WO2018177056A1 - 一种聚乙二醇马来酰亚胺衍生物和阻聚剂的组合物 - Google Patents

一种聚乙二醇马来酰亚胺衍生物和阻聚剂的组合物 Download PDF

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WO2018177056A1
WO2018177056A1 PCT/CN2018/077231 CN2018077231W WO2018177056A1 WO 2018177056 A1 WO2018177056 A1 WO 2018177056A1 CN 2018077231 W CN2018077231 W CN 2018077231W WO 2018177056 A1 WO2018177056 A1 WO 2018177056A1
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group
polymerization inhibitor
butyl
tert
hydroquinone
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PCT/CN2018/077231
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English (en)
French (fr)
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主辉
林美娜
魏真
赵宣
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北京键凯科技股份有限公司
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Priority claimed from CN201710530958.5A external-priority patent/CN108659498A/zh
Application filed by 北京键凯科技股份有限公司 filed Critical 北京键凯科技股份有限公司
Priority to EP18774544.3A priority Critical patent/EP3604480B1/en
Publication of WO2018177056A1 publication Critical patent/WO2018177056A1/zh
Priority to US16/588,246 priority patent/US11220559B2/en
Priority to US17/558,819 priority patent/US11844842B2/en

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Definitions

  • the invention relates to the technical field of polymers, in particular to a composition of a polyethylene glycol maleimide derivative and a polymerization inhibitor, in particular to an eight-arm polyethylene glycol maleimide derivative and a phenol.
  • a composition of a class of polymerization inhibitors in particular to an eight-arm polyethylene glycol maleimide derivative and a phenol.
  • Polyethylene glycol is a non-toxic, amphiphilic macromolecular compound formed by polymerization of ethylene glycol monomers.
  • PEG modification is a technology developed from the late 1970s. To solve many problems in the clinical application of some drugs such as peptides and protein drugs, some PEG modified products have achieved good results in the application as a drug.
  • the hydroxyl group at the end of the polyethylene glycol is a functional group for its chemical reaction, but the reactivity is poor, and a derivative of polyethylene glycol which is often activated by an appropriate method is used as a modifier.
  • the activated end groups such as amino, carboxyl, aldehyde, maleimide and the like play a decisive role in the application of polyethylene glycol.
  • Polyethylene glycol maleimide derivative (PEG-MAL) is a terminal group for introducing a maleimide group into PEG, and coupling of maleimide and sulfhydryl group is one of protein and polypeptide coupling.
  • PEG-MAL can be used as a polymer reagent to selectively trap thiol-containing peptides.
  • Genetically engineered thiol groups can be introduced into specific sites of peptides and protein molecules, and PEG-MAL can be used for site-specific modification. The modification selectivity is high, and the loss of biological activity of the protein can be avoided, and the immunogenicity is lowered.
  • PEG-MAL plays a key role in the linkage technology between proteins and peptides and liposomes. It is of great significance to study the targeting of liposomes and to expand the application of peptide compounds in medicine and biotechnology. Therefore, PEG-MAL is a polyethylene glycol derivative with a very high application value.
  • the maleimide derivative of polyethylene glycol contains an unsaturated double bond, and the reaction activity is high, resulting in poor stability of the derivative product, and polymerization at room temperature often occurs at room temperature to form a gel-like structure.
  • the insoluble matter causes the content of the derivative product to be low, and the shelf life is short, which causes great inconvenience to its preservation and transportation, thereby limiting its application.
  • the inventors of the present application have found through extensive experiments and studies that a polyethylene glycol maleimide derivative (especially an eight-arm polyethylene glycol maleimide derivative) and some polymerization inhibitors can be combined. Enhance its stability or reduce its photosensitivity, extending product pot life and shelf life.
  • the invention provides a composition of a polyethylene glycol maleimide derivative and a polymerization inhibitor.
  • the mass ratio of the polymerization inhibitor to the polyethylene glycol maleimide derivative is ⁇ 0.1 ⁇ g: 1 g.
  • the mass ratio of the polymerization inhibitor to the polyethylene glycol maleimide derivative may be from 0.1 ⁇ g to 10 mg: 1 g, such as from 0.1 to 100 ⁇ g. : 1 g (eg, 0.1 ⁇ g: 1 g, 1 ⁇ g: 1 g, 5 ⁇ g: 1 g, 10 ⁇ g: 1 g, 20 ⁇ g: 1 g, 30 ⁇ g: 1 g, 40 ⁇ g: 1 g, 50 ⁇ g: 1 g, 60 ⁇ g: 1 g, 70 ⁇ g: 1 g, 80 ⁇ g: 1 g, 90 ⁇ g : 1 g or 100 ⁇ g: 1 g), 100 ⁇ g - 1 mg: 1 g (eg, 100 ⁇ g: 1 g, 200 ⁇ g: 1 g, 300 ⁇ g: 1 g, 400 ⁇ g: 1 g, 500 ⁇ g: 1 g, 600 ⁇ g: 1 g, 700 ⁇
  • the polyethylene glycol maleimide derivative contains at least one maleimide end group.
  • the polyethylene glycol maleimide derivative has the following structure:
  • PEG is a polyethylene glycol residue
  • X is a linking group of PEG and MAL, and is selected from: -(CH 2 ) r -, -(CH 2 ) r O-, -(CH 2 ) r CO-, -(CH 2 ) r NH-, -(CH 2 ) r CONH-, -(CH 2 ) r NHCO-, -(CH 2 ) a combination of one or more of r S-, -(CH 2 ) r COO- and -(CH 2 ) r OCO-, r is an integer from 0 to 10,
  • MAL is a maleimide group
  • R 1 and R 2 are independently selected from the group consisting of: -H, a C1-6 alkyl group, a C1-6 alkoxy group, a C3-6 cycloalkyl group, and a C4-10 alkylene cycloalkyl group.
  • said R 1 and R 2 are independently selected from the group consisting of: -H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 and -OCH 2 CH 2 CH 3 , more preferably from: -H, -CH 3 , -OCH 3 and -OCH 2 CH 3 ; in a preferred embodiment of the invention, said R 1 is H and R 2 is -CH 3 , -OCH 3 or -OCH 2 CH 3 ; In a more preferred embodiment of the invention, R 1 is H and R 2 is -CH 3 .
  • the X is selected from the group consisting of: a single bond, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH(CH 3 )-, -CH 2 CH(CH 3 )-, -CH 2 CH 2 CH(CH 3 )-, -CH 2 CH 2 CH 2 CH(CH 3 )-, -CH 2 CH 2 CH 2 CH(CH 3 )-, -CH 2 CH 2 CH 2 CH(CH 3 )-, -CH 2 CH 2 CH 2 CH 2 CH(CH 3 )-, -(CH 2 ) r O- , -(CH 2 ) r CO-, -(CH 2 ) r NH-, -(CH 2 ) r CONH-, -(CH 2 ) r NHCO-, -(CH 2 ) r S-, -(CH 2
  • the X is selected from the group consisting of: a single bond, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 3 )-, -CH 2 CH(CH 3 )-, -CH 2 CH 2 CH(CH 3 )-, -(CH 2 ) r O-, -(CH 2 ) r CO-, -(CH 2 ) r NH-, -(CH 2) r CONH-, and - a combination of (CH 2) r NHCO- one or two or more.
  • r is an integer from 0 to 5, such as 0, 1, 2, 3, 4 or 5.
  • the X is -CH 2 CH 2 NHCOCH 2 CH 2 -.
  • the PEG may be a linear, Y- or multi-branched polyethylene glycol residue, for example, including a linear polyethylene glycol, a Y- or U-type PEG, and a 4-arm branch. Chain PEG, 6-arm branched PEG or 8-arm branched PEG, and the like.
  • the PEG is a linear polyethylene glycol residue having the structure shown in Formula II or III:
  • Y is a terminal group selected from the group consisting of: a C1-C6 alkoxy group, a hydroxyl group, a carboxyl group, a succinimide carbonate group, a succinimide acetate group, a succinimide propionate group, and a succinyl group.
  • a phenyl carbonate group, a silane group, and a carboxymethyl group a terminal group selected from the group consisting of: a C1-C6 alkoxy group, a hydroxyl group, a carboxyl group, a succinimide carbonate group, a succinimide acetate group, a succinimide propionate group, and a
  • p and q are independently selected from an integer of from 1 to 1400, preferably from 1 to 1200, more preferably from 200 to 1200.
  • said Y is methoxy
  • the PEG is a Y- or U-type polyethylene glycol residue having the structure shown in Formula IV or V:
  • i and k are independently selected from an integer from 1 to 1200, preferably from an integer from 1 to 600, more preferably from 100 to 600.
  • said Y is methoxy
  • the PEG is a multi-branched polyethylene glycol residue having the structure shown in Formula VI:
  • n is an integer from 1 to 800, preferably an integer from 1 to 400, more preferably an integer from 60 to 400,
  • l is an integer from 0 to 7
  • j is an integer from 1 to 8; preferably, 3 ⁇ j + l ⁇ 8,
  • R is a core molecule of a multi-branched polyethylene glycol, and R is selected from the group consisting of: pentaerythritol, oligo-pentaerythritol, methyl glucoside, sucrose, diethylene glycol, propylene glycol, glycerin, and polyglycerol residues.
  • said Y is methoxy
  • the l is zero.
  • the PEG is a multi-branched polyethylene glycol residue
  • the polyethylene glycol maleimide derivative has the following structure:
  • the polyethylene glycol maleimide derivative has the following structure:
  • the PEG is an eight-arm polyethylene glycol residue
  • the polyethylene glycol maleimide derivative is an eight-arm polyethylene glycol maleate Amine derivative.
  • the R has the structure represented by the formula IX or X:
  • the polyethylene glycol maleimide derivative has the following structure:
  • the PEG may have a molecular weight of 1-80 KDa, such as 1-10 KDa (specifically 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 KDa), 10-80 KDa (specifically 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70 or 80 KDa); preferably 10-50 KDa.
  • 1-10 KDa specifically 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 KDa
  • 10-80 KDa specifically 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70 or 80 KDa
  • 10-50 KDa preferably 10-50 KDa.
  • the PEG has a molecular weight of 10 KDa, 20 KDa or 40 KDa.
  • the polymerization inhibitor is a substance which converts a primary radical or a chain radical into a stable molecule or forms a stable radical which is low in activity and which is insufficient for the polymerization to proceed.
  • the polymerization inhibitor can be classified into a radical type, a phenol, a quinone, an aromatic amine, a nitro compound, a nitroso compound, a sulfur compound, an inorganic compound, or an organometallic compound depending on the kind of the substituent. , oxygen, etc. (See “Xiao Weidong, He Benqiao, He Peixin. Chemical Additives for Polymer Materials. Beijing: Chemical Industry Press, 2003:331-341").
  • the polymerization inhibitor is selected from one or more of a radical polymerization inhibitor, a phenol polymerization inhibitor, an inorganic compound polymerization inhibitor, and an organometallic compound polymerization inhibitor. combination.
  • the radical polymerization inhibitor includes, but is not limited to, 1,1-diphenyl-2-picrylyl radical (1,1-diphenyl-2-trinitrate) Benzoquinone, DPPH), nitroxide radicals such as 4,4'-dimethoxydiphenylnitroxyl radical (4,4'-dimethoxydiphenyl oxynitride, DMDPN), 4, 4'-Dinitrodiphenylnitroxyl radical (4,4'-dinitrodiphenyl oxynitride), di-tert-butyl nitroxyl radical (di-tert-butyl oxynitride, DTBNO), 2,2,6,6-tetramethyl-4-hydroxypiperidine nitroxyl radical (2,2,6,6-tetramethyl-4-hydroxypiperidine oxynitride, TEMPO), peroxide free One or more of benzoyl peroxide (BPO).
  • BPO benzoyl peroxide
  • the radical polymerization inhibitor is DPPH.
  • the phenolic polymerization inhibitor includes, but is not limited to, hydroquinone, tert-butyl p-phenol, methyl hydroquinone, p-tert-butyl catechol, p-hydroxybenzene.
  • the phenolic polymerization inhibitor is hydroquinone and/or tert-butyl p-phenol.
  • the inorganic compound polymerization inhibitor includes, but is not limited to, ferric chloride, cuprous chloride, copper chloride, copper sulfate, titanium trichloride, titanium chloride, sodium sulfate, One or more of sodium sulfide and ammonium thiocyanate.
  • the inorganic compound inhibitor is copper chloride.
  • the organometallic compound polymerization inhibitor includes, but is not limited to, copper naphthenate, chromium acetate, nickel acetate, copper dimethyl dithiocarbamate, and di-tert-butyl dithio.
  • copper naphthenate copper naphthenate
  • chromium acetate nickel acetate
  • copper dimethyl dithiocarbamate copper dimethyl dithiocarbamate
  • di-tert-butyl dithio di-tert-butyl dithio.
  • copper formate copper formate
  • the organometallic compound polymerization inhibitor is nickel acetate.
  • phenolic polymerization inhibitors such as hydroquinone and t-butyl p-phenol
  • polyethylene glycol maleimide derivatives especially eight-arm polyethylene glycol Malay
  • the combination of imide derivatives can significantly enhance the stability of the derivative, reduce its photosensitivity, extend the pot life and shelf life of the product, and is superior to other kinds of polymerization inhibitors and polyethylene glycol maleate.
  • a combination of amine derivatives can significantly enhance the stability of the derivative, reduce its photosensitivity, extend the pot life and shelf life of the product, and is superior to other kinds of polymerization inhibitors and polyethylene glycol maleate.
  • the polymerization inhibitor is a phenolic polymerization inhibitor, preferably from: hydroquinone, t-butyl p-phenol, methyl hydroquinone, Tert-butyl catechol, 2-tert-butyl hydroquinone, 2,5-di-tert-butyl hydroquinone, p-hydroxyanisole, 2,6-di-tert-butyl-4-methylphenol,
  • phenolic polymerization inhibitor preferably from: hydroquinone, t-butyl p-phenol, methyl hydroquinone, Tert-butyl catechol, 2-tert-butyl hydroquinone, 2,5-di-tert-butyl hydroquinone, p-hydroxyanisole, 2,6-di-tert-butyl-4-methylphenol,
  • 4,4'-dihydroxybiphenyl, pyrogallol and bisphenol A are more preferably hydroquinone or tert-butyl-p-phenol.
  • the polymerization inhibitor is a phenolic polymerization inhibitor, preferably hydroquinone or tert-butyl-p-phenol, the polyethylene glycol Malay
  • the imide derivative has the structure of the above formula VIII of the present invention, and the mass ratio of the phenolic polymerization inhibitor to the polyethylene glycol maleimide derivative may be from 1 ⁇ g to 1 mg: 1 g.
  • Another aspect of the invention also provides the use of a composition as described above for the preparation of a pharmaceutical conjugate.
  • Another aspect of the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a polymerization inhibitor and a combination of a polyethylene glycol maleimide derivative of the present invention and a drug.
  • the polymerization inhibitor is a phenolic polymerization inhibitor, more preferably: hydroquinone, t-butyl p-phenol, methyl hydroquinone, p-tert-butyl catechol, 2-tert-butyl Hydroquinone, 2,5-di-tert-butyl hydroquinone, p-hydroxyanisole, 2,6-di-tert-butyl-4-methylphenol, 4,4'-dihydroxybiphenyl, neighbor
  • benzenetriol and bisphenol A are most preferably hydroquinone and/or tert-butyl-p-phenol.
  • the drug is selected from the group consisting of amino acids, polypeptides, proteins, sugars, organic acids, alkaloids, flavonoids, terpenoids, terpenoids, phenylpropanoid phenols, steroids, and quinones.
  • the drugs are selected from the group consisting of amino acids, polypeptides, proteins, sugars, organic acids, alkaloids, flavonoids, terpenoids, terpenoids, phenylpropanoid phenols, steroids, and quinones.
  • the drugs is selected from the group consisting of amino acids, polypeptides, proteins, sugars, organic acids, alkaloids, flavonoids, terpenoids, terpenoids, phenylpropanoid phenols, steroids, and quinones.
  • the drug is a polypeptide or a protein drug.
  • the polypeptide or protein drug contains a free sulfhydryl group.
  • a thiol group is introduced at a specific site in the polypeptide or protein drug.
  • the polypeptide or protein drug includes, but is not limited to, a polypeptide hormone, a polypeptide cell growth regulator, other biochemical drugs containing a polypeptide component, a protein hormone, a plasma protein, and a protein cell. Growth regulators, mucins, lectins, antibodies and enzymes such as urea oxidase.
  • the polypeptide hormones include, but are not limited to, pituitary polypeptide hormones (such as corticotropin, melatonin, lipolysis hormone, oxytocin, etc.), hypothalamic hormones (such as thyroid stimulating hormone release) Hormone, auxin inhibitory hormone, gonadotropin-releasing hormone, etc.), thyroid hormone (such as parathyroid hormone, calcitonin, islet hormone: glucagon, pancreatic polypeptide, etc.), gastrointestinal hormones (such as Gastrin, cholecystokinin-trypsin, intestinal vasoactive peptide, etc.) and thymus hormones (such as thymosin, thymus serum factor, etc.).
  • pituitary polypeptide hormones such as corticotropin, melatonin, lipolysis hormone, oxytocin, etc.
  • hypothalamic hormones such as thyroid stimulating hormone release
  • Hormone such as auxin inhibitory hormone, gonadotropin-
  • the polypeptide cell growth regulators include, but are not limited to, epidermal growth factor, transfer factor, and atrial natriuretic peptide.
  • the other biochemical drugs containing the polypeptide component include, but are not limited to, bone lining, eye vitamins, blood activin, aminopeptin, keethin, brain aminopeptide, bee venom, Snake venom, embryonic hormone, cofactor, neurotrophic, placental extract, pollen extract, spleen hydrolysate, liver hydrolysate and cardiac hormone.
  • the protein hormone includes, but is not limited to, pituitary protein hormones (such as auxin, prolactin, thyrotropin, luteinizing hormone, follicle stimulating hormone, etc.), gonadotropin (such as Human chorionic gonadotropin, serotonin, etc.) and insulin and other protein hormones such as relaxin.
  • pituitary protein hormones such as auxin, prolactin, thyrotropin, luteinizing hormone, follicle stimulating hormone, etc.
  • gonadotropin such as Human chorionic gonadotropin, serotonin, etc.
  • insulin and other protein hormones such as relaxin.
  • the plasma protein includes, but is not limited to, albumin, plasminogen, plasma fibronectin, immunoglobulin, fibrinogen, and coagulation factors.
  • the proteinaceous cell growth regulators include, but are not limited to, interleukin (IL-1 to IL-38), colony stimulating factor (eg, granulocyte colony stimulating factor (G-CSF) ), macrophage colony-stimulating factor (M-CSF), granulocyte and macrophage colony-stimulating factor (GM-CSF), multi-colony stimulator (Multi-CSF), stem cell factor (SCF), erythropoietin (EPO) ), interferon ( ⁇ , ⁇ , ⁇ ), growth factors (such as epidermal growth factor, platelet-derived growth factor, fibroblast growth factor, hepatocyte growth factor, insulin-like growth factor, nerve growth factor, platelet-derived) Endothelial growth factor, vascular endothelial growth factor, transforming growth factor- ⁇ , etc., tumor necrosis factor, tissue plasminogen activator and erythropoietin.
  • IL-1 to IL-38 colony stimulating factor
  • the mucin comprises, but is not limited to, gastric factor, collagen, a basic protein, and a protease inhibitor such as a trypsin inhibitor.
  • the lectin includes, but is not limited to, concanavalin, wheat germ, peanut agglutinin, soybean lectin, and the like.
  • the antibodies include, but are not limited to, anti-CD20 antibodies, antibodies against the EGFR family (eg, anti-EGFR antibodies, anti-HER-2 antibodies), and anti-VEGF/VEGFR antibodies, and the like.
  • the enzyme includes, but is not limited to, L-asparaginase, glutaminase, urokinase, neuraminidase, superoxide dismutase, and the like.
  • Another aspect of the invention also provides a pharmaceutical conjugate prepared as described above.
  • Another aspect of the invention also provides the use of a polymerization inhibitor in the preparation of the above compositions, pharmaceutical combinations and pharmaceutical compositions.
  • the polymerization inhibitor is a phenolic polymerization inhibitor, more preferably: hydroquinone, t-butyl p-phenol, methyl hydroquinone, p-tert-butyl catechol, 2 -tert-butyl hydroquinone, 2,5-di-tert-butyl hydroquinone, p-hydroxyanisole, 2,6-di-tert-butyl-4-methylphenol, 4,4'-dihydroxy
  • One or more of biphenyl, pyrogallol and bisphenol A are most preferably hydroquinone and/or tert-butyl p-phenol.
  • the invention provides a composition of a polyethylene glycol maleimide derivative and a polymerization inhibitor, in particular an eight-arm polyethylene glycol maleimide derivative and a phenolic polymerization inhibitor (such as hydroquinone) And a composition of tert-butyl-p-phenol), wherein the composition and content of the polymerization inhibitor are selected reasonably, and the stability of the polyethylene glycol maleimide derivative can be greatly enhanced, thereby effectively avoiding storage thereof. And the phenomenon of curing gelation during polymerization occurs, prolonging the pot life and storage period of the product, and is effective for preparing drug conjugates, especially polypeptide and protein drug combinations.
  • Figure 1 shows the GPC pattern after 8 days of 8ARM(TP)-PEG-MAL-40K irradiation with a polymerization inhibitor.
  • Figure 2 shows the effect of the type and concentration of the inhibitor on the complete metamorphic time of 8ARM(TP)-PEG-MAL-40K.
  • Figure 3 shows the effect of the type and concentration of the inhibitor on the complete metamorphic time of 8ARM(TP)-PEG-MAL-20K.
  • Figure 4 shows the effect of the type and concentration of the inhibitor on the complete metamorphic time of 8ARM(TP)-PEG-MAL-10K.
  • Alkyl means a straight or branched hydrocarbon chain radical which does not contain an unsaturated bond
  • a C1-C6 alkyl group means an alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, N-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, n-hexyl, isohexyl and the like.
  • alkoxy means a substituent formed by substituting a hydrogen in a hydroxy group with an alkyl group
  • alkoxy group of C1-C6 means an alkoxy group having 1 to 6 carbon atoms, such as a methoxy group or an ethoxy group. , propoxy, butoxy, and the like.
  • Cycloalkyl means an alicyclic hydrocarbon such as containing from 1 to 4 monocyclic and/or fused rings containing from 3 to 18 carbon atoms, preferably from 3 to 10 carbon atoms, such as cyclopropyl, cyclohexyl or Adamantyl and the like
  • the C3-C6 cycloalkyl group in the present invention means a cycloalkyl group having 3 to 6 carbon atoms such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group.
  • the specific groups and chemical structures involved in the present invention correspond to the following: hydroxyl group, -OH, carboxyl group, Succinimide carbonate group, Succinimide acetate group, Succinimide propionate group, Succinimide succinate group, Succinimide group, Dithiopyridyl, or Propionic acid group, Aldehyde, -CHO; oxime ester (wherein Q 1 may be alkyl or heterocyclic, such as methyl, ethyl, n-propyl, t-butyl, pyridyl (eg ))); acrylic based, Acrylate group (acryloyloxy) Azido group, Glutaric acid group, such as Alkynyl, P-nitrophenyl carbonate group, Silyl group, (wherein Q 2 may be the same or different alkyl or alkoxy group, such as methyl, ethyl, propyl, butyl, pentyl
  • the "combination” means a group formed by linking two or more of the linked linking groups by chemical bonding, for example, -(CH 2 ) r -and-
  • the combination of (CH 2 ) r NHCO- may be -(CH 2 ) r NHCO(CH 2 ) r -; specifically, the combination of -CH 2 - and -CH 2 CH 2 NHCO- may be -CH 2 CH 2 NHCOCH 2 -, -CH 2 CH 2 CH 2 NHCO-.
  • the "combination” is used to define the chemical structure of the linking group, and does not involve the preparation steps, combination order, and the like of the linking group.
  • the polyethylene glycol maleimide derivative described in the present invention is a polyethylene glycol to which a maleimide group is attached, as shown in the formula I of the present invention, specifically as shown in the formula XI;
  • the linkage can be achieved by a covalent bond or by a linking group, and the reaction for achieving the linkage is well known to those skilled in the art, which is not specifically limited in the present invention.
  • polyethylene glycol maleimide derivative and a combination of polymerization inhibitors may further contain other components such as ultraviolet absorbers (UV-P) to improve product quality or Additives such as functions, those skilled in the art can add according to actual needs, or moisture, impurities and the like are inevitably contained in the production, transportation and storage of polyethylene glycol maleimide derivatives and their compositions.
  • UV-P ultraviolet absorbers
  • Additives such as functions those skilled in the art can add according to actual needs, or moisture, impurities and the like are inevitably contained in the production, transportation and storage of polyethylene glycol maleimide derivatives and their compositions.
  • the substance is not specifically limited in the present invention.
  • the compounds used in the present invention are either commercially available or can be prepared according to the disclosed preparation methods without limiting the scope of the invention.
  • the polyethylene glycol derivative used in the examples was supplied by Beijing Key Kai Technology Co., Ltd. Others are commercially available reagents.
  • composition powder of hydroquinone, DPPH, nickel acetate, copper chloride and 8ARM(TP)-PEG-MAL-40K 250 mg was respectively obtained, wherein hydroquinone, DPPH, nickel acetate and copper chloride were respectively obtained. 100ppm.
  • the above composition powders were separately placed in a watch glass and placed in a constant temperature light box (2750 Lux, 18.5 ° C) for two days, and the GPC results are shown in Fig. 1.
  • 8ARM(TP)-PEG-MAL-40K had the lowest degree of purity reduction and the best inhibition effect.
  • additives including hydroquinone, tert-butyl-p-phenol, a mixture of hydroquinone and UV absorber (hydroquinone & UV-P, the mass ratio of the two is 1: 1) A powder of a composition of DPPH, nickel acetate, copper chloride and 8ARM(TP)-PEG-MAL-40K (250 mg), wherein the concentration of each additive comprises 1, 20, 100, 400 and 1000 ppm.
  • the above composition powders were separately placed in a watch glass and placed in a constant temperature light box (2750 Lux, 18.5 ° C) to record the time required for complete deterioration (ie, the appearance of a gel insoluble in methanol). 2 (Note: If no additives are added, pure 8ARM(TP)-PEG-MAL-40K will completely deteriorate after two days of irradiation).
  • composition powder containing different concentrations of hydroquinone, DPPH, nickel acetate, copper chloride and 8ARM(TP)-PEG-MAL-20K was separately taken, wherein the concentration of each polymerization inhibitor included 1, 20 , 100, 400, 1000ppm.
  • concentration of each polymerization inhibitor included 1, 20 , 100, 400, 1000ppm.
  • the above composition powders were separately placed in a watch glass and placed in a constant temperature light box (2750 Lux, 18.5 ° C) to record the time required for complete deterioration (ie, the appearance of a gel insoluble in methanol). 3 (Note: If no inhibitor is added, pure 8ARM(TP)-PEG-MAL-20K will completely deteriorate after two days of irradiation).
  • composition powder containing different concentrations of hydroquinone, DPPH, nickel acetate, copper chloride and 8ARM(TP)-PEG-MAL-10K was separately taken, wherein the concentration of each polymerization inhibitor included 1, 20 , 100, 400, 1000ppm.
  • concentration of each polymerization inhibitor included 1, 20 , 100, 400, 1000ppm.
  • the above composition powders were separately placed in a watch glass and placed in a constant temperature light box (2750 Lux, 18.5 ° C) to record the time required for complete deterioration (ie, the appearance of a gel insoluble in methanol). 4 (Note: If no inhibitor is added, pure 8ARM(TP)-PEG-MAL-10K will completely deteriorate after one day of irradiation).
  • the 8ARM(TP)-PEG-MAL used in the embodiment of the present invention has the following structure:
  • the maleimide derivative of polyethylene glycol of other configurations and molecular weights can also be used to enhance the stability of the maleimide derivative of polyethylene glycol in combination with the polymerization inhibitor in the examples of the present invention. Sexuality, prolonging the product's pot life and shelf life, and not listing the experimental data.

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Abstract

本发明公开了一种聚乙二醇马来酰亚胺衍生物和阻聚剂的组合物，特别是一种八臂聚乙二醇马来酰亚胺衍生物和酚类阻聚剂的组合物，所述的组合物中阻聚剂的成分和含量选择合理，可大大增强聚乙二醇马来酰亚胺衍生物的稳定性，有效避免其在储存和运输过程中发生聚合出现固化凝胶的不良现象，延长其产品适用期和储存期。

Description

一种聚乙二醇马来酰亚胺衍生物和阻聚剂的组合物 技术领域
本发明涉及高分子技术领域，具体涉及一种聚乙二醇马来酰亚胺衍生物和阻聚剂的组合物，特别是一种八臂聚乙二醇马来酰亚胺衍生物和酚类阻聚剂的组合物。
背景技术
聚乙二醇(PEG)是一种由乙二醇单体聚合而成、无毒、两亲性的大分子化合物，PEG修饰是从20世纪70年代后期逐渐发展起来的一项技术，其可解决一些药物如多肽和蛋白类药物在临床应用过程中存在的诸多问题，一些PEG修饰产物在作为药物的应用中已取得了良好的效果。聚乙二醇末端的羟基是其化学反应的功能基团，但反应活性较差，常经过适当方式活化后形成聚乙二醇的衍生物用作修饰剂。活化后的端基如氨基、羧基、醛基、马来酰亚胺基等在聚乙二醇的应用中起着决定性作用，不同端基具有不同用途，这些活性基团的引入扩大了PEG的应用范围。聚乙二醇马来酰亚胺衍生物(PEG-MAL)是将马来酰亚胺基引入到PEG的端基，而马来酰亚胺和巯基的偶合是蛋白质和多肽偶联中的一个非常有用的反应，PEG-MAL则可被用作聚合物试剂来选择性诱捕含巯基的多肽，也可采用基因工程手段把巯基引入多肽、蛋白质分子的特定位点，利用PEG-MAL进行定点修饰，修饰选择性高，且可避免蛋白生物活性的丧失，降低免疫原性。近年来研究发现PEG-MAL在蛋白质及多肽与脂质体的连接技术中起关键作用，对脂质体的靶向性研究及扩大多肽类化合物在医药、生物技术等领域的应用有重要意义，因此PEG-MAL是一种应用价值非常高的聚乙二醇衍生物。但是，聚乙二醇的马来酰亚胺衍生物中含有不饱和双键，反应活性较高，造成该衍生物产品稳定性较差，在光照条件下室温保存常常发生聚合形成类似凝胶的不溶物，造成该衍生物产品含量不高，保质期短，给其保存和运输带来很大的不便，进而限制了其应用。
发明内容
本申请的发明人经过大量的试验和研究发现，将聚乙二醇马来酰亚胺衍生物(特别是八臂聚乙二醇马来酰亚胺衍生物)和某些阻聚剂组合可增强其稳定性或降低其光敏性，延长产品适用期和储存期。
本发明一方面提供一种聚乙二醇马来酰亚胺衍生物和阻聚剂的组合物。
所述组合物中，所述阻聚剂与聚乙二醇马来酰亚胺衍生物的质量比例≥0.1μg：1g。
在本发明的一个实施方式中，所述组合物中，所述阻聚剂与聚乙二醇马来酰亚胺衍生物的质量比例可为0.1μg-10mg：1g，如可为0.1-100μg：1g(如0.1μg：1g、1μg：1g、5μg：1g、10μg：1g、20μg：1g、30μg：1g、40μg：1g、50μg：1g、60μg：1g、70μg：1g、80μg：1g、90μg：1g或100μg：1g)、100μg-1mg：1g(如100μg：1g、200μg：1g、300μg：1g、400μg：1g、500μg：1g、600μg：1g、700μg：1g、800μg：1g、900μg：1g或1mg：1g)、1-10mg：1g(如1mg：1g、2mg：1g、3mg：1g、4mg：1g、5mg：1g、6mg：1g、7mg：1g、8mg：1g、9mg：1g或10mg：1g)；优选为1μg-1mg：1g。
所述的组合物中，所述的聚乙二醇马来酰亚胺衍生物中含有至少一个马来酰亚胺端基。
在本发明的一个实施方式中，所述聚乙二醇马来酰亚胺衍生物具有如下结构：
PEG-X-MAL
(Ⅰ)
其中，PEG为聚乙二醇残基，
X为PEG与MAL的连接基团，选自：-(CH 2) r-、
Figure PCTCN2018077231-appb-000001
-(CH 2) rO-、-(CH 2) rCO-、-(CH 2) rNH-、-(CH 2) rCONH-、-(CH 2) rNHCO-、-(CH 2) rS-、-(CH 2) rCOO-和-(CH 2) rOCO-中一种或两种以上的组合，r为0-10的整数，
MAL为马来酰亚胺基
Figure PCTCN2018077231-appb-000002
R 1和R 2独立地选自：-H、C1-6的烷基、C1-6的烷氧基、C3-6环烷基和C4-10亚烷基环烷基。
优选地，所述R 1和R 2独立地选自：-H、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-OCH 3、-OCH 2CH 3和-OCH 2CH 2CH 3，更优选自：-H、-CH 3、-OCH 3和-OCH 2CH 3；在本发明一个优选实施例中，所述R 1为H，R 2为-CH 3、-OCH 3或-OCH 2CH 3；在本发明一个更优选实施例中，所述R 1为H，R 2为-CH 3。
在本发明的一个具体实施方式中，所述X选自：单键、-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、-CH 2CH 2CH 2CH 2-、-CH 2CH 2CH 2CH 2CH 2-、-CH(CH 3)-、-CH 2CH(CH 3)-、-CH 2CH 2CH(CH 3)-、-CH 2CH 2CH 2CH(CH 3)-、-CH 2CH 2CH 2CH 2CH(CH 3)-、-CH 2CH 2CH 2CH 2CH 2CH(CH 3)-、-(CH 2) rO-、-(CH 2) rCO-、-(CH 2) rNH-、-(CH 2) rCONH-、-(CH 2) rNHCO-、-(CH 2) rS-、-(CH 2) rCOO-和-(CH 2) rOCO-中一种或两种以上的组合。
在本发明的一个优选实施例中，所述X选自：单键、-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、-CH(CH 3)-、-CH 2CH(CH 3)-、-CH 2CH 2CH(CH 3)-、-(CH 2) rO-、-(CH 2) rCO-、-(CH 2) rNH-、-(CH 2) rCONH-和-(CH 2) rNHCO-中一种或两种以上的组合。
在本发明的一个实施例中，r为0-5的整数，如0、1、2、3、4或5。
在本发明的一个更优选的实施例中，所述X为-CH 2CH 2NHCOCH 2CH 2-。
在本发明所述的组合物中，所述PEG可为直链、Y型或多分支的聚乙二醇残基，例如包括直链聚乙二醇、Y型或U型PEG、4臂支链PEG、6臂支链PEG或8臂支链PEG等。
在本发明的一个实施方式中，所述PEG为直链聚乙二醇残基，具有通式II或III所示的结构：
Figure PCTCN2018077231-appb-000003
Figure PCTCN2018077231-appb-000004
其中，Y为端基，选自：C1-C6的烷氧基、羟基、羧基、琥珀酰亚胺碳酸酯基、琥珀酰亚胺乙酸酯基、琥珀酰亚胺丙酸酯基、琥珀酰亚胺琥珀酸酯基、琥珀酰亚胺基、二硫吡啶基、丙酸基、醛基、巯酯基、丙烯酸基、丙烯酸酯基、叠氮基、戊二酸基、炔基、对硝基苯碳酸酯基、硅烷基和羧甲基中的一种；
p和q独立地选自1-2400的整数，优选为1-1200的整数，更优选为200-1200的整数。
在本发明的一个实施例中，式Ⅱ中，所述Y为甲氧基。
在本发明的一个实施方式中，所述PEG为Y型或U型聚乙二醇残基，具有通式IV或V所示的结构：
Figure PCTCN2018077231-appb-000005
其中，Y为端基，其具有本发明上述定义，
i和k独立地选自1-1200的整数，优选自1-600的整数，更优选为100-600的整数。
在本发明的一个实施例中，式IV和/或V中，所述Y为甲氧基。
在本发明的一个实施方式中，所述PEG为多分支聚乙二醇残基，具有通式VI 所示的结构：
Figure PCTCN2018077231-appb-000006
其中，Y为端基，其具有本发明上述定义，
n是1-800的整数，优选为1-400的整数，更优选为60-400的整数，
l是0-7的整数，j是1-8的整数；优选地，3≤j+l≤8，
R是多分支聚乙二醇的核心分子，R选自：季戊四醇、寡聚季戊四醇、甲基葡萄糖苷、蔗糖、二甘醇、丙二醇、甘油和聚甘油的残基。
在本发明的一个实施例中，式VI中，所述Y为甲氧基。
在本发明的一个实施例中，所述l为0。
在本发明的一个优选实施方式中，所述PEG为多分支聚乙二醇残基，所述聚乙二醇马来酰亚胺衍生物具有如下结构：
Figure PCTCN2018077231-appb-000007
在本发明一个实施例中，所述的聚乙二醇马来酰亚胺衍生物具有如下结构：
Figure PCTCN2018077231-appb-000008
优选地，所述式VIII中，j＝8，所述PEG为八臂聚乙二醇残基，所述聚乙二醇马来酰亚胺衍生物为八臂聚乙二醇马来酰亚胺衍生物。
在本发明的一个具体实施例方式中，所述式VIII中，j＝8，所述的R具有式IX或X所示的结构：
Figure PCTCN2018077231-appb-000009
在本发明的一个优选实施例中，所述的聚乙二醇马来酰亚胺衍生物具有如下结构：
Figure PCTCN2018077231-appb-000010
在本发明的一个实施例中，所述的PEG的分子量可为1-80KDa，例如1-10KDa(具体可为1、2、3、4、5、6、7、8、9或10KDa)、10-80KDa(具体可为10、15、20、25、30、35、40、45、50、60、70或80KDa)；优选为10-50KDa。
在本发明的一个优选实施例中，所述PEG的分子量为10KDa、20KDa或40KDa。
在本发明中，所述阻聚剂为能使初级自由基或链自由基转化成稳定分子或形成活性很低不足以使聚合反应继续进行的稳定自由基的物质。本领域技术人员可知， 根据取代基种类可将阻聚剂分为自由基型、酚类、醌类、芳胺类、硝基化合物、亚硝基化合物、含硫化合物、无机化合物、有机金属化合物、氧等(参见“肖卫东，何本桥，何培新.聚合物材料用化学助剂.北京：化学工业出版社，2003：331-341”)。
在本发明的一个实施方式中，所述的阻聚剂选自：自由基阻聚剂、酚类阻聚剂、无机化合物阻聚剂、有机金属化合物阻聚剂中的一种或多种的组合。
在本发明的一个实施方式中，所述的自由基阻聚剂包括但不限于：1,1-二苯基-2-苦肼基自由基(1,1-二苯基-2-三硝基苯肼，DPPH)、氮氧自由基如4,4’-二甲氧基二苯基氮氧自由基(4,4’-二甲氧基二苯基氮氧化物，DMDPN)、4,4’-二硝基二苯基氮氧自由基(4,4’-二硝基二苯基氮氧化物)、二叔丁基氮氧自由基(二叔丁基氮氧化物，DTBNO)、2,2,6,6-四甲基-4-羟基哌啶氮氧自由基(2,2,6,6-四甲基-4-羟基哌啶氮氧化物，TEMPO)、过氧化物自由基如过氧化苯甲酰(BPO)中的一种或多种。
在本发明的一个具体实施方式中，所述的自由基阻聚剂为DPPH。
在本发明的一个实施例中，所述的酚类阻聚剂包括但不限于：对苯二酚、叔丁基对苯酚、甲基对苯二酚、对叔丁基邻苯二酚、对羟基苯甲醚、2-叔丁基对苯二酚、2,5-二叔丁基对苯二酚、2,6-二叔丁基-4-甲基苯酚(BHT)、4,4′-二羟基联苯、邻苯三酚和双酚A中的一种或多种。
在本发明的一个优选实施例中，所述酚类阻聚剂为对苯二酚和/或叔丁基对苯酚。
在本发明的一个实施方式中，所述的无机化合物阻聚剂包括但不限于：氯化铁、氯化亚铜、氯化铜、硫酸铜、三氯化钛、氯化钛、硫酸钠、硫化钠和硫氰酸铵中的一种或多种。
在本发明的一个具体实施方式中，所述的无机化合物阻聚剂为氯化铜。
在本发明的一个实施方式中，所述的有机金属化合物阻聚剂包括但不限于：环烷酸铜、乙酸铬、乙酸镍、二甲基二硫代甲酸铜和二特丁基二硫代甲酸铜中的一种或多种。
在本发明的一个具体实施方式中，所述的有机金属化合物阻聚剂为乙酸镍。
本发明的发明人经过实验发现，酚类阻聚剂(如对苯二酚和叔丁基对苯酚)和 聚乙二醇马来酰亚胺衍生物(特别是八臂聚乙二醇马来酰亚胺衍生物)的组合可显著增强该衍生物的稳定性、降低其光敏性，延长产品适用期和储存期，且效果优于其他种类的阻聚剂与聚乙二醇马来酰亚胺衍生物的组合。
在本发明的一个优选实施例中，所述组合物中，所述阻聚剂为酚类阻聚剂，优选自：对苯二酚、叔丁基对苯酚、甲基对苯二酚、对叔丁基邻苯二酚、2-叔丁基对苯二酚、2,5-二叔丁基对苯二酚、对羟基苯甲醚、2,6-二叔丁基-4-甲基苯酚、4,4′-二羟基联苯、邻苯三酚和双酚A中的一种或多种，更优选为对苯二酚或叔丁基对苯酚。
在本发明的一个优选实施例中，所述组合物中，所述聚乙二醇马来酰亚胺衍生物具有上述式VIII结构，其中，优选地，j＝8，更优选地，所述R具有上述式IX或X的结构，最优选地，所述聚乙二醇马来酰亚胺衍生物具有上述式Ⅺ的结构；优选地，所述PEG的分子量为1-80KDa，例如1-10KDa(具体可为1、2、3、4、5、6、7、8、9或10KDa)、10-80KDa(具体可为10、15、20、25、30、35、40、45、50、60、70或80KDa)，更优选为10-50KDa，最优选为10KDa、20KDa和40KDa；所述组合物中，所述阻聚剂为酚类阻聚剂，优选自：对苯二酚、叔丁基对苯酚、甲基对苯二酚、对叔丁基邻苯二酚、2-叔丁基对苯二酚、2,5-二叔丁基对苯二酚、对羟基苯甲醚、2,6-二叔丁基-4-甲基苯酚、4,4′-二羟基联苯、邻苯三酚和双酚A中的一种或多种，更优选为对苯二酚或叔丁基对苯酚；所述组合物中，所述酚类阻聚剂与聚乙二醇马来酰亚胺衍生物的质量比例可为0.1μg-10mg：1g，如可为0.1-100μg：1g(如0.1μg：1g、1μg：1g、5μg：1g、10μg：1g、20μg：1g、30μg：1g、40μg：1g、50μg：1g、60μg：1g、70μg：1g、80μg：1g、90μg：1g、100μg：1g)、100μg-1mg：1g(如100μg：1g、200μg：1g、300μg：1g、400μg：1g、500μg：1g、600μg：1g、700μg：1g、800μg：1g、900μg：1g、1mg：1g)、1-10mg：1g(如1mg：1g、2mg：1g、3mg：1g、4mg：1g、5mg：1g、6mg：1g、7mg：1g、8mg：1g、9mg：1g、10mg：1g)。在本发明的一个更优选实施例中，所述组合物中，所述阻聚剂为酚类阻聚剂，优选为对苯二酚或叔丁基对苯酚，所述聚乙二醇马来酰亚胺衍生物具有本发明上述式VIII结构，所述酚类阻聚剂与聚乙二醇马来酰亚胺衍生物的质量比例可 为1μg-1mg：1g。
本发明另一方面还提供一种上述组合物在制备药物结合物中的应用。
本发明另一方面还提供一种药物组合物，所述药物组合物包括阻聚剂和本发明所述的聚乙二醇马来酰亚胺衍生物与药物的结合物。
优选地，所述的阻聚剂为酚类阻聚剂，更优选自：对苯二酚、叔丁基对苯酚、甲基对苯二酚、对叔丁基邻苯二酚、2-叔丁基对苯二酚、2,5-二叔丁基对苯二酚、对羟基苯甲醚、2,6-二叔丁基-4-甲基苯酚、4,4′-二羟基联苯、邻苯三酚和双酚A中的一种或多种，最优选为对苯二酚和/或叔丁基对苯酚。
在本发明的一个实施例中，所述的药物选自：氨基酸、多肽、蛋白质、糖类、有机酸、生物碱、黄酮类、醌类、萜类、苯丙素酚类、甾体和甙类药物中的一种或多种。
在本发明的一个具体实施方式中，所述的药物为多肽或蛋白类药物。
在本发明的一个具体实施方式中，所述的多肽或蛋白类药物中含有游离巯基。
在本发明的另一个具体实施方式中，所述的多肽或蛋白类药物中在特定位点引入巯基。
在本发明的一个具体实施方式中，所述的多肽或蛋白类药物包括但不限于：多肽激素、多肽类细胞生长调节因子、含有多肽成分的其他生化药物、蛋白质激素、血浆蛋白质、蛋白质类细胞生长调节因子、粘蛋白、凝集素、抗体和酶如尿素氧化酶等。
在本发明的一个实施例中，所述的多肽激素包括但不限于：垂体多肽激素(如促皮质素、促黑激素、脂肪水解激素、催产素等)、下丘脑激素(如促甲状腺激素释放激素、生长素抑制激素、促性腺激素释放激素等)、甲状腺激素(如甲状旁腺激素、降钙素等，胰岛激素：胰高血糖素、胰解痉多肽等)、胃肠道激素(如胃泌素、胆囊收缩素-促胰酶素、肠血管活性肽等)和胸腺激素(如胸腺素、胸腺血清因子等)。
在本发明的一个实施例中，所述的多肽类细胞生长调节因子包括但不限于：表皮生长因子、转移因子和心钠素等。
在本发明的一个实施例中，所述的含有多肽成分的其他生化药物包括但不限于：骨宁、眼生素、血活素、氨肽素、妇血宁、脑氨肽、蜂毒、蛇毒、胚胎素、助应素、神经营养素、胎盘提取物、花粉提取物、脾水解物、肝水解物和心脏激素等。
在本发明的一个实施例中，所述的蛋白质激素包括但不限于：垂体蛋白质激素(如生长素、催乳激素、促甲状腺素、促黄体生成激素、促卵泡激素等)、促性腺激(如人绒毛膜促性腺激素、血清型促性腺激素等)和胰岛素及其他蛋白质激素如松弛素等。
在本发明的一个实施例中，所述的血浆蛋白质包括但不限于：白蛋白、纤维蛋白溶酶原、血浆纤维结合蛋白、免疫球蛋白、纤维蛋白原和凝血因子等。
在本发明的一个实施例中，所述的蛋白质类细胞生长调节因子包括但不限于：白细胞介素(IL-1～IL-38)、集落刺激因子(如粒细胞集落刺激因子(G-CSF)、巨噬细胞集落刺激因子(M-CSF)、粒细胞和巨噬细胞集落刺激因子(GM-CSF)、多重集落刺激因子(Multi-CSF)、干细胞因子(SCF)、红细胞生成素(EPO)等)、干扰素(α、β、γ)、生长因子(如表皮生长因子、血小板衍生的生长因子、成纤维细胞生长因子、肝细胞生长因子、胰岛素样生长因子、神经生长因子、血小板衍生的内皮细胞生长因子、血管内皮细胞生长因子、转化生长因子-α等)、肿瘤坏死因子、组织纤溶酶原激活因子和促红细胞生成素等。
在本发明的一个实施例中，所述的粘蛋白包括但不限于：胃膜素、胶原蛋白、碱性蛋白质和蛋白酶抑制剂如胰蛋白酶抑制剂等。
在本发明的一个实施例中，所述的凝集素包括但不限于：刀豆素、麦胚素、花生凝集素和大豆凝集素等。
在本发明的一个实施例中，所述的抗体包括但不限于：抗CD20抗体、抗EGFR家族的抗体(如抗EGFR抗体、抗HER-2抗体)和抗VEGF/VEGFR抗体等。
在本发明的一个实施例中，所述的酶包括但不限于：L-天冬酰胺酶、谷氨酰胺酶、尿激酶、神经氨酸苷酶和超氧化物歧化酶等。
本发明另一方面还提供一种上述制备的药物结合物。
本发明另一方面还提供一种阻聚剂在制备上述组合物、药物结合物和药物组合 物中的应用。
优选地，上述应用中，所述的阻聚剂为酚类阻聚剂，更优选自：对苯二酚、叔丁基对苯酚、甲基对苯二酚、对叔丁基邻苯二酚、2-叔丁基对苯二酚、2,5-二叔丁基对苯二酚、对羟基苯甲醚、2,6-二叔丁基-4-甲基苯酚、4,4′-二羟基联苯、邻苯三酚和双酚A中的一种或多种，最优选为对苯二酚和/或叔丁基对苯酚。
本发明提供的聚乙二醇马来酰亚胺衍生物和阻聚剂的组合物，特别是八臂聚乙二醇马来酰亚胺衍生物和酚类阻聚剂(如对苯二酚和叔丁基对苯酚)的组合物，所述的组合物中阻聚剂的成分和含量选择合理，可大大增强聚乙二醇马来酰亚胺衍生物的稳定性，有效避免其在储存和运输过程中发生聚合出现固化凝胶的不良现象，延长其产品适用期和储存期，用于制备药物结合物特别是多肽和蛋白类药物结合物的效果好。
附图说明
图1所示为加入阻聚剂的8ARM(TP)-PEG-MAL-40K照射两天后的GPC图。
图2所示为阻聚剂种类及浓度对8ARM(TP)-PEG-MAL-40K完全变质时间的影响结果。
图3所示为阻聚剂种类及浓度对8ARM(TP)-PEG-MAL-20K完全变质时间的影响结果。
图4所示为阻聚剂种类及浓度对8ARM(TP)-PEG-MAL-10K完全变质时间的影响结果。
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，如：
“烷基”指的是直链或支链的且不含不饱和键的烃链自由基，C1-C6的烷基指含有1-6个碳原子的烷基，如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、叔戊基、正己基、异己基等。
“烷氧基”指的是羟基中的氢被烷基取代后形成的取代基，C1-C6的烷氧基指含有1-6个碳原子的烷氧基，如甲氧基、乙氧基、丙氧基、丁氧基等。
“环烷基”指的是脂环烃，如含1至4个单环和/或稠环、含3-18个碳原子，优选3-10个碳原子，如环丙基、环己基或金刚烷基等，本发明中所述C3-C6的环烷基指含有3-6个碳原子的环烷基，如环丙基、环丁基、环戊基和环己基。
另外，本发明中涉及的具体基团及其化学结构对应如下：羟基，-OH；羧基，
Figure PCTCN2018077231-appb-000011
琥珀酰亚胺碳酸酯基，
Figure PCTCN2018077231-appb-000012
琥珀酰亚胺乙酸酯基，
Figure PCTCN2018077231-appb-000013
琥珀酰亚胺丙酸酯基，
Figure PCTCN2018077231-appb-000014
琥珀酰亚胺琥珀酸酯基，
Figure PCTCN2018077231-appb-000015
琥珀酰亚胺基，
Figure PCTCN2018077231-appb-000016
二硫吡啶基，
Figure PCTCN2018077231-appb-000017
或
Figure PCTCN2018077231-appb-000018
丙酸基，
Figure PCTCN2018077231-appb-000019
醛基，-CHO；巯酯基
Figure PCTCN2018077231-appb-000020
(其中Q 1可为烷基或杂环基，如甲基、乙基、正丙基、叔丁基、吡啶基(如
Figure PCTCN2018077231-appb-000021
)等)；丙烯酸基，
Figure PCTCN2018077231-appb-000022
丙烯酸酯基(丙烯酰氧基)
Figure PCTCN2018077231-appb-000023
叠氮基，
Figure PCTCN2018077231-appb-000024
戊二酸基，如
Figure PCTCN2018077231-appb-000025
炔基，
Figure PCTCN2018077231-appb-000026
对硝基苯碳酸酯基，
Figure PCTCN2018077231-appb-000027
硅烷基，
Figure PCTCN2018077231-appb-000028
(其中Q 2可为相同或不同的烷基或烷氧基，如甲基、乙基、丙基、丁基、戊基、甲氧基、乙氧基、丙氧基、丁氧基等，优选地，Q 2均为甲基、乙基、正丙基、甲氧基、 乙氧基、正丙氧基等)；羧甲基，
Figure PCTCN2018077231-appb-000029
本发明中关于连接基团的定义中，所述“组合”是指所列举的连接基团中的两个以上通过化学键键合连接后形成的基团，例如-(CH 2) r-与-(CH 2) rNHCO-的组合可为-(CH 2) rNHCO(CH 2) r-；具体地，如-CH 2-与-CH 2CH 2NHCO-的组合可为-CH 2CH 2NHCOCH 2-、-CH 2CH 2CH 2NHCO-。所述“组合”用于限定连接基团的化学结构，不涉及连接基团的制备步骤、组合顺序等。
本发明中所述的聚乙二醇马来酰亚胺衍生物为连接有马来酰亚胺基的聚乙二醇，如本发明中式Ⅰ所示的结构，具体如式Ⅺ所示结构；所述连接可通过共价键实现，也可通过连接基团实现，实现连接的反应是本领域技术人员所熟知的，本发明对此不作具体限定。
本发明中所述的“聚乙二醇马来酰亚胺衍生物和阻聚剂的组合物”中，还可包含其他成分，如紫外吸收剂(UV-P)等用来改善产品质量或功能等的添加物，本领域技术人员可以根据实际需要进行添加，或水分、杂质等在聚乙二醇马来酰亚胺衍生物及其组合物在生产、运输和储存过程中不可避免含有的物质，本发明对此不作具体限定。
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付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。
本发明所用的化合物可以商购，也可以根据公开的制备方法进行制备，其并不限制本发明的范围。
实施例中所用的聚乙二醇衍生物由北京键凯科技股份有限公司提供。其他均为市售试剂。
实施例1
分别取对苯二酚、DPPH、乙酸镍、氯化铜与8ARM(TP)-PEG-MAL-40K(250mg)的组合物粉末，其中对苯二酚、DPPH、乙酸镍、氯化铜均为100ppm。将上述组合 物粉末分别平铺于表面皿中，并放置于恒温光照箱(2750Lux，18.5℃)中照射两天，其GPC结果如图1所示。
根据图1，可得加入阻聚剂的8ARM(TP)-PEG-MAL-40K照射两天后的GPC浓度对比结果如表1所示。
表1加入阻聚剂的8ARM(TP)-PEG-MAL-40K照射两天后的GPC浓度
Figure PCTCN2018077231-appb-000030
如表1所示，在上述四种阻聚剂中，加入对苯二酚后，8ARM(TP)-PEG-MAL-40K纯度下降程度最低，阻聚效果最好。
实施例2
分别取含不同种类、不同浓度的添加剂：包括对苯二酚、叔丁基对苯酚、对苯二酚与紫外吸收剂的混合物(对苯二酚&UV-P，二者的质量比为1：1)、DPPH、乙酸镍、氯化铜与8ARM(TP)-PEG-MAL-40K(250mg)的组合物粉末，其中每种添加剂的浓度包括1、20、100、400和1000ppm。将上述组合物粉末分别平铺于表面皿中，并放置于恒温光照箱(2750Lux，18.5℃)中照射，记录其完全变质(即出现不溶于甲醇的凝胶)所需的时间，结果如图2所示(注：如不加任何添加剂，单纯8ARM(TP)-PEG-MAL-40K在照射两天后即完全变质)。
由图2可知，酚类阻聚剂如对苯二酚、叔丁基对苯酚的效果优于其他种类的阻聚剂的效果，且对苯二酚与UV-P的混合阻聚的效果与对苯二酚单独使用得阻聚效果相当。
实施例3
分别取含不同浓度的对苯二酚、DPPH、乙酸镍、氯化铜与8ARM(TP)-PEG-MAL-20K(250mg)的组合物粉末，其中每种阻聚剂的浓度包括1、20、100、400、1000ppm。将上述组合物粉末分别平铺于表面皿中，并放置于恒温光照箱(2750Lux，18.5℃)中照射，记录其完全变质(即出现不溶于甲醇的凝胶)所需的时间，结果如图3所示(注：如不加任何阻聚剂，单纯 8ARM(TP)-PEG-MAL-20K即在照射两天后完全变质)。
实施例4
分别取含不同浓度的对苯二酚、DPPH、乙酸镍、氯化铜与8ARM(TP)-PEG-MAL-10K(250mg)的组合物粉末，其中每种阻聚剂的浓度包括1、20、100、400、1000ppm。将上述组合物粉末分别平铺于表面皿中，并放置于恒温光照箱(2750Lux，18.5℃)中照射，记录其完全变质(即出现不溶于甲醇的凝胶)所需的时间，结果如图4所示(注：如不加任何阻聚剂，单纯8ARM(TP)-PEG-MAL-10K在照射一天后即完全变质)。
由实施例2-4可知，上述阻聚剂特别是对苯二酚对不同分子量的聚乙二醇马来酰亚胺衍生物都有较好的稳定效果。
本发明实施例中所用的8ARM(TP)-PEG-MAL，具有如下结构：
Figure PCTCN2018077231-appb-000031
其他构型和分子量的聚乙二醇的马来酰亚胺衍生物与本发明实施例中的阻聚剂组合也可取得很好的增强聚乙二醇的马来酰亚胺衍生物的稳定性、延长其产品适用期和储存期的效果，在此不一一罗列实验数据。
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。

Claims (16)

  1. 一种聚乙二醇马来酰亚胺衍生物和阻聚剂的组合物，所述的组合物中，所述阻聚剂与聚乙二醇马来酰亚胺衍生物的质量比例≥0.1μg：1g，所述的聚乙二醇马来酰亚胺衍生物中含有至少一个马来酰亚胺端基。
  2. 如权利要求1所述的组合物，其特征在于，所述的阻聚剂选自：自由基阻聚剂、酚类阻聚剂、无机化合物阻聚剂和有机金属化合物阻聚剂中的一种或多种的组合。
  3. 如权利要求1所述的组合物，其特征在于，所述阻聚剂与聚乙二醇马来酰亚胺衍生物的质量比例为0.1μg-10mg：1g。
  4. 如权利要求1-3任一项所述的组合物，其特征在于，所述聚乙二醇马来酰亚胺衍生物具有如下结构：
    PEG-X-MAL
    (Ⅰ)
    其中，PEG为聚乙二醇残基，
    X为PEG与MAL的连接基团，选自：-(CH 2) r-、
    Figure PCTCN2018077231-appb-100001
    -(CH 2) rO-、-(CH 2) rCO-、-(CH 2) rNH-、-(CH 2) rCONH-、-(CH 2) rNHCO-、-(CH 2) rS-、-(CH 2) rCOO-和-(CH 2) rOCO-中一种或多种的组合，r为0-10的整数，
    MAL为马来酰亚胺基
    Figure PCTCN2018077231-appb-100002
    R 1和R 2独立地选自：-H、C1-6的烷基、C1-6的烷氧基、C3-6环烷基和C4-10亚烷基环烷基。
  5. 如权利要求4所述的组合物，其特征在于，所述X选自：单键、-CH 2-、 -CH 2CH 2-、-CH 2CH 2CH 2-、-CH(CH 3)-、-CH 2CH(CH 3)-、-CH 2CH 2CH(CH 3)-、-(CH 2) rO-、-(CH 2) rCO-、-(CH 2) rNH-、-(CH 2) rCONH-和-(CH 2) rNHCO-中一种或两种以上的组合；和/或，所述r为0-5的整数。
  6. 如权利要求4所述的组合物，其特征在于，所述PEG为直链聚乙二醇残基，具有通式Ⅱ或Ⅲ所示的结构：
    Figure PCTCN2018077231-appb-100003
    其中，p和q独立地选自1-2400的整数；或，
    所述PEG为Y型或U型聚乙二醇残基，具有通式IV或V所示的结构：
    Figure PCTCN2018077231-appb-100004
    其中，i和k独立地选自1-1200的整数；或，
    所述PEG为多分支聚乙二醇残基，具有通式Ⅴ所示的结构：
    Figure PCTCN2018077231-appb-100005
    其中，n是1-800的整数，
    l是0-7的整数，j是1-8的整数，
    R是多分支聚乙二醇的核心分子，R选自：季戊四醇、寡聚季戊四醇、甲基葡萄糖苷、蔗糖、二甘醇、丙二醇、甘油和聚甘油的残基；
    Y为端基，选自：C1-C6的烷氧基、羟基、羧基、琥珀酰亚胺碳酸酯基、琥珀酰亚胺乙酸酯基、琥珀酰亚胺丙酸酯基、琥珀酰亚胺琥珀酸酯基、琥珀酰亚胺基、二硫吡啶基、丙酸基、醛基、巯酯基、丙烯酸基、丙烯酸基、叠氮基、戊二酸基、炔基、对硝基苯碳酸酯基、硅烷基和羧甲基中的一种。
  7. 如权利要求6所述的组合物，其特征在于，所述的聚乙二醇马来酰亚胺衍生物具有如下结构：
    Figure PCTCN2018077231-appb-100006
    优选地，所述j＝8，所述PEG为八臂聚乙二醇残基。
  8. 如权利要求7所述的组合物，其特征在于，所述的R具有式IX或X所示的结构：
    Figure PCTCN2018077231-appb-100007
    Figure PCTCN2018077231-appb-100008
  9. 如权利要求6-8任一项所述的组合物，其特征在于，所述的PEG的分子量为1-80KDa。
  10. 如权利要求1-9任一项所述的组合物，其特征在于，所述的自由基阻聚剂选自：1,1-二苯基-2-三硝基苯肼、4,4’-二甲氧基二苯基氮氧化物、4,4’-二硝基二苯基氮氧化物、二叔丁基氮氧化物、2,2,6,6-四甲基-4-羟基哌啶氮氧化物和过氧化苯甲酰中的一种或多种；和/或，
    所述的酚类阻聚剂选自：对苯二酚、甲基对苯二酚、对叔丁基邻苯二酚、2-叔丁基对苯二酚、对羟基苯甲醚、2,5-二叔丁基对苯二酚、2,6-二叔丁基-4-甲基苯酚、4,4′-二羟基联苯、邻苯三酚和双酚A中的一种或多种；和/或，
    所述的无机化合物阻聚剂选自：氯化铁、氯化亚铜、氯化铜、硫酸铜、三氯化钛、氯化钛、硫酸钠、硫化钠和硫氰酸铵中的一种或多种；和/或，
    所述的有机金属化合物阻聚剂选自：环烷酸铜、乙酸铬、乙酸镍、二甲基二硫代甲酸铜和二特丁基二硫代甲酸铜中的一种或多种。
  11. 如权利要求1-9任一项所述的组合物，其特征在于，所述的自由基阻聚剂为1,1-二苯基-2-三硝基苯肼；和/或，
    所述的酚类阻聚剂为对苯二酚或叔丁基对苯酚；和/或，
    所述的无机化合物阻聚剂为氯化铜；和/或，
    所述的有机金属化合物阻聚剂为乙酸镍。
  12. 如权利要求1-9任一项所述的组合物，其特征在于，所述的阻聚剂 为酚类阻聚剂，优选自：对苯二酚、甲基对苯二酚、对叔丁基邻苯二酚、2-叔丁基对苯二酚、对羟基苯甲醚、2,5-二叔丁基对苯二酚、2,6-二叔丁基-4-甲基苯酚、4,4′-二羟基联苯、邻苯三酚和双酚A中的一种或多种，更优选为对苯二酚或叔丁基对苯酚。
  13. 一种如权利要求1-12任一项所述的组合物在制备药物结合物中的应用；优选地，所述的药物选自：氨基酸、多肽、蛋白质、糖类、有机酸、生物碱、黄酮类、醌类、萜类、苯丙素酚类、甾体和甙类药物；更优选为多肽或蛋白类药物；进一步优选地，所述的多肽或蛋白类药物中含有游离巯基；和/或，所述的多肽或蛋白类药物中在特定位点引入巯基。
  14. 一种权利要求13所述的应用制备的药物结合物。
  15. 一种药物组合物，其包括阻聚剂和聚乙二醇马来酰亚胺衍生物与药物的结合物；
    优选地，所述的药物选自：氨基酸、多肽、蛋白质、糖类、有机酸、生物碱、黄酮类、醌类、萜类、苯丙素酚类、甾体和甙类药物；更优选为多肽或蛋白类药物；进一步优选地，所述的多肽或蛋白类药物中含有游离巯基；和/或，所述的多肽或蛋白类药物中在特定位点引入巯基；
    优选地，所述的阻聚剂为酚类阻聚剂，更优选自：对苯二酚、叔丁基对苯酚、甲基对苯二酚、对叔丁基邻苯二酚、2-叔丁基对苯二酚、2,5-二叔丁基对苯二酚、对羟基苯甲醚、2,6-二叔丁基-4-甲基苯酚、4,4′-二羟基联苯、邻苯三酚和双酚A中的一种或多种，最优选为对苯二酚和/或叔丁基对苯酚。
  16. 一种阻聚剂在制备权利要求1-12任一项所述的组合物、权利要求14所述的药物结合物或权利要求15所述的药物组合物中的应用；
    优选地，所述的阻聚剂为酚类阻聚剂，更优选自：对苯二酚、叔丁基对苯酚、甲基对苯二酚、对叔丁基邻苯二酚、2-叔丁基对苯二酚、2,5-二叔丁基对苯二酚、对羟基苯甲醚、2,6-二叔丁基-4-甲基苯酚、4,4′-二羟基联苯、邻苯三酚和双酚A中的一种或多种，最优选为对苯二酚和/或叔丁基对苯酚。
PCT/CN2018/077231 2017-03-31 2018-02-26 一种聚乙二醇马来酰亚胺衍生物和阻聚剂的组合物 WO2018177056A1 (zh)

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