WO2019114689A1 - 负载抗肿瘤药物的氰基丙烯酸酯材料 - Google Patents

负载抗肿瘤药物的氰基丙烯酸酯材料 Download PDF

Info

Publication number
WO2019114689A1
WO2019114689A1 PCT/CN2018/120260 CN2018120260W WO2019114689A1 WO 2019114689 A1 WO2019114689 A1 WO 2019114689A1 CN 2018120260 W CN2018120260 W CN 2018120260W WO 2019114689 A1 WO2019114689 A1 WO 2019114689A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
cyanoacrylate
branched
straight
mono
Prior art date
Application number
PCT/CN2018/120260
Other languages
English (en)
French (fr)
Inventor
徐亮
张涛
张伟
刘克良
Original Assignee
中国人民解放军军事医学科学院毒物药物研究所
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 中国人民解放军军事医学科学院毒物药物研究所 filed Critical 中国人民解放军军事医学科学院毒物药物研究所
Publication of WO2019114689A1 publication Critical patent/WO2019114689A1/zh

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to the field of biomedicine and materials, and in particular to a cyanoacrylate material loaded with an antitumor drug.
  • Intratumoral injection therapy is a new treatment plan for cancer in recent years. By directly injecting drugs into tumors and making them play a role in fixed-point treatment, it can avoid or reduce the first-pass effect that oral and intravenous injections need to face. And systemic side effects and so on. Treatments with intratumoral injections have unique advantages in areas that are not accessible with open surgical instruments, as well as those that are not conducive to surgical resection, or where postoperative aesthetics are considered.
  • the approved tumor-removing virus therapy such as Amgen's IMLYGIC, domestically-born, and Ankerui, all use intratumoral injection.
  • a number of drug development studies have also been administered intratumorally, such as MultiVir's intratumoral injection of the drug Ad-IL-24 for the treatment of head and neck tumors.
  • existing clinically relevant technical means are mature, and multi-site intratumoral injection can be realized.
  • B-ultrasound, CT, magnetic resonance and other images minimally invasive treatment of tumor puncture can be achieved.
  • the intratumoral pressure is higher than normal tissue, the liquid drug is likely to overflow after being injected into the tumor, and the second is that the tumor is rich in blood vessels. After the drug spreads quickly from the tumor site to other tissues, the purpose of long-term administration is not achieved.
  • Cyanoacrylate is a kind of compound which can be rapidly solidified and produces bonding properties. Its structure has very active olefinic double bonds, and the monomer can rapidly undergo intermolecular polymerization under anionic conditions to become a polymer.
  • the cyanoacrylate monomer is generally liquid and fluid, so it can be used in applications such as coating and injection. Depending on the mode of use, the polymer after polymerization can be a solid block or a film.
  • cyanoacrylates can also be used as biomedical materials, for example as medical glues for wound bonding, hemostasis, embolization, etc., or as a nanopharmaceutical carrier for delivery of drugs.
  • the present inventors have creatively discovered through a large amount of research work that the selective use of a certain structure of cyanoacrylate and an antitumor drug can prepare a drug-loaded gel having a good antitumor effect, thereby providing the following invention:
  • the present invention provides a composition comprising an antitumor drug and a cyanoacrylate, wherein the cyanoacrylate is a single alpha cyanoacrylate or a double alpha cyanoacrylate diester , or a combination of a plurality (for example, 2 or 3) of mono ⁇ -cyanoacrylates, or a combination of plural (for example, 2 or 3) double ⁇ -cyanoacrylate diesters, or a single ⁇ -cyano group a combination of an acrylate and a double alpha-cyanoacrylate diester (for example, a combination of a single alpha-cyanoacrylate and a double alpha-cyanoacrylate diester, a single alpha-cyanoacrylate and a plurality of a combination of bis-cyanoacrylate diesters, a combination of a plurality of mono- ⁇ -cyanoacrylates with a double ⁇ -cyanoacrylate diester, or a plurality of mono- ⁇ -cyanoacrylates and various
  • the mono alpha-cyanoacrylate has a structure as shown in formula (I):
  • R is selected from:
  • R 1 and R 2 are each independently selected from a C 1-6 alkylene group, and R 3 is a C 1-6 alkyl group;
  • n is each independently selected from 1 An integer between 500 (eg, 1-10, 10-100, 100-200, 200-300, 300-400, or 400-500).
  • the C 1-30 straight or branched alkyl group is selected from: C 1-4 straight or branched alkyl, C 4-8 straight or branched alkyl, C 1- 8 straight or branched alkyl, C 1-10 straight or branched alkyl, C 1-20 straight or branched alkyl.
  • the C 2-30 straight or branched alkenyl group is selected from the group consisting of: C 2-4 straight or branched alkenyl, C 4-8 straight or branched alkenyl, C 2 - 8 linear or branched alkenyl, C 2-10 straight or branched alkenyl, C 2-20 straight or branched alkenyl.
  • the C 2-30 straight or branched alkynyl group is selected from the group consisting of: C 2-4 straight or branched alkynyl, C 4-8 straight or branched alkynyl, C 2 ⁇ 8 straight or branched alkynyl, C 2-10 straight or branched alkynyl, C 2-20 straight or branched alkynyl.
  • the halogen atom is selected from the group consisting of: fluorine, chlorine, bromine, and iodine.
  • the halo C 1-4 alkyl group is selected from fluoro C 1-4 alkyl or chloro C 1-4 alkyl.
  • R is selected from the group consisting of methyl, ethyl, n-butyl, n-octyl, 2-isooctyl, -C 2 H 4 -O-CH 3 , -C 2 H 4 -OC 2 H 4 -O-CH 3 .
  • R is selected from the group consisting of: n-butyl, n-octyl, 2-isooctyl, -C 2 H 4 -O-CH 3 , -C 2 H 4 -OC 2 H 4 -O-CH 3 .
  • the bis- ⁇ -cyanoacrylate diester has a structure as shown in formula (II):
  • W is selected from:
  • the C 1-30 straight or branched alkylene group is selected from the group consisting of: C 1-4 straight or branched alkylene, C 4-8 straight or branched alkylene, C 1-8 straight or branched alkylene, C 1-10 straight or branched alkylene, C 1-20 straight or branched alkylene.
  • the C 2-30 straight or branched alkenylene group is selected from the group consisting of: C 2-4 straight or branched alkenylene, C 4-8 straight or branched alkenylene, C 2-8 straight or branched alkenylene, C 2-10 straight or branched alkenylene, C 2-20 straight or branched alkenylene.
  • the C 2-30 straight or branched alkynylene group is selected from the group consisting of: C 2-4 straight or branched alkynylene, C 4-8 straight or branched alkynylene, C 2-8 straight or branched alkynylene, C 2-10 straight or branched alkynylene, C 2-20 straight or branched alkynylene.
  • the halogen atom is selected from the group consisting of: fluorine, chlorine, bromine, and iodine.
  • the halo C 1-4 alkyl group is selected from fluoro C 1-4 alkyl or chloro C 1-4 alkyl.
  • W is selected from the group consisting of ethylene, n-butylene, n-octylene, polyethylene glycol segments, and the polyethylene glycol segments are as shown in formula (III)
  • p is selected from an integer between 0 and 100, preferably an integer between 1 and 50 (e.g., 1-10, 10-20, 20-30, 30-40 or 40-50).
  • the composition comprises: (1) a single alpha-cyanoacrylate, (2) multiple (eg, two or three) mono alpha-cyanoacrylates, (3) A double alpha-cyanoacrylate diester, or (4) an alpha-monocyanoacrylate and a double alpha-cyanoacrylate diester.
  • the mono alpha-cyanoacrylate is selected from the group consisting of: n-butyl cyanoacrylate (BCA), methoxyethyl ⁇ -cyanoacrylate (MOE-CA), alpha-cyanide (Methoxydiethylene glycol) acrylate (MOEOE-CA).
  • the bis- ⁇ -cyanoacrylate diester is selected from the group consisting of: bis- ⁇ -cyanoacrylate triethylene glycol ester (CA-TEG-CA), bis- ⁇ -cyanoacrylic acid PEG 600 ester (CA-PEG 600- CA), bis-cyanoacrylic acid PEG 2000 ester (CA-PEG 2000- CA).
  • the lower marks in PEG 600 and PEG 2000 represent the number average molecular weight of the polyethylene glycol segments, and the number of corresponding repeating units is about 14 and about 45, respectively.
  • the composition comprises a molar ratio of 2-150:1 (eg, 2:1, 2.3:1, 5:1, 5.3:1, 10:1, 13:1, 13.9:1, 30:1, 32.5:1, 40:1, 44:1, 100:1, 125.3:1 or 150:1) mono- ⁇ -cyanoacrylate and bis- ⁇ -cyanoacrylate diester.
  • 2-150:1 eg, 2:1, 2.3:1, 5:1, 5.3:1, 10:1, 13:1, 13.9:1, 30:1, 32.5:1, 40:1, 44:1, 100:1, 125.3:1 or 150:1
  • the composition comprises a mass ratio of from 99:1 to 50:50 (eg, 99:1, 98:2, 97:3, 96:4, 95:5, 94:6, 93: 7, 92:8, 91:9, 90:10, 89:11, 88:12, 87:13, 86:14, 85:15, 84:16, 83:17, 82:18, 81:19, 80:20, 79:21, 78:22, 77:23, 76:24, 75:25, 74:26, 73:27, 72:28, 71:29, 70:30, 69:31, 68: 32, 67:33, 66:34, 65:35, 64:36, 63:37, 62:38, 61:39, 60:40, 59:41, 58:42, 57:43, 56:44, Mono- ⁇ -cyanoacrylate and bis- ⁇ -cyanoacrylate diester at 55:45, 54:46, 53:
  • the composition comprises a single alpha-cyanoacrylate and a double alpha-cyanoacrylate diester selected from the group consisting of: BCA, MOE-CA
  • the bis- ⁇ -cyanoacrylate diester is selected from the group consisting of CA-TEG-CA, CA-PEG 600- CA, CA-PEG 2000- CA.
  • the composition comprises MOE-CA and CA-TEG-CA.
  • the composition comprises BCA and CA-TEG-CA.
  • the composition comprises MOE-CA and CA-PEG 600- CA.
  • the composition comprises BCA and CA-PEG 600- CA.
  • the composition comprises MOE-CA and CA-PEG 2000- CA.
  • the composition comprises BCA and CA-PEG 2000- CA.
  • the composition comprises a molar ratio of 2-150:1 (eg, 2:1, 2.3:1, 5:1, 5.3:1, 10:1, 13:1, 13.9:1, Two single alpha-cyanoacrylates of 30:1, 32.5:1, 40:1, 44:1, 100:1, 125.3:1 or 150:1).
  • 2-150:1 eg, 2:1, 2.3:1, 5:1, 5.3:1, 10:1, 13:1, 13.9:1, Two single alpha-cyanoacrylates of 30:1, 32.5:1, 40:1, 44:1, 100:1, 125.3:1 or 150:1).
  • the composition comprises a mass ratio of from 99:1 to 50:50 (eg, 99:1, 98:2, 97:3, 96:4, 95:5, 94:6, 93: 7, 92:8, 91:9, 90:10, 89:11, 88:12, 87:13, 86:14, 85:15, 84:16, 83:17, 82:18, 81:19, 80:20, 79:21, 78:22, 77:23, 76:24, 75:25, 74:26, 73:27, 72:28, 71:29, 70:30, 69:31, 68: 32, 67:33, 66:34, 65:35, 64:36, 63:37, 62:38, 61:39, 60:40, 59:41, 58:42, 57:43, 56:44, Two single alpha-cyanoacrylates at 55:45, 54:46, 53:47, 52:48, 51:49 or
  • the composition comprises two mono alpha-cyanoacrylates selected from the group consisting of: BCA, MOE-CA, MOEOE-CA.
  • the composition comprises BCA and MOE-CA.
  • the composition comprises BCA and MOEOE-CA.
  • the composition comprises MOE-CA and MOEOE-CA.
  • the same load material may have different drug release rates for different drugs, and different load materials may have different drug release rates for the same drug.
  • the rate of drug release may be related to factors such as the microstructure of the material, the degradation of the material, and the interaction of the material and drug.
  • the invention can adjust the degradation rate of the material and the drug release rate by selecting the cyanoacrylate monomer to meet different therapeutic needs.
  • the antitumor drug preferably has a drug molecule which does not contain a functional group such as an amino group or an amine group which can cause anionic polymerization of the cyanoacrylate.
  • the medicaments useful in the compositions of the present invention preferably have suitable solubility in cyanoacrylates and have suitable interaction forces with cyanoacrylates to render the compositions of the present invention clinically compatible The required effective drug release can, in turn, produce an actual therapeutic effect.
  • the anti-tumor drug is selected from the group consisting of mesylate derivatives, polyols, anthracycline derivatives, pyrimidine derivatives, taxane derivatives, and any combination thereof.
  • the anti-tumor drug is selected from the group consisting of: Busulfan, Myleran 17-24, dibromomannitol, dibromodusol, fluorouracil, paclitaxel, docetaxel, oxaliplatin , docetaxel, epirubicin, gemcitabine, isovinblastine, doxorubicin, pirarubicin, capecitabine, hydroxycamptothecin, and any combination thereof.
  • the anti-tumor drug is selected from the group consisting of: fluorouracil, curcumin, doxorubicin, paclitaxel, docetaxel, and any combination thereof.
  • the anti-tumor drug is present in the composition at a level of from 0.001% to 20%, preferably from 0.1% to 10% (eg, from 0.1% to 5%, such as 0.1%, 0.25%, 0.3125) by mass. %, 0.5%, 0.625%, 0.75%, 1%, 1.25%, 1.5%, 2% or 2.5%).
  • compositions of the invention may also contain auxiliaries, such as synthetic auxiliaries, reactive auxiliaries, functional auxiliaries, process auxiliaries and/or stabilizing auxiliaries.
  • auxiliaries such as synthetic auxiliaries, reactive auxiliaries, functional auxiliaries, process auxiliaries and/or stabilizing auxiliaries.
  • the antitumor drug can be directly dissolved in a monomeric cyanoacrylate liquid to give a composition of the present invention.
  • the corresponding monomer components can be mixed under nitrogen protection to obtain a clear, transparent formulation gel; the formulation gel can be mixed with the drug to obtain Clarify the clear drug-loaded gel solution.
  • mixing between the components can be promoted using agitation, shaking, heating, and the like.
  • the present invention provides a composition comprising an antitumor drug and a polycyanoacrylate, wherein the polycyanoacrylate is selected from the group consisting of a homopolymer of a single alpha-cyanoacrylate, a double alpha- a homopolymer of a cyanoacrylate diester, a copolymer of a plurality (for example, two or three kinds) of mono-cyanoacrylates, and a plurality of (for example, two or three kinds) of double ⁇ -cyanoacrylate diesters.
  • a copolymer, or a copolymer of a mono- ⁇ -cyanoacrylate and a double ⁇ -cyanoacrylate diester for example, a copolymer of ⁇ -monocyanoacrylate and a double ⁇ -cyanoacrylate diester, one a copolymer of a single ⁇ -cyanoacrylate with various bis- ⁇ -cyanoacrylate diesters, a copolymer of a plurality of mono- ⁇ -cyanoacrylates and a double ⁇ -cyanoacrylate diester, or a plurality of a copolymer of a single ⁇ -cyanoacrylate and a plurality of bis- ⁇ -cyanoacrylate diesters).
  • the mono- ⁇ -cyanoacrylate has a structure as shown in formula (I).
  • the bis- ⁇ -cyanoacrylate diester has a structure as shown in formula (II).
  • the mono alpha-cyanoacrylate is selected from the group consisting of: n-butyl cyanoacrylate (BCA), methoxyethyl ⁇ -cyanoacrylate (MOE-CA), alpha-cyanide (Methoxydiethylene glycol) acrylate (MOEOE-CA).
  • the bis- ⁇ -cyanoacrylate diester is selected from the group consisting of: bis- ⁇ -cyanoacrylate triethylene glycol ester (CA-TEG-CA), bis- ⁇ -cyanoacrylic acid PEG 600 ester (CA-PEG 600- CA), bis-cyanoacrylic acid PEG 2000 ester (CA-PEG 2000- CA).
  • the polycyanoacrylate comprises a single alpha-cyanoacrylate monomer unit and a dual alpha-cyanoacrylate diester monomer unit in a molar ratio of 2-150:1 ( For example, 2:1, 2.3:1, 5:1, 5.3:1, 10:1, 13:1, 13.9:1, 30:1, 32.5:1, 40:1, 44:1, 100:1, 125.3 :1 or 150:1).
  • the polycyanoacrylate comprises a single alpha-cyanoacrylate monomer unit and a dual alpha-cyanoacrylate diester monomer unit in a mass ratio of 99: 1-50: 50 (eg 99:1, 98:2, 97:3, 96:4, 95:5, 94:6, 93:7, 92:8, 91:9, 90:10, 89:11, 88:12) 87:13, 86:14, 85:15, 84:16, 83:17, 82:18, 81:19, 80:20, 79:21, 78:22, 77:23, 76:24, 75 :25, 74:26, 73:27, 72:28, 71:29, 70:30, 69:31, 68:32, 67:33, 66:34, 65:35, 64:36, 63:37 62:38, 61:39, 60:40, 59:41, 58:42, 57:43, 56:
  • the composition comprises a copolymer of a single alpha-cyanoacrylate and a double alpha-cyanoacrylate diester selected from the group consisting of: BCA, MOE-CA, the bis- ⁇ -cyanoacrylate diester is selected from the group consisting of CA-TEG-CA, CA-PEG 600- CA, CA-PEG 2000- CA.
  • the polycyanoacrylate comprises two mono- ⁇ -cyanoacrylate monomer units in a molar ratio of 2-150:1 (eg, 2:1, 2.3:1, 5) : 1, 5.3: 1, 10: 1, 13: 1, 13.9: 1, 30: 1, 32.5: 1, 40: 1, 44: 1, 100: 1, 125.3: 1 or 150: 1).
  • the polycyanoacrylate comprises two mono- ⁇ -cyanoacrylate monomer units in a mass ratio of 99:1 to 50:50 (eg, 99:1, 98:2) , 97:3, 96:4, 95:5, 94:6, 93:7, 92:8, 91:9, 90:10, 89:11, 88:12, 87:13, 86:14, 85 : 15, 84:16, 83:17, 82:18, 81:19, 80:20, 79:21, 78:22, 77:23, 76:24, 75:25, 74:26, 73:27 72:28, 71:29, 70:30, 69:31, 68:32, 67:33, 66:34, 65:35, 64:36, 63:37, 62:38, 61:39, 60 : 40, 59:41, 58:42, 57:43, 56:44, 55:45, 54:46, 53:47
  • the polycyanoacrylate comprises two mono- ⁇ -cyanoacrylate monomer units selected from the group consisting of: BCA, MOE-CA, MOEOE-CA.
  • the anti-tumor drug is selected from the group consisting of mesylate derivatives, polyols, anthracycline derivatives, pyrimidine derivatives, taxane derivatives, and any combination thereof.
  • the anti-tumor drug is selected from the group consisting of: Busulfan, Myleran 17-24, dibromomannitol, dibromodusol, fluorouracil, paclitaxel, docetaxel, oxaliplatin , docetaxel, epirubicin, gemcitabine, isovinblastine, doxorubicin, pirarubicin, capecitabine, hydroxycamptothecin, and any combination thereof.
  • the anti-tumor drug is selected from the group consisting of: fluorouracil, curcumin, doxorubicin, paclitaxel, docetaxel, and any combination thereof.
  • the anti-tumor drug is present in the composition at a level of from 0.001% to 20%, preferably from 0.1% to 10% (eg, from 0.1% to 5%, such as 0.1%, 0.25%, 0.3125) by mass. %, 0.5%, 0.625%, 0.75%, 1%, 1.25%, 1.5%, 2% or 2.5%).
  • the composition further comprises an adjuvant, such as a synthetic aid, a reactive auxiliary, a functional adjuvant, a process aid, and/or a stabilizing aid.
  • an adjuvant such as a synthetic aid, a reactive auxiliary, a functional adjuvant, a process aid, and/or a stabilizing aid.
  • the composition is made from a composition comprising an anti-tumor drug and a cyanoacrylate as described above.
  • the invention further relates to a pharmaceutical preparation comprising the composition of any of the above.
  • the composition containing an antitumor drug and a cyanoacrylate is usually in a liquid state, and is suitable for injection (for example, an injection solution or a concentrated solution for injection), and in particular, for intratumoral injection.
  • Cyanoacrylate polymerizes in the tumor to form a solid drug-loaded rubber block.
  • the polymer acts as a drug reservoir, and can quantitatively release the drug loaded in a certain period of time according to the needs of the treatment, and play a fixed point.
  • the polymerization of cyanoacrylate itself may destroy the micro blood supply in the tumor, and may cause the tumor to have a sensitizing and synergistic effect on the drug; on the other hand, due to the polymerization of cyanoacrylate
  • the bonding property enables the polymer to adhere well to the tumor or the corresponding tissue, avoiding the risk of detachment and the like.
  • the present invention also relates to the use of a composition according to any of the above for the preparation of a medicament for treating a tumor-related disease in a subject, the tumor-associated disease being capable of containing an antitumor drug contained in the composition Treated diseases.
  • the present invention also relates to a method of treating a tumor-associated disease comprising administering to a subject in need thereof an effective amount of a composition according to any one of the above, the tumor-associated disease being an anti-tumor drug contained in the composition A disease that can be treated.
  • a tumor refers to a neogrowth formed by local tissue cell proliferation under the action of various tumorigenic factors.
  • Tumors of the invention include benign and malignant tumors, as well as neoplastic polyps.
  • the tumor-related diseases include, but are not limited to, brain tumor, lung cancer, squamous cell carcinoma, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, and uterus.
  • Endometrial cancer rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, female genital tract cancer, carcinoma in situ, lymphoma, neurofibromatosis, thyroid cancer, bone cancer, skin cancer, Brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, prostate tumor, mast cell tumor, multiple myeloma, melanoma, glioma or sarcoma.
  • the subject is preferably a mammal, such as a bovine, equine, porcine, canine, feline, rodent, primate; for example, the subject Are people.
  • C 1-30 linear or branched alkyl group as used in the present invention means a straight or branched alkyl group having 1 to 30 carbon atoms, and includes, for example, a "C 1-4 straight or branched alkyl group.
  • C 4-8 linear or branched alkyl "C 1-8 straight or branched alkyl", “C 1-10 straight or branched alkyl”, “C 1-20 straight a chain or branched alkyl group, a “C 10-20 linear or branched alkyl group”, a “C 20-30 linear or branched alkyl group”, and the like, and specific examples include, but are not limited to, methyl, ethyl, N-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, 2-isooctyl and the like.
  • C 1-4 alkoxy group as used in the present invention means “C 1-4 alkyl-O-", and the "C 1-4 alkyl group” means a linear or branched chain containing 1-4.
  • the "C 2-30 linear or branched alkenyl group” as used in the present invention means a linear or branched alkenyl group having at least one carbon-carbon double bond and having 2 to 30 carbon atoms, and includes, for example, “C 2 -4 straight or branched alkenyl", “C 4-8 straight or branched alkenyl”, “C 2-8 straight or branched alkenyl", “C 2-10 straight or branched olefin”",”C 2-20 straight or branched alkenyl", “C 10-20 straight or branched alkenyl", “C 20-30 straight or branched alkenyl” and the like.
  • Examples thereof include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentyl Alkenyl, 3-pentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,4-hexyl Dienyl and the like.
  • the "C 2-30 straight-chain or branched alkynyl group” as used in the present invention means a straight-chain or branched alkynyl group having at least one carbon-carbon triple bond and having 2 to 30 carbon atoms, and includes, for example, "C 2 -4 linear or branched alkynyl", “C 4-8 straight or branched alkynyl", “C 2-8 straight or branched alkynyl", “C 2-10 straight or branched alkyne”","C 2-20 straight or branched alkynyl", “C 10-20 straight or branched alkynyl", “C 20-30 straight or branched alkynyl” and the like.
  • Examples thereof include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-pentyne A group, a 1,3-pentadiynyl group, a 1,4-pentadiynyl group, a 1-hexynyl group, a 2-hexynyl group, a 3-hexynyl group.
  • the "C 1-30 linear or branched alkylene group” as used in the present invention means a linear or branched alkane having 1 to 30 carbon atoms and a group derived from hydrogen which is not on the same carbon atom.
  • the "C 2-30 straight or branched alkenylene group” as used in the present invention means a linear or branched olefin having 2 to 30 carbon atoms which is derivatized by two hydrogens which are not on the same carbon atom.
  • C 2-30 linear or branched alkynylene group as used in the present invention means that a linear or branched alkyne having 2 to 30 carbon atoms is derived by removing two hydrogens which are not on the same carbon atom.
  • halogen atom as used in the present invention means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • Halo as used in the present invention means substituted by "halogen atom”.
  • auxiliary refers to an auxiliary material in the production process and/or use of the adhesive.
  • Adhesive additives include but are not limited to: synthetic auxiliaries, reactive auxiliaries, functional auxiliaries, process auxiliaries and stabilizing auxiliaries.
  • synthetic aid is used primarily in the synthesis and/or formulation of adhesives or other materials having adhesive properties, using emulsifiers, initiators, polymerization inhibitors, catalysts, Solvents, oxidizing agents, dispersing agents, chain extenders, regulators, neutralizers and terminators.
  • the term "reactive aid” refers to a compound having a reactive group that reacts with a matrix polymer in an adhesive or other material having an adhesive property to form a network or cross.
  • the joint structure mainly includes a toughening agent, a curing agent, a crosslinking agent, a photoinitiator, a promoter and a reactive flame retardant.
  • auxiliaries also known as “modification auxiliaries” refers to auxiliaries that improve the original properties of adhesives or other materials with adhesive properties, or impart new functions. , mainly including plasticizers, coupling agents, tackifiers, foaming agents, colorants, reinforcing agents, fillers, flame retardants, softeners, antistatic agents, taste masking agents, toughening agents, accelerators and Chelating agents, etc.
  • process auxiliaries refers to auxiliaries used for the ease of formulation and use of adhesives or other materials having adhesive properties, and to ensure their intended properties, including thickeners, A foaming agent, an antifreeze, a release agent, a diluent, a thixotropic agent, and a scorch retarder.
  • the term "stabilizing aid” means that it is capable of preventing the deterioration of the adhesive or other adhesive properties during synthesis, storage, and use, prolonging the service life and/or improving storage stability.
  • the additives mainly include antioxidants, heat stabilizers, light stabilizers, fungicides, preservatives and metal ion passivators.
  • the present invention provides a composition comprising a cyanoacrylate monomer and an antitumor drug, wherein the cyanoacrylate monomer is in a liquid state before polymerization, and has good solubility and compatibility against tumor drugs, and The effect of the loaded drug; the composition has good fluidity and can be injected into the tumor by site-directed injection.
  • the polymerizable nature of the cyanoacrylate monomer allows the composition to form a solid drug-loaded gum mass within the tumor or at the corresponding suitable tissue within seconds of exposure to human tissue.
  • the cyanoacrylate polymer formed by polymerization can play the role of drug storage, and can quantitatively release the drug loaded therein for a certain period of time according to the needs of treatment, and exert a fixed-point therapeutic effect;
  • cyanoacrylate The polymerization of the monomer may destroy the micro blood supply in the tumor, and may cause the tumor to have a sensitizing and synergistic effect on the drug;
  • the drug-loading rubber block may be very It is well fixed to adhere to the tumor or the corresponding tissue to avoid the risk of shedding and dislocation.
  • the drug and the loading material have a synergistic (promoting) therapeutic effect with a better therapeutic effect relative to a single drug group or blank material group.
  • Figure 1 is a peak area-concentration standard curve of the fluorouracil content in Example 3.
  • Fig. 2 exemplarily shows drug release profiles of drug-loaded gels (J-Fu-0.3125, J-Fu-0.625, J-Fu-1.25) loaded with different concentrations of drugs.
  • Figure 3 shows the cell viability of each group in an in vitro cytotoxicity assay.
  • Fig. 4 exemplarily shows the morphology of cells observed by microscopy in an in vitro cytotoxicity test, wherein A: J group, B: J-Fu-1.25 group, C: J-Fu-0.625 group, D: J-Fu -0.3125 group, E: normal group, F: Fu group.
  • Figure 5 shows the change in tumor volume of each group of mice in the in vivo anti-tumor test of Example 6.
  • Figure 6 shows the survival rate of each group of mice in the in vivo anti-tumor test of Example 6.
  • Figure 7 is a graph showing changes in body weight of mice in each group in the in vivo antitumor test of Example 6.
  • Fig. 8 exemplarily shows the tumor condition of each group of mice on the 14th day of the in vivo anti-tumor test, wherein A: PBS group, B: Fu group, C: J group, D: J-Fu-1.25 group.
  • Figure 9 is a photograph of H&E staining of major organs of J-Fu-1.25 mice on day 36 of in vivo anti-tumor test administration.
  • Figure 10 is a photograph of H&E staining of the skin, muscle and major organs of the J-Fu-1.25 group on the 30th day after the subcutaneous implantation test of SD rats.
  • Formulation gels were prepared according to the formulations in Table 1 using cyanoacrylate monomers BCA, MOE-CA, CA-TEG-CA, CA-PEG 600- CA, CA-PEG 2000- CA. Under the conditions of nitrogen protection, the corresponding monomer components are mixed by stirring, shaking, etc., to obtain a clear and transparent formula.
  • the formulated glue is polymerized at normal temperature and pressure and in air to form a rubber block. The degradation rate and bond strength of the rubber block were tested. The results are shown in Table 1.
  • the formulation gels in Table 1 were mixed with fluorouracil, curcumin, doxorubicin, paclitaxel, and docetaxel, respectively, and each drug was used in multiple mass ratios (0.1%, 0.25%, 0.5%, 0.75%, 1%, 1.25%, 1.5%, 2%, 2.5%) can obtain a clear and transparent drug-loaded gel solution.
  • Preparation of material extract Take 7.5mg of drug-free J group formula (referred to as J group), and J group formula glue (differently referred to as J-, respectively) loaded with different concentrations (1.25%, 0.625% and 0.3125%) of fluorouracil Fu-1.25, J-Fu-0.625, J-Fu-0.3125), after solidification in a 48-well cell culture plate (diameter 10.2 mm), placed at 37 ° C with physiological saline (7.5 mg/mL), volume fraction 5 The extract was incubated for 24 hours in a %CO 2 incubator; the extract was filtered through a 0.22 ⁇ m sterile filter, added to RPMI-1640 medium, and diluted according to (1/1, v/v) to obtain a sample to be tested.
  • J group drug-free J group formula
  • J- J group formula glue
  • MCF-7 cells were purchased from the Concord Cell Bank; monoculture-cultured 48-hour-grown MCF-7 cells were digested with 0.25% trypsin and mixed with RPMI-1640 medium containing 10% fetal bovine serum. The cell suspension was seeded in a 96-well culture plate with 5 ⁇ 10 3 cells at a volume of 100 ⁇ L per well, placed in a carbon dioxide incubator, and cultured at 37 ° C, 5% CO 2 and saturated humidity for 24 h until the cells adhered.
  • the culture solution was aspirated, and 100 ⁇ L of the sample to be tested was added to each well of the culture plate, wherein the negative control was RPMI-1640 medium (normal group) containing 10% fetal calf serum; the positive control was PBS solution containing 1.25% fluorouracil. (referred to as Fu group); cell viability was measured by MTT (tetramethylazozolium salt) method.
  • Figure 3 shows the cell viability of each group
  • Figure 4 shows the cell morphology observed by microscopy, wherein A: J group, B: J-Fu-1.25 group, C: J-Fu-0.625 group, D: J- Fu-0.3125 group, E: normal group, F: Fu group.
  • Model construction 40 Balb/c nude mice (8 weeks old, female, 20 g or so) were taken, and 200 ⁇ L of 2 ⁇ 10 6 MCF-7 cell suspension (normal saline) was injected subcutaneously into Balb/ with a disposable plastic syringe (1 mL). c Nude mice were placed under the right forelimb and kept for 15 days.
  • Figure 5 shows the tumor volume changes of each group of mice;
  • Figure 6 shows the survival rate of each group of mice;
  • Figure 7 shows the body weight changes of each group of mice;
  • Figure 8 shows the tumor status of each group of mice on the 14th day of the experiment.
  • A PBS group
  • B Fu group
  • C J group
  • D J-Fu-1.25 group.
  • the drug-loaded gel J-Fu-1.25 effectively inhibited tumor growth, improved mouse survival, and the body weight of the mice during the test. No significant changes have occurred.
  • the tumors of the J-Fu-1.25 group showed more inflammation and necrosis than the other three groups. The above results together demonstrate that the drug-loaded gel J-Fu-1.25 has a good anti-tumor effect.
  • the anti-tumor effect of the J-Fu-1.25 group is superior to that of the Fu group and also superior to the J group.
  • the above results indicate that the cyanoacrylate monomer and/or polymer can promote the action of fluorouracil at least within a certain dosage range, and the combination of the two can produce a synergistic antitumor effect.
  • Figure 10 shows H&E staining photographs of skin, muscle, and rat organs on the 30th day of the experiment. Although a certain degree of inflammation was observed in the gel implantation site during the first few days after the test, on the 30th day of the experiment, all the test rats survived and the inflammation site returned to normal, and can be recovered from Figure 10. It can be seen that no inflammation was observed in the skin, muscle and the main organs (heart, liver, spleen and kidney) of the polymer gel, indicating that the implanted polymer gel was not systemic.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

一种负载抗肿瘤药物的氰基丙烯酸酯材料，以及含有所述氰基丙烯酸酯材料和抗肿瘤药物的组合物，包含所述组合物的药物制剂，例如可用于肿瘤内注射的药物制剂。

Description

负载抗肿瘤药物的氰基丙烯酸酯材料 技术领域
本发明涉及生物医学领域和材料领域，具体涉及一种负载抗肿瘤药物的氰基丙烯酸酯材料。
背景技术
肿瘤瘤内注射治疗是近年发展的肿瘤治疗新方案，通过将药物直接注射到肿瘤内，使其发挥定点治疗的作用，可一定程度上避免或减轻口服、静脉注射等手段需要面临的首过效应和全身毒副作用等。在一些不采用开放性手术器械就可到达的部位，以及一些不利于手术切除的部位，或者在考虑到术后美观程度等情况下，采用瘤内注射药物的治疗方案具有独特的优势。
已批准上市的融瘤病毒疗法，如安进公司的IMLYGIC、国内的今又生、安柯瑞等新药都是采用瘤内注射方法。此外，多项药物开发研究也采用了瘤内注射给药，如MultiVir公司采用瘤内注射的方式输送治疗头颈瘤的药物Ad-IL-24。再者，现有临床相关技术手段成熟，可实现多部位的瘤内注射，如在B超、CT、磁共振等影像引导下可实现肿瘤穿刺微创治疗，临床已有氩氮刀冷冻、射频加热等手段可使用。
但是，瘤内注射的方案中，有两个风险问题需要引起特别关注，一是由于瘤内压力高于正常组织，因此液体药物注射到瘤内后容易溢出，二是肿瘤内血管丰富，给药后药物容易较快地从肿瘤部位扩散至其他组织，达不到长效给药的目的。
因此，提供瘤内注射的新制剂或新材料，避免药物溢出的风险，实现长时间瘤内定点缓释给药具有实际应用价值。
发明内容
氰基丙烯酸酯是一类可快速固化并产生粘接性质的化合物，其结构中烯双键非常活泼，单体在阴离子条件下能快速发生分子间聚合，成为聚合物。氰基丙烯酸酯单体一般呈液态，具有流动性，因此可满足涂布和注射等使用方式。根据使用方式的不同，其聚合后的高聚物可为固体胶块或胶膜。除生活和工业粘接用途外，氰基丙烯酸酯还可以用作生物医学材料，例如作为医用胶用于伤口粘接、止血、栓塞等目的，或者作为纳米药物载体递送药物。
本发明人通过大量的研究工作，创造性地发现了：选择性使用一定结构的氰基丙烯 酸酯与抗肿瘤药物混合，可制备具有良好抗肿瘤效果的载药胶，由此提供了下述发明：
在一个方面，本发明提供了一种组合物，其含有抗肿瘤药物和氰基丙烯酸酯，其中，所述氰基丙烯酸酯为单α-氰基丙烯酸酯，或者双α-氰基丙烯酸二酯，或者多种(例如2种或3种)单α-氰基丙烯酸酯的组合，或者多种(例如2种或3种)双α-氰基丙烯酸二酯的组合，或者单α-氰基丙烯酸酯与双α-氰基丙烯酸二酯的组合(例如一种单α-氰基丙烯酸酯与一种双α-氰基丙烯酸二酯的组合，一种单α-氰基丙烯酸酯与多种双α-氰基丙烯酸二酯的组合，多种单α-氰基丙烯酸酯与一种双α-氰基丙烯酸二酯的组合，或多种单α-氰基丙烯酸酯与多种双α-氰基丙烯酸二酯的组合)。
在某些实施方案中，所述单α-氰基丙烯酸酯具有如式(I)所示的结构：
Figure PCTCN2018120260-appb-000001
其中，R选自：
(1)C 1-30直链或支链烷基，被酰氧基、卤代C 1-4烷基、C 1-4烷氧基、卤素原子或氰基取代的C 1-30直链或支链烷基，C 2-30直链或支链烯基，C 2-30直链或支链炔基，5-10元环烷基，C 6-10芳基-C 1-4烷基，C 1-4烷基-C 6-10芳基，C 6-10芳基；
(2)-R 1-O-R 2-O-R 3，其中，R 1、R 2各自独立地选自C 1-6亚烷基，R 3为C 1-6烷基；
(3)-(C 2H 4O) nCH 3、-(C 2H 4O) nC 2H 5、-(C 2H 4O) nH，其中，n各自独立地选自1-500(例如1-10、10-100、100-200、200-300、300-400或400-500)之间的整数。
在某些实施方案中，所述C 1-30直链或支链烷基选自：C 1-4直链或支链烷基、C 4-8直链或支链烷基、C 1-8直链或支链烷基、C 1-10直链或支链烷基、C 1-20直链或支链烷基。
在某些实施方案中，所述C 2-30直链或支链烯基选自：C 2-4直链或支链烯基、C 4-8直链或支链烯基、C 2-8直链或支链烯基、C 2-10直链或支链烯基、C 2-20直链或支链烯基。
在某些实施方案中，所述C 2-30直链或支链炔基选自：C 2-4直链或支链炔基、C 4-8直链或支链炔基、C 2-8直链或支链炔基、C 2-10直链或支链炔基、C 2-20直链或支链炔基。
在某些实施方案中，所述卤素原子选自：氟、氯、溴、碘。
在某些实施方案中，所述卤代C 1-4烷基选自氟代C 1-4烷基或氯代C 1-4烷基。
在某些实施方案中，R选自：甲基、乙基、正丁基、正辛基、2-异辛基、-C 2H 4-O-CH 3、-C 2H 4-O-C 2H 4-O-CH 3。
在某些实施方案中，R选自：正丁基、正辛基、2-异辛基、-C 2H 4-O-CH 3、 -C 2H 4-O-C 2H 4-O-CH 3。
在某些实施方案中，所述双α-氰基丙烯酸二酯具有如式(II)所示的结构：
Figure PCTCN2018120260-appb-000002
其中，W选自：
(1)C 1-30直链或支链亚烷基，被酰氧基、卤代C 1-4烷基、C 1-4烷氧基、卤素原子或氰基取代的C 1-30直链或支链亚烷基，C 2-30直链或支链亚烯基，C 2-30直链或支链亚炔基，5-10元环亚烷基，C 6-10芳基-C 1-4亚烷基，C 1-4烷基-C 6-10亚芳基，C 6-10亚芳基；
(2)以下聚合物的链段：聚乙二醇(PEG)、聚乳酸(PLA)、聚羟基乙酸(PGA)、乳酸-羟基乙酸共聚物(PLGA)、含聚羟基酸和聚二醇类化合物的共聚物(如PLA-PEG-PLA嵌段共聚物、PGA-PEG-PGA嵌段共聚物)。
在某些实施方案中，所述C 1-30直链或支链亚烷基选自：C 1-4直链或支链亚烷基、C 4-8直链或支链亚烷基、C 1-8直链或支链亚烷基、C 1-10直链或支链亚烷基、C 1-20直链或支链亚烷基。
在某些实施方案中，所述C 2-30直链或支链亚烯基选自：C 2-4直链或支链亚烯基、C 4-8直链或支链亚烯基、C 2-8直链或支链亚烯基、C 2-10直链或支链亚烯基、C 2-20直链或支链亚烯基。
在某些实施方案中，所述C 2-30直链或支链亚炔基选自：C 2-4直链或支链亚炔基、C 4-8直链或支链亚炔基、C 2-8直链或支链亚炔基、C 2-10直链或支链亚炔基、C 2-20直链或支链亚炔基。
在某些实施方案中，所述卤素原子选自：氟、氯、溴、碘。
在某些实施方案中，所述卤代C 1-4烷基选自氟代C 1-4烷基或氯代C 1-4烷基。
在某些实施方案中，W选自：亚乙基、亚正丁基、亚正辛基、聚乙二醇链段，所述聚乙二醇链段如式(III)所示
Figure PCTCN2018120260-appb-000003
其中，p选自0-100之间的整数，优选1-50(例如1-10、10-20、20-30、30-40或40-50)之间的整数。
在某些实施方案中，所述组合物包含：(1)一种单α-氰基丙烯酸酯，(2)多种(例如2种或3种)单α-氰基丙烯酸酯，(3)一种双α-氰基丙烯酸二酯，或者，(4)一种 α-单氰基丙烯酸酯和一种双α-氰基丙烯酸二酯。
在某些实施方案中，所述单α-氰基丙烯酸酯选自：α-氰基丙烯酸正丁酯(BCA)、α-氰基丙烯酸甲氧乙基酯(MOE-CA)、α-氰基丙烯酸(甲氧基二乙二醇)酯(MOEOE-CA)。
在某些实施方案中，所述双α-氰基丙烯酸二酯选自：双α-氰基丙烯酸二缩三乙二醇酯(CA-TEG-CA)、双α-氰基丙烯酸PEG 600酯(CA-PEG 600-CA)、双α-氰基丙烯酸PEG 2000酯(CA-PEG 2000-CA)。
本发明中，PEG 600和PEG 2000中的下角标表示聚乙二醇链段的数均分子量，其对应的重复单元个数分别是约14和约45。
在某些实施方案中，所述组合物包含摩尔比为2-150:1(例如2:1、2.3:1、5:1、5.3:1、10:1、13:1、13.9:1、30:1、32.5:1、40:1、44:1、100:1、125.3:1或150:1)的单α-氰基丙烯酸酯和双α-氰基丙烯酸二酯。
在某些实施方案中，所述组合物包含质量比为99:1-50:50(例如99:1、98:2、97:3、96:4、95:5、94:6、93:7、92:8、91:9、90:10、89:11、88:12、87:13、86:14、85:15、84:16、83:17、82:18、81:19、80:20、79:21、78:22、77:23、76:24、75:25、74:26、73:27、72:28、71:29、70:30、69:31、68:32、67:33、66:34、65:35、64:36、63:37、62:38、61:39、60:40、59:41、58:42、57:43、56:44、55:45、54:46、53:47、52:48、51:49或50:50)的单α-氰基丙烯酸酯和双α-氰基丙烯酸二酯。
在某些实施方案中，所述组合物包含一种单α-氰基丙烯酸酯和一种双α-氰基丙烯酸二酯，所述单α-氰基丙烯酸酯选自：BCA、MOE-CA，所述双α-氰基丙烯酸二酯选自：CA-TEG-CA、CA-PEG 600-CA、CA-PEG 2000-CA。
在某些实施方案中，所述组合物包含MOE-CA和CA-TEG-CA。
在某些实施方案中，所述组合物包含BCA和CA-TEG-CA。
在某些实施方案中，所述组合物包含MOE-CA和CA-PEG 600-CA。
在某些实施方案中，所述组合物包含BCA和CA-PEG 600-CA。
在某些实施方案中，所述组合物包含MOE-CA和CA-PEG 2000-CA。
在某些实施方案中，所述组合物包含BCA和CA-PEG 2000-CA。
在某些实施方案中，所述组合物包含摩尔比为2-150:1(例如2:1、2.3:1、5:1、5.3:1、10:1、13:1、13.9:1、30:1、32.5:1、40:1、44:1、100:1、125.3:1或150:1)的两种单α-氰基丙烯酸酯。
在某些实施方案中，所述组合物包含质量比为99:1-50:50(例如99:1、98:2、97:3、96:4、95:5、94:6、93:7、92:8、91:9、90:10、89:11、88:12、87:13、86:14、85:15、84:16、 83:17、82:18、81:19、80:20、79:21、78:22、77:23、76:24、75:25、74:26、73:27、72:28、71:29、70:30、69:31、68:32、67:33、66:34、65:35、64:36、63:37、62:38、61:39、60:40、59:41、58:42、57:43、56:44、55:45、54:46、53:47、52:48、51:49或50:50)的两种单α-氰基丙烯酸酯。
在某些实施方案中，所述组合物包含两种单α-氰基丙烯酸酯，所述单α-氰基丙烯酸酯选自：BCA、MOE-CA、MOEOE-CA。
在某些实施方案中，所述组合物包含BCA和MOE-CA。
在某些实施方案中，所述组合物包含BCA和MOEOE-CA。
在某些实施方案中，所述组合物包含MOE-CA和MOEOE-CA。
本发明中，相同的负载材料对于不同的药物可能会有不同的药物释放速度，不同的负载材料对相同的药物也可能会有不同的药物释放速度。药物释放速度可能与材料的微观结构、材料的降解，以及材料和药物的相互作用等因素相关。本发明可以通过对氰基丙烯酸酯单体进行选择，调节材料的降解速率和药物释放速度，以满足不同治疗需要。
本发明中，抗肿瘤药物优选结构中不含有氨基、胺基等可以导致氰基丙烯酸酯发生阴离子聚合的官能团的药物分子。此外，可用于本发明组合物的药物优选地在氰基丙烯酸酯中具有合适的溶解性，并且与氰基丙烯酸酯之间具有合适的相互作用力，以使本发明的组合物具有符合临床治疗要求的有效的药物释放，进而可以产生实际的治疗效果。
在某些实施方案中，所述抗肿瘤药物选自：甲磺酸酯类衍生物、多元醇类、蒽环类衍生物、嘧啶类衍生物、紫杉烷类衍生物及其任意组合。
在某些实施方案中，所述抗肿瘤药物选自：白消安(Busulfan、马利兰Myleran17-24)、二溴甘露醇、二溴卫矛醇、氟尿嘧啶、紫杉醇、多烯紫杉醇、奥沙利铂、多西他赛、表柔比星、吉西他滨、异长春花碱、多柔比星、吡柔比星、卡培他滨、羟基喜树碱及其任意组合。
在某些实施方案中，所述抗肿瘤药物选自：氟尿嘧啶、姜黄素、多柔比星、紫杉醇、多烯紫杉醇及其任意组合。
在某些实施方案中，所述抗肿瘤药物在组合物中的含量按照质量计为0.001％-20％，优选0.1％-10％(例如0.1％-5％，例如0.1％、0.25％、0.3125％、0.5％、0.625％、0.75％、1％、1.25％、1.5％、2％或2.5％)。
本发明的组合物还可以含有助剂，例如合成助剂、反应性助剂、功能助剂、工艺助剂和/或稳定助剂。
可以将抗肿瘤药物直接溶解在单体态的氰基丙烯酸酯液体中，得到本发明的组合物。 在某些实施方案中，使用多种氰基丙烯酸酯单体，可以在氮气保护的条件下，将对应的单体成分进行混合，获得澄清透明的配方胶；将配方胶与药物混合，可获得澄清透明的载药胶溶液。任选地，可以使用搅拌、振荡、加热等方式促进组分间的混合。
本发明还涉及上述任一项组合物通过发生聚合反应得到的载药聚合物胶块。因此，本发明提供了一种组合物，其含有抗肿瘤药物和聚氰基丙烯酸酯，其中，所述聚氰基丙烯酸酯选自：单α-氰基丙烯酸酯的均聚物，双α-氰基丙烯酸二酯的均聚物，多种(例如2种或3种)单α-氰基丙烯酸酯的共聚物，多种(例如2种或3种)双α-氰基丙烯酸二酯的共聚物，或者单α-氰基丙烯酸酯与双α-氰基丙烯酸二酯的共聚物(例如一种α-单氰基丙烯酸酯和一种双α-氰基丙烯酸二酯的共聚物，一种单α-氰基丙烯酸酯与多种双α-氰基丙烯酸二酯的共聚物，多种单α-氰基丙烯酸酯与一种双α-氰基丙烯酸二酯的共聚物，或多种单α-氰基丙烯酸酯与多种双α-氰基丙烯酸二酯的共聚物)。
在某些实施方案中，所述单α-氰基丙烯酸酯具有如式(I)所示结构。在某些实施方案中，所述双α-氰基丙烯酸二酯具有如式(II)所示结构。在某些实施方案中，所述单α-氰基丙烯酸酯选自：α-氰基丙烯酸正丁酯(BCA)、α-氰基丙烯酸甲氧乙基酯(MOE-CA)、α-氰基丙烯酸(甲氧基二乙二醇)酯(MOEOE-CA)。在某些实施方案中，所述双α-氰基丙烯酸二酯选自：双α-氰基丙烯酸二缩三乙二醇酯(CA-TEG-CA)、双α-氰基丙烯酸PEG 600酯(CA-PEG 600-CA)、双α-氰基丙烯酸PEG 2000酯(CA-PEG 2000-CA)。
在某些实施方案中，所述聚氰基丙烯酸酯包含单α-氰基丙烯酸酯单体单元和双α-氰基丙烯酸二酯单体单元，二者的摩尔比为2-150:1(例如2:1、2.3:1、5:1、5.3:1、10:1、13:1、13.9:1、30:1、32.5:1、40:1、44:1、100:1、125.3:1或150:1)。
在某些实施方案中，所述聚氰基丙烯酸酯包含单α-氰基丙烯酸酯单体单元和双α-氰基丙烯酸二酯单体单元，二者的质量比为99:1-50:50(例如99:1、98:2、97:3、96:4、95:5、94:6、93:7、92:8、91:9、90:10、89:11、88:12、87:13、86:14、85:15、84:16、83:17、82:18、81:19、80:20、79:21、78:22、77:23、76:24、75:25、74:26、73:27、72:28、71:29、70:30、69:31、68:32、67:33、66:34、65:35、64:36、63:37、62:38、61:39、60:40、59:41、58:42、57:43、56:44、55:45、54:46、53:47、52:48、51:49或50:50)。
在某些实施方案中，所述组合物包含一种单α-氰基丙烯酸酯与一种双α-氰基丙烯酸二酯的共聚物，所述单α-氰基丙烯酸酯选自：BCA、MOE-CA，所述双α-氰基丙烯酸二酯选自：CA-TEG-CA、CA-PEG 600-CA、CA-PEG 2000-CA。
在某些实施方案中，所述聚氰基丙烯酸酯包含两种单α-氰基丙烯酸酯单体单元，二 者的摩尔比为2-150:1(例如2:1、2.3:1、5:1、5.3:1、10:1、13:1、13.9:1、30:1、32.5:1、40:1、44:1、100:1、125.3:1或150:1)。
在某些实施方案中，所述聚氰基丙烯酸酯包含两种单α-氰基丙烯酸酯单体单元，二者的质量比为99:1-50:50(例如99:1、98:2、97:3、96:4、95:5、94:6、93:7、92:8、91:9、90:10、89:11、88:12、87:13、86:14、85:15、84:16、83:17、82:18、81:19、80:20、79:21、78:22、77:23、76:24、75:25、74:26、73:27、72:28、71:29、70:30、69:31、68:32、67:33、66:34、65:35、64:36、63:37、62:38、61:39、60:40、59:41、58:42、57:43、56:44、55:45、54:46、53:47、52:48、51:49或50:50)。
在某些实施方案中，所述聚氰基丙烯酸酯包含两种单α-氰基丙烯酸酯单体单元，所述单α-氰基丙烯酸酯选自：BCA、MOE-CA、MOEOE-CA。
在某些实施方案中，所述抗肿瘤药物选自：甲磺酸酯类衍生物、多元醇类、蒽环类衍生物、嘧啶类衍生物、紫杉烷类衍生物及其任意组合。
在某些实施方案中，所述抗肿瘤药物选自：白消安(Busulfan、马利兰Myleran17-24)、二溴甘露醇、二溴卫矛醇、氟尿嘧啶、紫杉醇、多烯紫杉醇、奥沙利铂、多西他赛、表柔比星、吉西他滨、异长春花碱、多柔比星、吡柔比星、卡培他滨、羟基喜树碱及其任意组合。
在某些实施方案中，所述抗肿瘤药物选自：氟尿嘧啶、姜黄素、多柔比星、紫杉醇、多烯紫杉醇及其任意组合。
在某些实施方案中，所述抗肿瘤药物在组合物中的含量按照质量计为0.001％-20％，优选0.1％-10％(例如0.1％-5％，例如0.1％、0.25％、0.3125％、0.5％、0.625％、0.75％、1％、1.25％、1.5％、2％或2.5％)。
在某些实施方案中，所述组合物还包含助剂，例如合成助剂、反应性助剂、功能助剂、工艺助剂和/或稳定助剂。
在某些实施方案中，所述组合物由如上任一项包含抗肿瘤药物和氰基丙烯酸酯的组合物制得。
本发明还涉及包含如上任一项组合物的药物制剂。
本发明中，含有抗肿瘤药物和氰基丙烯酸酯的组合物通常为液态，适于制成注射剂(例如注射液或注射用浓溶液)，特别地，可用于肿瘤内注射。氰基丙烯酸酯在肿瘤内发生聚合，形成固态的载药胶块，一方面，聚合物发挥了药物储库作用，可按照治疗需要，在一定时间内定量缓释出其中负载的药物，发挥定点治疗作用；另一方面，氰基丙 烯酸酯本身的聚合，可能破坏肿瘤内的微血供，并且可能使肿瘤对药物产生了增敏增效作用；再一方面，由于氰基丙烯酸酯聚合产生的粘接性能，使聚合物能够很好地固定粘附在肿瘤内或相应组织上，避免脱落移位等风险。
本发明还涉及如上任一项组合物用于制备药物的用途，所述药物用于治疗受试者中的肿瘤相关疾病，所述肿瘤相关疾病为所述组合物中包含的抗肿瘤药物所能够治疗的疾病。
本发明还涉及一种治疗肿瘤相关疾病的方法，包括给有此需要的受试者施用有效量的如上任一项组合物，所述肿瘤相关疾病为所述组合物中包含的抗肿瘤药物所能够治疗的疾病。
本发明中，肿瘤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(neogrowth)。本发明的肿瘤包括良性肿瘤和恶性肿瘤，还包括肿瘤性息肉。
本发明中，所述肿瘤相关疾病包括但不限于：脑瘤、肺癌、鳞状上皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、胰腺癌、乳腺癌、头颈癌、子宫颈癌、子宫内膜癌、直肠癌、肝癌、肾癌、食管腺癌、食管鳞状细胞癌、前列腺癌、雌性生殖道癌、原位癌、淋巴瘤、神经纤维瘤、甲状腺癌、骨癌、皮肤癌、脑癌、结肠癌、睾丸癌、胃肠道间质瘤、前列腺肿瘤、肥大细胞肿瘤、多发性骨髓瘤、黑色素瘤、胶质瘤或肉瘤。
本发明中，所述受试者优选为哺乳动物，例如牛科动物、马科动物、猪科动物、犬科动物、猫科动物、啮齿类动物、灵长类动物；例如，所述受试者为人。
在本发明中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。并且，本文中所涉及的实验室操作步骤均为相应领域内广泛使用的常规步骤。同时，为了更好地理解本发明，下面提供相关术语的定义和解释。
本发明所述的“C 1-30直链或支链烷基”表示直链或支链的含有1-30个碳原子的烷基，包括例如“C 1-4直链或支链烷基”、“C 4-8直链或支链烷基”、“C 1-8直链或支链烷基”、“C 1-10直链或支链烷基”、“C 1-20直链或支链烷基”、“C 10-20直链或支链烷基”、“C 20-30直链或支链烷基”等，具体实例包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、正己基、正庚基、正辛基、2-异辛基等。
本发明所述的“C 1-4烷氧基”是指“C 1-4烷基-O-”，所述的“C 1-4烷基”表示直链或支链的含有1-4个碳原子的烷基。
本发明所述的“C 2-30直链或支链烯基”是指含有至少一个碳碳双键且碳原子数为2-30的直链或支链的烯基，包括例如“C 2-4直链或支链烯基”、“C 4-8直链或支链烯基”、“C 2-8 直链或支链烯基”、“C 2-10直链或支链烯基”、“C 2-20直链或支链烯基”、“C 10-20直链或支链烯基”、“C 20-30直链或支链烯基”等。其实例包括但不限于：乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、1,3-丁二烯基、1-戊烯基、2-戊烯基、3-戊烯基、1,3-戊二烯基、1,4-戊二烯基、1-己烯基、2-己烯基、3-己烯基、1,4-己二烯基等。
本发明所述的“C 2-30直链或支链炔基”是指含有至少一个碳碳三键且碳原子数为2-30的直链或支链的炔基，包括例如“C 2-4直链或支链炔基”、“C 4-8直链或支链炔基”、“C 2-8直链或支链炔基”、“C 2-10直链或支链炔基”、“C 2-20直链或支链炔基”、“C 10-20直链或支链炔基”、“C 20-30直链或支链炔基”等。其实例包括但不限于：乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、1-戊炔基、2-戊炔基、3-戊炔基、1,3-戊二炔基、1,4-戊二炔基、1-己炔基、2-己炔基、3-己炔基。
本发明所述的“C 1-30直链或支链亚烷基”是指直链或支链的含1-30个碳原子的烷烃去除两个不在同一碳原子上的氢所衍生的基团，包括“C 1-4直链或支链亚烷基”、“C 4-8直链或支链亚烷基”、“C 1-8直链或支链亚烷基”、“C 1-10直链或支链亚烷基”、“C 1-20直链或支链亚烷基”、“C 10-20直链或支链亚烷基”、“C 20-30直链或支链亚烷基”等，具体实例包括但不限于：-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、-CH 2CH 2CH 2CH 2-、-CH 2CH 2CH 2CH 2CH 2-、-CH 2CH 2CH 2CH 2CH 2CH 2-等。
本发明所述的“C 2-30直链或支链亚烯基”是指直链或支链的含2-30个碳原子的烯烃去除两个不在同一碳原子上的氢所衍生的基团，包括“C 2-4直链或支链亚烯基”、“C 4-8直链或支链亚烯基”、“C 2-8直链或支链亚烯基”、“C 2-10直链或支链亚烯基”、“C 2-20直链或支链亚烯基”、“C 10-20直链或支链亚烯基”、“C 20-30直链或支链亚烯基”等，具体实例包括但不限于-CH＝CH-、-CH＝CHCH 2-、-CH 2CH＝CHCH 2-、-CH＝CHCH＝CH-、-CH 2CH 2CH＝CHCH 2-等。
本发明所述的“C 2-30直链或支链亚炔基”是指直链或支链的含2-30个碳原子的炔烃去除两个不在同一碳原子上的氢所衍生的基团，包括“C 2-4直链或支链亚炔基”、“C 4-8直链或支链亚炔基”、“C 2-8直链或支链亚炔基”、“C 2-10直链或支链亚炔基”、“C 2-20直链或支链亚炔基”、“C 10-20直链或支链亚炔基”、“C 20-30直链或支链亚炔基”等，具体实例包括但不限于：-C≡C-、-C≡CCH 2、-H 2CC≡CCH 2-、-C≡CCH 2CH-、-H 2CC≡CCH 2CH-、-H 2CC≡CCH 2C≡C-等。
本发明所述的“卤素原子”是指氟原子、氯原子、溴原子或碘原子。
本发明所述的“卤代”是指被“卤素原子”取代。
本发明所述的“助剂”是指胶黏剂生产过程和/或使用过程中的辅助原料。胶黏剂助剂 包括但不限于：合成助剂、反应性助剂、功能助剂、工艺助剂和稳定助剂。
如本文中使用的，术语“合成助剂”主要包括在胶黏剂或其他具有胶黏性质的物质的合成和/或配制过程中，所使用的乳化剂、引发剂、阻聚剂、催化剂、溶剂、氧化剂、分散剂、扩链剂、调节剂、中和剂和终止剂等。
如本文中使用的，术语“反应性助剂”是指带有反应性基团的化合物，其能与胶黏剂或其他具有胶黏性质的物质中的基体聚合物反应，形成网状或交联结构，主要包括增韧剂、固化剂、交联剂、光引发剂、促进剂和反应型阻燃剂等。
如本文中使用的，术语“功能助剂”也称“改性助剂”，是指能改善胶黏剂或其他具有胶黏性质的物质的原有性能，或赋予其新的功能的助剂，主要包括增塑剂、偶联剂、增粘剂、发泡剂、着色剂、增强剂、填充剂、阻燃剂、软化剂、抗静电剂、遮味剂、增韧剂、促进剂和螯合剂等。
如本文中使用的，术语“工艺助剂”是指为了胶黏剂或其他具有胶黏性质的物质的配制和使用方便，并且保证其预期性能而使用的助剂，主要包括增稠剂、消泡剂、防冻剂、防粘剂、稀释剂、触变剂和防焦剂等。
如本文中使用的，术语“稳定助剂”是指能够防止胶黏剂或其他具有胶黏性质的物质在合成制备、储运和使用过程中老化变质，延长使用寿命和/或提高储存稳定性的助剂，主要包括抗氧剂、热稳定剂、光稳定剂、杀菌剂、防腐剂和金属离子钝化剂等。
发明的有益效果
本发明提供了一种包含氰基丙烯酸酯单体和抗肿瘤药物的组合物，其中，氰基丙烯酸酯单体在聚合前呈液态，可对抗肿瘤药物具有良好的溶解度和相容度，起到负载药物的作用；组合物具有良好的流动性，可通过定点注射的方式注射到肿瘤内部。氰基丙烯酸酯单体的可聚合特性，使组合物在接触到人体组织的数秒内，在肿瘤内部或相应适用组织处形成固态的载药胶块。一方面，聚合形成的氰基丙烯酸酯聚合物可以发挥药物储库作用，可按照治疗需要，在一定时间内定量缓释出其中负载的药物，发挥定点治疗作用；另一方面，氰基丙烯酸酯单体的聚合，有可能破坏肿瘤内微血供，并且可能使肿瘤对药物产生增敏增效作用；再一方面，由于氰基丙烯酸酯聚合产生的粘接性能，使得载药胶块可以很好地固定粘附在肿瘤内或相应组织上，避免脱落移位等风险。
本发明的组合物中，药物和负载材料(氰基丙烯酸酯单体和/或聚合物)具有协同(促进)治疗作用，相对于单一的药物组或空白材料组，具有更佳的治疗效果。
下面将结合附图和实施例对本发明的实施方案进行详细描述，但是，本领域技术人员将理解，下列附图和实施例仅用于说明本发明，而不是对本发明的范围的限定。根据附图和优选实施方案的下列详细描述，本发明的各种目的和有利方面对于本领域技术人员来说将变得显然。
附图说明
图1为实施例3中，氟尿嘧啶含量的峰面积-浓度标准曲线。
图2示例性地显示了负载不同浓度药物的载药胶块(J-Fu-0.3125、J-Fu-0.625、J-Fu-1.25)的药物释放曲线。
图3显示了体外细胞毒性试验中，各组的细胞存活率。
图4示例性地显示了体外细胞毒性试验中，显微镜观察到的细胞形态，其中，A：J组，B：J-Fu-1.25组，C：J-Fu-0.625组，D：J-Fu-0.3125组，E：正常组，F：Fu组。
图5显示了实施例6的体内抗肿瘤试验中，各组小鼠的肿瘤体积变化。
图6显示了实施例6的体内抗肿瘤试验中，各组小鼠的存活率。
图7显示了实施例6的体内抗肿瘤试验中，各组小鼠的体重变化。
图8示例性地显示了体内抗肿瘤试验第14天时，各组小鼠肿瘤情况，其中，A：PBS组，B：Fu组，C：J组，D：J-Fu-1.25组。
图9为体内抗肿瘤试验给药第36天时，J-Fu-1.25组小鼠主要脏器的H&E染色照片。
图10为SD大鼠背部皮下植入试验第30天，J-Fu-1.25组大鼠皮肤、肌肉以及主要脏器的H&E染色照片。
具体实施方式
下面将结合附图和实施例对本发明的实施方案进行详细描述，但是本领域技术人员将会理解，下列附图和实施例仅用于说明本发明，而不应视为限定本发明的范围。附图和实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。所用无水溶剂均为市售。
实施例1配方胶的制备
使用氰基丙烯酸酯单体BCA、MOE-CA、CA-TEG-CA、CA-PEG 600-CA、CA-PEG 2000-CA，按照表1中的配方制备配方胶。在氮气保护的条件下，将对应的单 体成分通过搅拌、振荡等方式混合，可获得澄清透明的配方胶。配方胶在常温常压、空气中发生聚合，形成胶块。对胶块的降解速率和粘接强度进行测试，结果见表1。
各单体的结构如下：
Figure PCTCN2018120260-appb-000004
表1 配方胶的组成以及胶块的降解速率和粘接强度
Figure PCTCN2018120260-appb-000005
a.表观降解速率测试方法：将聚合物胶块称重(W 0)，放置在50毫升PBS溶液中，在37℃恒温摇床(荣华)中震摇14天后，干燥称重(W 1)。表观降解速率＝(W 0–W 1)/W 0
b.按照标准规定“YYT 0729.1-2009组织粘合剂粘接性能试验方法”进行测试。
c.表示24小时聚合物即完全消失溶解。
从表1中可以看到，不同结构的胶块具有差异性的表观降解速率和粘接强度(剪切拉伸)。在实际使用中，可以根据特定的需要(例如需要胶块具有一定的降解速率或粘接强度)选择合适的单体配方。
实施例2载药胶的制备
将表1中的配方胶分别与氟尿嘧啶、姜黄素、多柔比星、紫杉醇、多烯紫杉醇混合，各个药物均采用多个质量比(0.1％、0.25％、0.5％、0.75％、1％、1.25％、1.5％、2％、2.5％)，均可获得澄清透明的载药胶溶液。
实施例3不同单体配方的载药胶的体外药物释放试验
以含1.25％的氟尿嘧啶的载药胶溶液为例。在A组、F组、G组、I组、J组、K组、M组的配方胶中，分别加入1.25％质量比的氟尿嘧啶，混合均匀，可得澄清溶液状载药胶。取0.1g载药胶溶液，聚合为胶块(面积2.5×1cm 2)，置于50mL PBS溶液中(pH7.4)，再将含有胶块的溶液放入37℃条件下的恒温摇床(SHZ-82A,JINTAN RONGHUA,China,60rpm)。一定时间点取样，测试溶液中的氟尿嘧啶含量，进而计算得到各组的药物释放量。氟尿嘧啶的含量测定：首先通过高效液相的方法，配置不同浓度标准品，绘制峰面积-浓度标准曲线(图1)，再通过测定具体样品中的峰面积从而计算获得对应浓度。结果如表2、表3、表4所示。
表2 M组、A组、F组、K组的体外药物释放量(％)
Figure PCTCN2018120260-appb-000006
从表2可以看出，同一种单α-氰基丙烯酸酯以相同的比例与不同的双α-氰基丙烯 酸二酯组合，可以得到释药速率不同的载药胶。
表3 I组、J组、K组的体外药物释放量(％)
Figure PCTCN2018120260-appb-000007
表4 G组、F组的体外药物释放量(％)
Figure PCTCN2018120260-appb-000008
从表3和表4可以看出，同样的单α-氰基丙烯酸酯与双α-氰基丙烯酸二酯以不同的比例组合，可以得到释药速率不同的载药胶。
从表2、表3、表4中可以看出，不同结构的聚氰基丙烯酸酯材料均能够将药物释放出来，但不同的配方制得的载药胶具有不同的药物释放速率，这可能与聚合物的降解性质、微观结构上的致密程度以及材料与药物分子的相互作用力相关。可以通过 调节单体的组成和含量，对药物的释放速率进行调节。
实施例4不同药物浓度的载药胶的体外释放试验
取J组配方胶，加入0.3125％、0.625％或1.25％的氟尿嘧啶，按照实施例3中的方法，测试载药胶块的体外释放曲线，结果如图2所示。从图中可以看出，负载不同浓度药物的载药胶块(J-Fu-0.3125、J-Fu-0.625、J-Fu-1.25)具有相似的药物释放曲线，说明同样单体配方的载药胶，其药物释放行为比较稳定，受到药物浓度的影响较小，可以根据需要灵活地调节药物浓度。
实施例5体外抗肿瘤试验
材料浸提液制备：取7.5mg不含药物的J组配方胶(简称为J组)，以及负载不同浓度(1.25％，0.625％和0.3125％)氟尿嘧啶的J组配方胶(分别简称为J-Fu-1.25，J-Fu-0.625，J-Fu-0.3125)，于48孔细胞培养板(直径10.2mm)中固化完全后，以生理盐水(7.5mg/mL)置于37℃、体积分数5％CO 2培养箱中浸提24h；浸提液以0.22μm无菌滤膜过滤，加入RPMI-1640培养基，按照(1/1，v/v)进行稀释，得到待测样品。
体外细胞试验：MCF-7细胞购自协和细胞库；用0.25％胰蛋白酶消化单层培养的传代48h生长旺盛的MCF-7细胞，用含10％胎牛血清的RPMI-1640培养基配成单个细胞悬液，以5×10 3个细胞接种于96孔培养板中，每孔体积100μL，放入二氧化碳恒温培养箱，在37℃、5％CO 2及饱和湿度条件下培养24h至细胞贴壁；吸取培养液，将100μL待测样品加入到培养板各个孔中，其中，阴性对照为含有10％胎牛血清的RPMI-1640培养基(正常组)；阳性对照为含有1.25％氟尿嘧啶的PBS溶液(简称为Fu组)；采用MTT(四甲基偶氮唑盐)法检测细胞存活率。
图3显示了各组的细胞存活率，图4为显微镜观察到的细胞形态，其中，A：J组，B：J-Fu-1.25组，C：J-Fu-0.625组，D：J-Fu-0.3125组，E：正常组，F：Fu组。
从图3和图4的试验结果可以看出，相比于阴性对照组，负载不同浓度氟尿嘧啶的载药胶对MCF-7均显示出一定的抑制活性，并且，从图3可以看出，J-Fu-1.25组显示出比阳性对照更强的抑制活性，说明，氰基丙烯酸酯单体和/或聚合物对氟尿嘧啶的疗效产生了促进作用。
实施例6裸鼠体内抗肿瘤试验
模型构建：取40只Balb/c裸鼠(8周龄，雌性，20g左右)，将200μL2×10 6MCF-7细胞悬液(生理盐水)以一次性塑料注射器(1mL)皮下注射至Balb/c裸鼠右前肢腋下，正常饲养15天。
给药及药效评价：将40只Balb/c肿瘤裸鼠随机分为四组，每组10只。其中，PBS组：瘤内注射60μL PBS溶液；Fu组：瘤内注射60μL含有1.25％氟尿嘧啶的PBS溶液；J组：瘤内注射60μL空白J组配方胶；J-Fu-1.25组：瘤内注射60μL含1.25％氟尿嘧啶的J组配方胶。观察随时间变化每组小鼠的肿瘤体积大小、体重变化、生存率，其中肿瘤体积大小(V)计算方法为V＝短径 2×长径×0.5。
图5显示了各组小鼠肿瘤体积变化；图6显示了各组小鼠的存活率；图7显示了各组小鼠的体重变化；图8显示了试验第14天各组小鼠肿瘤情况，其中，A：PBS组，B：Fu组，C：J组，D：J-Fu-1.25组。
从图5-7的数据可以看出，相比于其他三组，载药胶J-Fu-1.25有效地抑制了肿瘤的生长，提高了小鼠的生存率，且在试验期间小鼠的体重未发生明显变化。从图8可以看出，给药后第14天，相比于其他三组，J-Fu-1.25组小鼠的肿瘤出现更多的炎症、坏死现象。上述结果共同说明了载药胶J-Fu-1.25具备良好的抗肿瘤效果。
此外，从图5-7可以看出，J-Fu-1.25组的抗肿瘤效果优于Fu组，也优于J组。上述结果说明，至少在一定剂量范围内下，氰基丙烯酸酯单体和/或聚合物可以对氟尿嘧啶发挥促进作用，二者组合可以产生协同抗肿瘤的作用。
参照上述模型构建方法和给药方法，对D、I、J、K、L、M、N和R组进行试验，结果如表5所示。
表5
Figure PCTCN2018120260-appb-000009
实施例7安全性评价
试验一、Balb/c裸鼠肿瘤内植入试验
在实施例6的体内抗肿瘤试验给药第40天时，将存活的J-Fu-1.25组小鼠全部脱 臼处死，取其心、肝、脾、肾等主要脏器，以福尔马林固定，通过对组织进行H&E染色，病理分析J-Fu-1.25的系统毒性。图9为主要脏器的H&E染色照片。从图中可以看出，给药后第36天，J-Fu-1.25组Balb/c裸鼠主要脏器(心、肝、脾、肾)H&E染色未观察到炎症情况，相比于正常动物对照组，无显著差异，说明J-Fu-1.25无系统毒性。
试验二、SD大鼠背部皮下植入试验
将20mg液态的J-Fu-1.25配方胶在室温条件下固化为圆形聚合物胶块(直径为60mm)；取18只SD大鼠(220g左右，雌性)，以10％水合氯醛麻醉后，脱去背部毛发，将聚合物胶块皮下植入SD大鼠背部皮肤，观察随时间变化(2天，4天，6天，10天，14天，30天；每个时间点3只动物)聚合物胶块接触的皮肤、肌肉的炎症情况。将大鼠脱臼处死，取下皮肤、肌肉以及大鼠脏器(心、肝、脾、肾)进行H&E染色病理分析。
图10显示了试验第30天皮肤、肌肉以及大鼠脏器的H&E染色照片。虽然在试验后的前几天时间里，观察到胶块植入部位出现一定程度的炎症，但在试验第30天，所有的试验大鼠均存活下来，炎症部位恢复正常，且从图10可以看出，聚合物胶块接触的皮肤、肌肉以及大鼠的主要脏器(心、肝、脾、肾)均未观察到炎症情况，说明植入的聚合物胶块无系统毒性。
上述两个试验结果共同证实了：本发明的载药聚合物胶块具有良好的生物相容性。
尽管本发明的具体实施方式已经得到详细的描述，但本领域技术人员将理解：根据已经公开的所有教导，可以对细节进行各种修改和变动，并且这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。

Claims (11)

  1. 一种组合物，其含有抗肿瘤药物和氰基丙烯酸酯，其中，所述氰基丙烯酸酯为单α-氰基丙烯酸酯，或者双α-氰基丙烯酸二酯，或者多种单α-氰基丙烯酸酯的组合，或者多种双α-氰基丙烯酸二酯的组合，或者单α-氰基丙烯酸酯与双α-氰基丙烯酸二酯的组合。
  2. 权利要求1的组合物，其中，所述单α-氰基丙烯酸酯具有如式(I)所示的结构：
    Figure PCTCN2018120260-appb-100001
    其中，R选自：
    (1)C 1-30直链或支链烷基，被酰氧基、卤代C 1-4烷基、C 1-4烷氧基、卤素原子或氰基取代的C 1-30直链或支链烷基，C 2-30直链或支链烯基，C 2-30直链或支链炔基，5-10元环烷基，C 6-10芳基-C 1-4烷基，C 1-4烷基-C 6-10芳基，C 6-10芳基；
    (2)-R 1-O-R 2-O-R 3，其中，R 1、R 2各自独立地选自C 1-6亚烷基，R 3为C 1-6烷基；
    (3)-(C 2H 4O) nCH 3、-(C 2H 4O) nC 2H 5、-(C 2H 4O) nH，其中，n各自独立地选自1-500(例如1-10、10-100、100-200、200-300、300-400或400-500)之间的整数。
  3. 权利要求2的组合物，其中，所述C 1-30直链或支链烷基选自：C 1-4直链或支链烷基、C 4-8直链或支链烷基、C 1-8直链或支链烷基、C 1-10直链或支链烷基、C 1-20直链或支链烷基；
    优选地，所述C 2-30直链或支链烯基选自：C 2-4直链或支链烯基、C 4-8直链或支链烯基、C 2-8直链或支链烯基、C 2-10直链或支链烯基、C 2-20直链或支链烯基；
    优选地，所述C 2-30直链或支链炔基选自：C 2-4直链或支链炔基、C 4-8直链或支链炔基、C 2-8直链或支链炔基、C 2-10直链或支链炔基、C 2-20直链或支链炔基；
    优选地，所述卤素原子选自：氟、氯、溴、碘；
    优选地，所述卤代C 1-4烷基选自氟代C 1-4烷基或氯代C 1-4烷基；
    优选地，R选自：甲基、乙基、正丁基、正辛基、2-异辛基、-C 2H 4-O-CH 3、-C 2H 4-O-C 2H 4-O-CH 3；
    更优选地，R选自：正丁基、正辛基、2-异辛基、-C 2H 4-O-CH 3、-C 2H 4-O-C 2H 4-O-CH 3。
  4. 权利要求1-3任一项的组合物，所述双α-氰基丙烯酸二酯具有如式(II)所示的结构：
    Figure PCTCN2018120260-appb-100002
    其中，W选自：
    (1)C 1-30直链或支链亚烷基，被酰氧基、卤代C 1-4烷基、C 1-4烷氧基、卤素原子或氰基取代的C 1-30直链或支链亚烷基，C 2-30直链或支链亚烯基，C 2-30直链或支链亚炔基，5-10元环亚烷基，C 6-10芳基-C 1-4亚烷基，C 1-4烷基-C 6-10亚芳基，C 6-10亚芳基；
    (2)以下聚合物的链段：聚乙二醇(PEG)、聚乳酸(PLA)、聚羟基乙酸(PGA)、乳酸-羟基乙酸共聚物(PLGA)、含聚羟基酸和聚二醇类化合物的共聚物(如PLA-PEG-PLA嵌段共聚物、PGA-PEG-PGA嵌段共聚物)。
  5. 权利要求4的组合物，其中，所述C 1-30直链或支链亚烷基选自：C 1-4直链或支链亚烷基、C 4-8直链或支链亚烷基、C 1-8直链或支链亚烷基、C 1-10直链或支链亚烷基、C 1-20直链或支链亚烷基；
    优选地，所述C 2-30直链或支链亚烯基选自：C 2-4直链或支链亚烯基、C 4-8直链或支链亚烯基、C 2-8直链或支链亚烯基、C 2-10直链或支链亚烯基、C 2-20直链或支链亚烯基；
    优选地，所述C 2-30直链或支链亚炔基选自：C 2-4直链或支链亚炔基、C 4-8直链或支链亚炔基、C 2-8直链或支链亚炔基、C 2-10直链或支链亚炔基、C 2-20直链或支链亚炔基；
    优选地，所述卤素原子选自：氟、氯、溴、碘；
    优选地，所述卤代C 1-4烷基选自氟代C 1-4烷基或氯代C 1-4烷基；
    优选地，W选自：亚乙基、亚正丁基、亚正辛基、聚乙二醇链段，所述聚乙二醇链段如式(III)所示
    Figure PCTCN2018120260-appb-100003
    其中，p选自0-100之间的整数，优选1-50(例如1-10、10-20、20-30、30-40或40-50) 之间的整数。
  6. 权利要求1-5任一项的组合物，其包含：(1)一种单α-氰基丙烯酸酯，(2)多种(例如2种或3种)单α-氰基丙烯酸酯，(3)一种双α-氰基丙烯酸二酯，或者，(4)一种α-单氰基丙烯酸酯和一种双α-氰基丙烯酸二酯；
    优选地，所述单α-氰基丙烯酸酯选自：α-氰基丙烯酸正丁酯(BCA)、α-氰基丙烯酸甲氧乙基酯(MOE-CA)、α-氰基丙烯酸(甲氧基二乙二醇)酯(MOEOE-CA)；
    优选地，所述双α-氰基丙烯酸二酯选自：双α-氰基丙烯酸二缩三乙二醇酯(CA-TEG-CA)、双α-氰基丙烯酸PEG 600酯(CA-PEG 600-CA)、双α-氰基丙烯酸PEG 2000酯(CA-PEG 2000-CA)；
    优选地，所述组合物包含摩尔比为2-150:1的单α-氰基丙烯酸酯和双α-氰基丙烯酸二酯；
    优选地，所述组合物包含质量比为99:1-50:50的单α-氰基丙烯酸酯和双α-氰基丙烯酸二酯；
    优选地，所述组合物包含一种单α-氰基丙烯酸酯和一种双α-氰基丙烯酸二酯，所述单α-氰基丙烯酸酯选自：BCA、MOE-CA，所述双α-氰基丙烯酸二酯选自：CA-TEG-CA、CA-PEG 600-CA、CA-PEG 2000-CA。
    优选地，所述组合物包含摩尔比为2-150:1的两种单α-氰基丙烯酸酯；
    优选地，所述组合物包含质量比为99:1-50:50的两种单α-氰基丙烯酸酯；
    优选地，所述组合物包含两种单α-氰基丙烯酸酯，所述单α-氰基丙烯酸酯选自：BCA、MOE-CA、MOEOE-CA。
  7. 一种组合物，其含有抗肿瘤药物和聚氰基丙烯酸酯，其中，所述聚氰基丙烯酸酯选自：单α-氰基丙烯酸酯的均聚物，双α-氰基丙烯酸二酯的均聚物，多种单α-氰基丙烯酸酯的共聚物，多种(例如2种或3种)双α-氰基丙烯酸二酯的共聚物，或者单α-氰基丙烯酸酯与双α-氰基丙烯酸二酯的共聚物；
    优选地，所述单α-氰基丙烯酸酯选自如权利要求2或3定义的单α-氰基丙烯酸酯；
    优选地，所述双α-氰基丙烯酸二酯选自如权利要求4或5定义的双α-氰基丙烯酸二酯；
    优选地，所述单α-氰基丙烯酸酯选自：α-氰基丙烯酸正丁酯(BCA)、α-氰基丙烯酸甲氧乙基酯(MOE-CA)、α-氰基丙烯酸(甲氧基二乙二醇)酯(MOEOE-CA)；
    优选地，所述双α-氰基丙烯酸二酯选自：双α-氰基丙烯酸二缩三乙二醇酯(CA-TEG-CA)、双α-氰基丙烯酸PEG 600酯(CA-PEG 600-CA)、双α-氰基丙烯酸PEG 2000酯(CA-PEG 2000-CA)；
    优选地，所述聚氰基丙烯酸酯包含单α-氰基丙烯酸酯单体单元和双α-氰基丙烯酸二酯单体单元，二者的摩尔比为2-150:1；
    优选地，所述聚氰基丙烯酸酯包含单α-氰基丙烯酸酯单体单元和双α-氰基丙烯酸二酯单体单元，二者的质量比为99:1-50:50；
    优选地，所述组合物包含一种单α-氰基丙烯酸酯与一种双α-氰基丙烯酸二酯的共聚物，所述单α-氰基丙烯酸酯选自：BCA、MOE-CA，所述双α-氰基丙烯酸二酯选自：CA-TEG-CA、CA-PEG 600-CA、CA-PEG 2000-CA；
    优选地，所述聚氰基丙烯酸酯包含两种单α-氰基丙烯酸酯单体单元，二者的摩尔比为2-150:1；
    优选地，所述聚氰基丙烯酸酯包含两种单α-氰基丙烯酸酯单体单元，二者的质量比为99:1-50:50；
    优选地，所述聚氰基丙烯酸酯包含两种单α-氰基丙烯酸酯单体单元，所述单α-氰基丙烯酸酯选自：BCA、MOE-CA、MOEOE-CA；
    优选地，所述组合物由权利要求1-6任一项的组合物制得。
  8. 权利要求1-7任一项的组合物，所述抗肿瘤药物选自：甲磺酸酯类衍生物、多元醇类、蒽环类衍生物、嘧啶类衍生物、紫杉烷类衍生物及其任意组合；
    优选地，所述抗肿瘤药物选自：白消安、二溴甘露醇、二溴卫矛醇、氟尿嘧啶、紫杉醇、多烯紫杉醇、奥沙利铂、多西他赛、表柔比星、吉西他滨、异长春花碱、多柔比星、吡柔比星、卡培他滨、羟基喜树碱及其任意组合；
    更优选地，所述抗肿瘤药物选自：氟尿嘧啶、姜黄素、多柔比星、紫杉醇、多烯紫杉醇及其任意组合；
    优选地，所述抗肿瘤药物在所述组合物中的含量按照质量计为0.001％-20％，优选0.1％-10％。
  9. 权利要求1-8任一项的组合物，所述组合物还含有助剂，例如合成助剂、反应性助剂、功能助剂、工艺助剂和/或稳定助剂。
  10. 一种药物制剂，其包含权利要求1-9任一项的组合物；
    优选地，所述药物制剂用于注射给药，其包含权利要求1-6、8、9任一项的组合物；更优选地，所述药物制剂用于肿瘤内注射。
  11. 权利要求1-9任一项的组合物用于制备药物的用途，所述药物用于治疗受试者中的肿瘤相关疾病，所述肿瘤相关疾病为所述组合物中包含的抗肿瘤药物所能够治疗的疾病。
PCT/CN2018/120260 2017-12-13 2018-12-11 负载抗肿瘤药物的氰基丙烯酸酯材料 WO2019114689A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201711326225.6A CN109908356B (zh) 2017-12-13 2017-12-13 负载抗肿瘤药物的氰基丙烯酸酯材料
CN201711326225.6 2017-12-13

Publications (1)

Publication Number Publication Date
WO2019114689A1 true WO2019114689A1 (zh) 2019-06-20

Family

ID=66818981

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/120260 WO2019114689A1 (zh) 2017-12-13 2018-12-11 负载抗肿瘤药物的氰基丙烯酸酯材料

Country Status (2)

Country Link
CN (1) CN109908356B (zh)
WO (1) WO2019114689A1 (zh)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109303918A (zh) * 2018-09-28 2019-02-05 中国人民解放军军事科学院军事医学研究院 可用于透皮给药的氰基丙烯酸酯及其组合物
CN114891197B (zh) * 2022-05-24 2023-04-18 山西医科大学 双氰基丙烯酸酯-聚己内酯二元醇及其制备方法、应用、生物材料及其制备方法、应用

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1533765A (zh) * 2003-03-31 2004-10-06 清华大学 抗癌药秋水仙碱微球冻干剂的制备方法
CN1679575A (zh) * 2005-01-04 2005-10-12 复旦大学 10－羟基喜树碱长循环囊泡及其冻干制剂
CN101259099A (zh) * 2008-01-23 2008-09-10 西北农林科技大学 一种长春花生物碱类抗肿瘤药物的纳米粒制剂及其制备方法
CN101653414A (zh) * 2008-08-19 2010-02-24 中国科学院上海药物研究所 多西他赛长循环固体脂质纳米粒及其制备方法
CN102579341A (zh) * 2011-01-11 2012-07-18 沈阳药科大学 一种多西他赛固体脂质纳米粒及其制备方法
CN103083718A (zh) * 2011-11-02 2013-05-08 中国人民解放军军事医学科学院毒物药物研究所 一种可生物降解的医用粘合剂及其制备方法和用途

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1533765A (zh) * 2003-03-31 2004-10-06 清华大学 抗癌药秋水仙碱微球冻干剂的制备方法
CN1679575A (zh) * 2005-01-04 2005-10-12 复旦大学 10－羟基喜树碱长循环囊泡及其冻干制剂
CN101259099A (zh) * 2008-01-23 2008-09-10 西北农林科技大学 一种长春花生物碱类抗肿瘤药物的纳米粒制剂及其制备方法
CN101653414A (zh) * 2008-08-19 2010-02-24 中国科学院上海药物研究所 多西他赛长循环固体脂质纳米粒及其制备方法
CN102579341A (zh) * 2011-01-11 2012-07-18 沈阳药科大学 一种多西他赛固体脂质纳米粒及其制备方法
CN103083718A (zh) * 2011-11-02 2013-05-08 中国人民解放军军事医学科学院毒物药物研究所 一种可生物降解的医用粘合剂及其制备方法和用途

Also Published As

Publication number Publication date
CN109908356A (zh) 2019-06-21
CN109908356B (zh) 2021-02-12

Similar Documents

Publication Publication Date Title
US11191842B2 (en) Injectable thermoresponsive polyelectrolytes
JP6334405B2 (ja) 生分解性医療用接着剤、その調製法及び使用
ES2899023T3 (es) Adhesivos de tejidos hidrófobos
JP2004520134A (ja) 放射線架橋ハイドロゲル
AU2016374669B2 (en) Biodegradable amphiphilic polymer, polymer vesicle prepared therefrom and use in preparing target therapeutic medicine for lung cancer
JP2010519183A (ja) 生理溶液の溶出のためのタンパク質の沈殿を用いる重合
WO2019114689A1 (zh) 负载抗肿瘤药物的氰基丙烯酸酯材料
EP2817013A2 (en) Antimicrobial compositions, the preparation and use thereof
US20150099808A1 (en) Amphiphilic copolymers and compositions containing such polymers
US20220008543A1 (en) Macromolecular prodrug-based thermosensitive injectable gel as a novel drug delivery platform
KR101040561B1 (ko) 효소촉발형 생체주입형 하이드로젤과 그 생의학적 용도
KR20130093769A (ko) 카테콜 기를 가지는 감마 폴리글루탐산, 이의 제조 방법 및 이를 포함하는 조직 접착제
US20180133362A1 (en) Phosphazene-based polymer for tissue adhesion, a method for preparing the same, and use thereof
KR20130034382A (ko) 카테콜 기를 함유하는 아크릴산 고분자 화합물 및 시아노아크릴레이트를 포함하는 생체접착제 조성물 및 이의 제조방법
US20220387596A1 (en) Biodegradable hydrogel and methods for use thereof
KR101605528B1 (ko) 신규한 히알루론산 기반 하이드로겔 및 이의 용도
RU2697551C2 (ru) Новые производные peg
Monteiro et al. In situ generated hemostatic adhesives: From mechanisms of action to recent advances and applications
JP5966582B2 (ja) 架橋ポリマー、インジェクタブルハイドロゲル、ハイドロゲル形成キット
CN108283728B (zh) 一种pH敏感型自调释药肿瘤栓塞微球及其制备方法
WO2023055473A1 (en) Shear-thinning compositions for ablation
CN102389571B (zh) 一种可体内注射的药物缓释栓剂
CN103127514A (zh) 一种可体内注射的药物缓释栓剂

Legal Events

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

Ref document number: 18887879

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18887879

Country of ref document: EP

Kind code of ref document: A1