粘膜-粘附膜剂)、注射剂(例如，皮下注射、静脉注射、肌内注射、腹膜内注射)、静脉滴注剂、透皮吸收制剂、软膏剂、洗剂、粘附制剂、栓剂(例如，直肠栓剂、阴道栓剂)、小药丸、鼻制剂、肺制剂(吸入剂)、眼睛滴剂等等。
具体地，上述药物组合物可以经胃肠给药或经非胃肠给药，如通过静脉内、肌内、皮内、皮下、腹膜内途径给药。
具体地，上述药物组合物中，上述两种活性成分(聚乙二醇修饰的喜树碱类衍生物或其药学上可接受的盐、酯、前药、溶剂化物，与，替莫唑胺或其药学上可接受的盐、酯、前药、溶剂化物)可以以相同或不同的给药途径进行给药，例如，聚乙二醇修饰的喜树碱类衍生物或其药学上可接受的盐、酯、前药、溶剂化物可以以非胃肠道途径给药(例如静脉内、肌内、皮内、皮下、腹膜内途径给药)，而替莫唑胺或其药学上可接受的盐、酯、前药、溶剂化物以胃肠道途径给药(例如口服给药)。
具体地，上述药物组合物中，上述两种活性成分(聚乙二醇修饰的喜树碱类衍生物或其药学上可接受的盐、酯、前药、溶剂化物，与，替莫唑胺或其药学上可接受的盐、酯、前药、溶剂化物)可以配制用于同时给药、分别给药或序贯给药(simultaneous,separate or sequential administration)。
在本发明的一个实施方式中，上述药学上可接受的辅料为药学上可接受的注射剂辅料，例如等渗的无菌盐溶液(磷酸二氢钠、磷酸氢二钠、氯化钠、氯化钾、氯化钙、氯化镁等，或上述盐的混合物)，或干燥的例如是冷冻干燥的组合物，其适当地通过加入无菌水或生理盐水形成可注射溶质。
本发明的药物组合物的各种剂型可以按照药学领域的常规生产方法制备。例如使活性成分与一种或多种药学上可接受的辅料混合，然后将其制成所需的剂型。
具体地，本发明的药物组合物可以含有重量比为0.1-99.5％(具体如0.1％、0.5％、1％、2％、3％、4％、5％、6％、7％、8％、9％、10％、20％、 30％、40％、50％、60％、70％、80％、90％、95％、99％、99.5％)的活性成分。
本发明还提供一种上述药物组合物在制备治疗肿瘤的药物中的应用。
具体地，上述应用中，肿瘤为恶性肿瘤，其包括但不限于：淋巴瘤、母细胞瘤、肉瘤、脂肪肉瘤、滑膜细胞肉瘤、神经内分泌肿瘤、类癌肿瘤、胃泌素瘤、胰岛细胞癌、间皮瘤、神经鞘瘤、听神经瘤、脑膜瘤、腺癌、黑素瘤、白血病、鳞状细胞癌、上皮鳞状细胞癌、肺癌(如小细胞肺癌、非小细胞肺癌)、腺癌肺癌、肺鳞癌、腹膜癌、肝细胞癌、胃癌、肠癌、胰腺癌、胶质瘤、子宫颈癌、卵巢癌、肝癌、膀胱癌、肝癌、乳腺癌、结肠癌、直肠癌、结肠直肠癌、子宫癌、唾液腺癌、肾癌、前列腺癌、外阴癌、甲状腺癌、肝癌、肛门癌、阴茎癌、梅克尔细胞癌、食管癌、胆道肿瘤、头颈部癌，等等。
具体地，上述肿瘤可以选自中晚期肿瘤、复发和/或难治性肿瘤、经化疗药物治疗失败和/或复发肿瘤、经放疗失败和/或复发肿瘤、经靶向药物治疗失败和/或复发肿瘤、经免疫治疗失败和/或复发肿瘤。
在本发明的一个实施方式中，上述应用中，肿瘤为脑部肿瘤，如胶质瘤，胶质瘤可以包括：星形细胞瘤、多形性胶质母细胞瘤、室管膜瘤、室管膜母细胞瘤、髓母细胞瘤、少枝胶质瘤和少枝胶质母细胞瘤，特别是成人顽固性多形性成胶质细胞瘤及复发或进展性的多形性胶质母细胞瘤、间变性星形细胞瘤。
在本发明的一个实施方式中，上述应用中，肿瘤为母细胞瘤，包括但不限于：胶质母细胞瘤、髓母细胞瘤、神经母细胞瘤、血管母细胞瘤、肝母细胞瘤、视网膜母细胞瘤等。
在本发明的一个实施例中，上述应用中，肿瘤为神经母细胞瘤，特别是复发或难治性神经母细胞瘤。
本发明还提供一种上述药物组合物在增强聚乙二醇修饰的喜树碱类衍生物(例如聚乙二醇修饰的伊立替康)或替莫唑胺的药效中的应用。
本发明还提供一种聚乙二醇修饰的喜树碱类衍生物(例如聚乙二醇修饰 的伊立替康)或其药学上可接受的盐、酯、前药、溶剂化物在增强替莫唑胺的药效中的应用。
本发明还提供一种替莫唑胺或其药学上可接受的盐、酯、前药、溶剂化物在增强聚乙二醇修饰的喜树碱类衍生物(例如聚乙二醇修饰的伊立替康)的药效中的应用。
具体地，上述应用中，所述药效为抗肿瘤效果，例如抑制肿瘤生长(例如减小肿瘤体积)。
具体地，上述增强可以为使抗肿瘤效果提高1％、5％、10％、20％、30％、40％、50％、60％、70％、80％、90％、100％、200％、300％、400％、500％等。
具体地，上述应用中，聚乙二醇修饰的喜树碱类衍生物、肿瘤具有本发明上述相应定义。
本发明还提供一种治疗肿瘤的方法，其包括向有此需要的受试者施用治疗有效量的聚乙二醇修饰的喜树碱类衍生物或其药学上可接受的盐、酯、前药、溶剂化物以及替莫唑胺或其药学上可接受的盐、酯、前药、溶剂化物，或本发明上述药物组合物的步骤。
具体地，上述方法中，肿瘤、聚乙二醇修饰的喜树碱类衍生物、药物组合物具有本发明上述相应定义。
具体地，上述方法中，聚乙二醇修饰的喜树碱类衍生物或其药学上可接受的盐、酯、前药、溶剂化物，与，替莫唑胺或其药学上可接受的盐、酯、前药、溶剂化物可以以相同或不同的给药途径进行给药，例如，聚乙二醇修饰的喜树碱类衍生物或其药学上可接受的盐、酯、前药、溶剂化物可以以非胃肠道途径给药(例如静脉内、肌内、皮内、皮下、腹膜内途径给药)，而替莫唑胺或其药学上可接受的盐、酯、前药、溶剂化物以胃肠道途径给药(例如口服给药)。
具体地，上述方法中，聚乙二醇修饰的喜树碱类衍生物或其药学上可接受的盐、酯、前药、溶剂化物，与，替莫唑胺或其药学上可接受的盐、酯、 前药、溶剂化物可以配制用于同时给药、分别给药或序贯给药(simultaneous,separate or sequential administration)。
具体地，上述受试者为哺乳动物，如人类。
在本发明的一个实施例中，上述方法中，肿瘤为神经母细胞瘤，特别是复发或难治性神经母细胞瘤。
具体地，上述治疗有效量可根据给药途径、患者的年龄、体重、所治疗的疾病类型和严重程度等变化，可以一次或多次施用。
通过动物实验发现，聚乙二醇修饰的喜树碱类衍生物(特别是聚乙二醇修饰的伊立替康)与替莫唑胺联合给药对肿瘤(例如神经母细胞瘤)表现出极强的治疗效果，肿瘤抑制率可高达98％，显著优于单药治疗组，因此本发明提供的药物组合物对于肿瘤治疗具有较佳的应用前景。
附图说明
图1所示为各组小鼠体重变化情况，其中，数据点表示群体平均体重，误差条表示均值的标准误差(SEM)。
图2所示为各组小鼠肿瘤体积变化情况，其中，数据点表示组平均值，误差条表示均值的标准误差(SEM)。
图3所示为各组小鼠的生存率，每治疗组共有10只动物，给药后动物的死亡与抑瘤率相关。
具体实施方式
除非另有定义，本发明中所使用的所有科学和技术术语具有与本发明涉及技术领域的技术人员通常理解的相同的含义。
在高分子化学中，同一聚合物试样往往由分子量不等的同系物混合而成，分子量存在一定的分布，通常所指的分子量为平均分子量。平均分子量有多种表示法，最常用的是数均分子量(Mn)和重均分子量(Mw)。在本 发明中，对聚合物(例如聚乙二醇)而言，由于通常由其平均分子量而非重复单元限定的PEG化合物的潜在不均一性，优选用分子量表征。
术语“盐”应理解为本发明相应化合物的任意形式，其中该化合物为离子形式或者为带电荷的且与带相反电荷的离子(阳离子或阴离子)耦合或在溶液中。该定义还包括季铵盐和该分子与其它分子和离子的复合物，特别是通过离子相互作用形成的复合物。
术语“酯”应理解为酸与本发明相应化合物的羟基反应生成的化合物。
术语“溶剂化物”应理解为是指本发明相应化合物的任意形式，其中该化合物通过非共价键与另一个分子相连(通常为极性溶剂)，特别是包括水化物和醇化物，例如甲醇化物。
术语“前药”使用其广义含义，并涵盖在体内可转化成本发明化合物的衍生物。前药的例子包括但不限于本发明相应化合物的衍生物和代谢物，包括可生物水解的部分，如可生物水解的酰胺、可生物水解的酯、可生物水解的氨基甲酸酯、可生物水解的碳酸酯、可生物水解的酰脲和可生物水解的磷酸酯类似物。优选地，具有羧基官能团的前体药物为羧酸的低级烷基酯。所述的羧酸酯易由存在于分子中的任何羧酸部分进行酯化得到。前药通常可由已知方法来制备，如在Burger“Medicinal Chemistry and Drug Discovery第六版(Donald J.Abraham ed.，2001，Wiley)和“Design and Applications of Prodrugs”(H.Bundgaard ed.，1985，Harwood Academic Publishers)中描述的方法。
术语“肿瘤”(tumour)是指机体在各种致瘤因子作用下，局部组织细胞增生所形成的新生物，根据新生物的细胞特性及对机体的危害性程度，又将肿瘤分为良性肿瘤和恶性肿瘤两大类。“恶性肿瘤”是指以不可控制的恶性细胞生长和扩散，以及组织浸润为特征，并经病理检验确定符合国家卫生部公布的“疾病和死因分类”标准归属于恶性肿瘤之列的疾病。
术语“抗肿瘤效果”，指的是生物学效应，其可由肿瘤体积的减少、肿瘤 细胞数的减少、转移数的减少、预期寿命的增加或与癌性病症相关的各种生理症状的改善清楚表示。
术语“脑部肿瘤”是指生长在颅腔的新生物，又称颅内肿瘤、脑癌，可起源于脑、脑膜、神经、血管及脑附件，或由身体的其他组织或脏器转移侵入颅内而形成。最常见的脑部肿瘤为胶质瘤，约占1/3～1/2以上；其组织来源为外胚层发生的肿瘤，半数以上属恶性。胶质瘤根据病理和临床可分为：星形细胞瘤、多形性胶质母细胞瘤、室管膜瘤、室管膜母细胞瘤、髓母细胞瘤、少枝胶质瘤和少枝胶质母细胞瘤。其次为脑膜瘤、神经鞘瘤(90％为听神经瘤)、垂体腺瘤和颅咽管瘤(为最常见的颅内先天性肿瘤)等。
术语“神经母细胞瘤”是在肾上腺、颈、胸或脊髓的神经组织中形成恶性(癌)细胞的疾病，其为从神经母细胞(多能交感神经细胞)产生的交感神经系统的胚胎性肿瘤。神经母细胞瘤被诊断出时，该癌症通常已转移(扩散)，最常见地是转移到淋巴结、骨、骨髓、肝和皮肤。
术语“治疗”是指在疾病发作之后预防、治愈、逆转、减弱、减轻、最小化、抑制、制止和/或停止疾病的一种或多种临床症状。
术语“预防”指在疾病发作之前，通过治疗以避免、最小化或令疾病难于发作或发展。
术语“患者”或“受试者”等等在本文中可交换使用，是指根据本文所述的方法治疗的任何动物或其细胞，不论是体外或原位。具体地，前述动物包括哺乳动物，例如，大鼠、小鼠、豚鼠、兔、犬、猴子或人类，特别是人类。
本文所引用的各种出版物、专利和公开的专利说明书，其公开内容通过引用整体并入本文。
下面将结合本发明实施例，对本发明的技术方案进行清楚、完整地描述，显然，所描述的实施例仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1
1、实验材料
1.1实验动物
种属：小鼠
品系：NOD/SCID
年龄：6-8周
性别：雌性
数量：120只(100％额外动物)
动物来源：上海灵畅实验动物有限公司
1.2饲养条件
小鼠饲养于键凯指定CRO动物房。
动物到达后，动物房工作人员将动物从运输包装中转移至鼠笼并对每只动物进行检查。检查范围包括外观、四肢和孔腔等，以及动物静止或运动时是否有异常表现。适应期7天。
环境：小鼠将被安置于动物房的透明树脂塑料笼(300mm x 180mm x 120mm)中，每笼5只。鼠笼垫料为经高压灭菌的木屑和玉米芯垫料，每星期更换两次。整个实验期间安置动物的房间号将记录在实验记录里。动物房间配备高效空气过滤器，通风换气次数为每小时15-25次。温度将保持在20-26℃(68-79°F)之间，相对湿度为40-70％。持续观测并记录温度和湿度。照明条件为每天12小时(08:00-20:00)日光灯照射和12小时无照明。
食物和饮水：实验用小鼠可无限量获取专用鼠粮(经辐照消毒，上海斯莱克实验动物责任有限公司，中国)。实验用小鼠可无限量获取经CRO内部处理的饮用水。
笼子和动物标识：每只动物均分配有一个唯一编号。在对动物进行分组之前，应在鼠笼的标签上标注项目编号、种属/品系、性别、笼号及动物号。
动物分组后，鼠笼用彩色标签标注组别信息及上述信息。分组情况应记录在随机分组文件中。用笼架将鼠笼分层以减轻环境因素对实验的影响。
1.3待测化合物
待测化合物配制如下表所示。
表1化合物配制
Figure PCTCN2021129184-appb-000019
注：上述PEG-伊立替康具有如下结构：
Figure PCTCN2021129184-appb-000020
其中PEG部分的分子量为21000-23000。
2、实验方法及步骤
2.1细胞培养
在添加10％热灭活胎牛血清、100μg/ml青霉素和100μg/ml链霉素的 EMEM培养基中培养SK-N-SH细胞(培养箱环境：37℃，5％CO 2)。每周常规传代两次。采集指数生长期的细胞，计数接种肿瘤。
2.2肿瘤接种和分组
将含5x 10 6SK-N-SH细胞的100μL-EMEM混合50％基质胶接种于小鼠右腹侧皮下，观察肿瘤生长情况。将80只动物根据肿瘤体积(103mm 3)采用Excel分组随机化方法随机化。这确保了所有组在基线上是可比较的。每组有10只荷瘤动物。
给药分组如下表所示。
表2给药分组
Figure PCTCN2021129184-appb-000021
2.3观察
本研究中与动物处理、护理和治疗相关的所有程序均按照上海润诺生物科技有限公司CRO公司批准的“实验动物关怀与使用委员会(IACUC)”的评估核准进行，遵循实验室动物护理评估和认证协会(AAALAC，认证号：001516)的指导。在常规监测时，检查动物是否存在肿瘤生长和/或治疗对正常行为的任何不利影响，如对活动性的影响，食物和水的消耗(仅通过观察)以及体重 的增加/减少(在给药前阶段每周测量两次体重，在给药阶段每天测量一次体重)，眼睛/头发垫和任何其他异常影响。
用游标卡尺每周两次测量肿瘤体积。体积以mm 3表示，公式为:V＝0.5a x b 2，其中a和b分别为肿瘤的长径和短径。
相对肿瘤增殖率T/C％＝T RTV/C RTV×100％(RTV＝Vt/V0)
抑瘤率TGI％＝(1-T/C)×100％
2.4统计分析
采用two-way ANOVA分析比较体重和肿瘤体积。所有数据均采用GraphPad Prism 5进行分析。p<0.05具有统计学意义。
3、实验结果
3.1动物体重
各组受试动物的体重变化如表3和图1所示。
表3各组小鼠体重变化情况
Figure PCTCN2021129184-appb-000022
Figure PCTCN2021129184-appb-000023
Figure PCTCN2021129184-appb-000024
注：每组动物数量n＝10。
3.2肿瘤体积
表4和图2显示所有给药组在不同时间点的肿瘤体积(mm 3)。
表4各组小鼠肿瘤体积变化情况
Figure PCTCN2021129184-appb-000025
Figure PCTCN2021129184-appb-000026
注：每组动物数量n＝10。
3.3肿瘤生长抑制效应
各组肿瘤生长抑制效果见表5。
表5不同给药组的抗肿瘤活性
Figure PCTCN2021129184-appb-000027
Figure PCTCN2021129184-appb-000028
4、实验结果总结及讨论
本研究测试了PEG-伊立替康、替莫唑胺以及替莫唑胺和PEG-伊立替康联合给药对SK-N-SH在裸鼠皮下瘤模型中的治疗作用。
肿瘤接种后不同时间点各组体重见表3和图1。在研究期间，各组的体重都是稳定的，没有显著差异，表明了本研究中各种治疗方案对测试小鼠没有显著毒副作用。
在这6组治疗方案中，第4和6组有极其显著的治疗效果，组中的肿瘤抑制率分别为96.1％和98.0％(P<0.001)。
2、3、5组有轻微的肿瘤抑制效果，其抑制率分别为25.0％、31.0％、50.5％(P<0.001)。这几组的数据显示联合用药比单药的抑瘤效果有所增强。
综上所述，联合用药治疗组在本研究的SK-N-SH体内皮下肿瘤模型中都表现出了极强的治疗效果。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换等，均应包含在本发明的保护范围之内。
本发明中描述的前述实施例和方法可以基于本领域技术人员的能力、经验和偏好而有所不同。
本发明中仅按一定顺序列出方法的步骤并不构成对方法步骤顺序的任何限制。

Claims (13)

  1. 一种药物组合物，其活性成分包括或由其组成：
    (1)聚乙二醇修饰的喜树碱类衍生物或其药学上可接受的盐、酯、前药、溶剂化物；以及
    (2)替莫唑胺或其药学上可接受的盐、酯、前药、溶剂化物。
  2. 如权利要求1所述的药物组合物，其特征在于，所述替莫唑胺与聚乙二醇修饰的喜树碱类衍生物的质量比为1:0.1-10，优选为1:1-10，更优选为1:1-5。
  3. 如权利要求1所述的药物组合物，其特征在于，所述聚乙二醇修饰的喜树碱类衍生物具有通式(Ⅰ)的结构：
    Figure PCTCN2021129184-appb-100001
    其中：
    PEG表示聚乙二醇残基，PEG的分子量为300-60000道尔顿；
    A 1和A 2表示相同或不同的氨基酸残基；
    m是2-12的整数；
    n是0-6的整数；
    CPT为喜树碱类衍生物的残基。
  4. 如权利要求3所述的药物组合物，其特征在于，所述CPT选自如下结构：
    Figure PCTCN2021129184-appb-100002
    优选地，所述CPT为
    Figure PCTCN2021129184-appb-100003
  5. 如权利要求3所述的药物组合物，其特征在于，所述PEG具有通式(Ⅱ)的结构：
    Figure PCTCN2021129184-appb-100004
    其中，i为10-1500的整数；或，
    所述PEG具有通式(Ⅲ)的结构：
    Figure PCTCN2021129184-appb-100005
    其中，h为5-700的整数；或，
    所述PEG具有通式(Ⅳ)的结构：
    Figure PCTCN2021129184-appb-100006
    其中：
    k是1-500的整数；
    j是3-12的整数；
    R是多分支聚乙二醇的核心分子，选自：季戊四醇、甲基葡萄糖苷、蔗糖、二甘醇、丙二醇、甘油或聚甘油的残基。
  6. 如权利要求3所述的药物组合物，其特征在于，所述PEG的分子量为20000-40000道尔顿。
  7. 如权利要求3所述的药物组合物，其特征在于，所述A 1为
    Figure PCTCN2021129184-appb-100007
    和/或，
    所述A 2选自
    Figure PCTCN2021129184-appb-100008
    Figure PCTCN2021129184-appb-100009
  8. 如权利要求3所述的药物组合物，其特征在于，所述
    Figure PCTCN2021129184-appb-100010
    为
    Figure PCTCN2021129184-appb-100011
  9. 如权利要求3-8任一项所述的药物组合物，其特征在于，所述的聚乙二醇修饰的喜树碱类衍生物具有通式(Ⅴ)的结构：
    Figure PCTCN2021129184-appb-100012
    或，
    所述聚乙二醇修饰的喜树碱类衍生物具有通式(Ⅵ)的结构：
    Figure PCTCN2021129184-appb-100013
  10. 如权利要求3-8任一项所述的药物组合物，其特征在于，所述聚乙二醇修饰的喜树碱类衍生物具有如下结构：
    Figure PCTCN2021129184-appb-100014
  11. 一种权利要求1-10任一项所述药物组合物在制备治疗肿瘤的药物中的应用。
  12. 一种权利要求1-10任一项所述药物组合物在增强所述聚乙二醇修饰的喜树碱类衍生物或替莫唑胺的抗肿瘤效果中的应用。
  13. 如权利要求11或12所述的应用，其特征在于，所述肿瘤选自：中 晚期肿瘤、复发和/或难治性肿瘤、经化疗药物治疗失败和/或复发肿瘤、经放疗失败和/或复发肿瘤、经靶向药物治疗失败和/或复发肿瘤、经免疫治疗失败和/或复发肿瘤；
    优选地，所述肿瘤为胶质瘤；
    更优选地，所述胶质瘤选自：星形细胞瘤、多形性胶质母细胞瘤、室管膜瘤、室管膜母细胞瘤、髓母细胞瘤、少枝胶质瘤和少枝胶质母细胞瘤，特别是成人顽固性多形性成胶质细胞瘤及复发或进展性的多形性胶质母细胞瘤、间变性星形细胞瘤；
    优选地，所述肿瘤为母细胞瘤；
    更优选地，所述母细胞瘤选自：胶质母细胞瘤、髓母细胞瘤、神经母细胞瘤、血管母细胞瘤、肝母细胞瘤、视网膜母细胞瘤，特别是神经母细胞瘤。
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