CN106267227A - Antitumor drug - Google Patents

Antitumor drug Download PDF

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Publication number
CN106267227A
CN106267227A CN201610664162.4A CN201610664162A CN106267227A CN 106267227 A CN106267227 A CN 106267227A CN 201610664162 A CN201610664162 A CN 201610664162A CN 106267227 A CN106267227 A CN 106267227A
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poly
acid
conjugate
poly conjugate
active medicine
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Inventor
温光辉
宛六
宛六一
王浩军
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BEIJING LABWORLD BIO-MEDICINE TECHNOLOGY Co Ltd
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BEIJING LABWORLD BIO-MEDICINE TECHNOLOGY Co Ltd
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Priority to CN201610664162.4A priority Critical patent/CN106267227A/en
Publication of CN106267227A publication Critical patent/CN106267227A/en
Priority to PCT/CN2017/096548 priority patent/WO2018028589A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/48—Polymers modified by chemical after-treatment
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G81/00—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers

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  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Polymers & Plastics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

The present invention relates to antitumor drug, it has below formula R: wherein: R is the side chain of hydrogen or natural amino acid；N is the integer of 2～100；PA is amino acid polymer, and the aminoacid forming this amino acid polymer is aspartic acid, or the aminoacid forming this polyamino acid polymers is aspartic acid and glutamic acid combination.Antitumor drug of the present invention has excellent effect as used in the description.

Description

Antitumor drug
Technical field
The present invention relates to medical antitumor drug, particularly to SN-38 SN38 and aggretion type macromole The poly conjugate (polyconjunctions) that peptides is combined chemically to form.
Background technology
Irinotecan (irinotecan), the most often uses its hydrochlorate (trihydrate), is used for into metastatic human big One line medication of intestinal cancer treatment, for the patient failed through the chemotherapy containing 5-Fu, this product can be as second line treatment medication.Meanwhile, she The vertical various clinical test well afoot being applied to gastric cancer, the esophageal carcinoma, extensive phase small cell lung cancer for health.
The English language Chemical of DQ-2805 is entitled: (S)-4,11-diethyl-3,4,12,14- tetrahydro-4-hydroxy-3,14-dioxo1H-pyrano[3',4':6,7]-indolizino[1,2-b] Quinolin-9-yl-[Isosorbide-5-Nitrae ' bipiperidine]-1'-carboxylate, monohydrochloride, trihydrate, Its chemical formula is: C33H38N4O6·HCl·3H2O, molecular weight is: 677.19, and its chemical structural formula is:
Irinotecan, in vivo through metabolism, forms its active metabolite SN38, and CAS registration number is 86639-52-3, the chemical structural formula of this active metabolite generally also known as SN38, SN38 is:
People once attempted directly as active therapeutic agent, SN38 is applied to the tumor disease that human body is correlated with treatment, but In view of the poorly water-soluble of SN38, it is extremely difficult when drug administration by injection.Therefore SN38 makes its soluble derivative seem It it is a kind of effective scheme.Such as, CN1429121A (Chinese Patent Application No. 01809441.4) and CN101507820A (China Number of patent application 200910127655.4) disclose camptothecine or its analog such as SN38 and polyglutamic acid formation conjugate.
But, as Puja Sapra etc., (Puja Sapra, etc., Novel Delivery of SN38Markedly Inhibits Tumor Growth in Xenografts,Including a Camptothecin-11-Refractory MSN38el, Clin Cancer Res2008；14 (6) March 15,2008:1888) in mention, there is biologic activity The SN38 of lactone type has the possibility in its E ring open loop, forms the inert matter of carboxylic acid type, it may be assumed that
Showing the hydroxyl of on its E ring 20 in above SN38 structure, it can be described as 20-hydroxyl in this article.
Above-mentioned open loop forms carboxylic acid type to be needed to do one's utmost to avoid.Unfortunately, prior art in the face of on When stating problem, its solution is unsatisfactory.
Therefore, those skilled in the art still expect a kind of method having new treatment tumor, such as, expect have Yi Li to replace Health active metabolite SN38 is applied to the new method of clinic；And expect this method, including the therapeutic agent provided by the method The advantage with one or more aspect.
Summary of the invention
It is an object of the invention to provide a kind of method treating tumor, such as, expect to provide a kind of with irinotecan activity Metabolite SN38 is that active substance is to the method treating above-mentioned disease；And expect this method, including provided by the method The advantage that therapeutic agent has one or more aspect.In the present invention, it has been unexpectedly discovered that pass through aggretion type macromole The SN38 poly conjugate formed with SN38 chemical combination shows at least one complete beat all character.The present invention finds based on this And be accomplished.
To this end, first aspect present invention provides the poly conjugate of a kind of hyoscine, it includes active medicine and divides greatly Sub-polymer, described active medicine and described macromolecule polyalcohol pass through chemical bonds.
The poly conjugate of any embodiment according to a first aspect of the present invention, wherein said active medicine is SN38, i.e. SN38, or
The poly conjugate of any embodiment according to a first aspect of the present invention, wherein said macromolecule polyalcohol is amino Acid polymer.
The poly conjugate of any embodiment according to a first aspect of the present invention, wherein the 20-hydroxyl of SN38 is via one Aminoacid is connected with described macromolecule polyalcohol.This aminoacid the most also referred to as bridges aminoacid.
The poly conjugate of any embodiment according to a first aspect of the present invention, wherein the 20-hydroxyl of SN38 is via one Aminoacid is connected with described macromolecule polyalcohol, and a described amino acid whose carboxyl forms ester bond, amino with the 20-hydroxyl of SN38 One amino of acid is connected with macromolecule polyalcohol.
The poly conjugate of any embodiment according to a first aspect of the present invention, wherein the 20-hydroxyl of SN38 is via one Aminoacid is connected with described macromolecule polyalcohol, and a described amino acid whose carboxyl forms ester bond, amino with the 20-hydroxyl of SN38 One amino of acid forms amido link with the carboxyl on macromolecule polyalcohol.
The poly conjugate of any embodiment according to a first aspect of the present invention, on the most each macromolecule polyalcohol molecule In conjunction with one or more active drug molecules.
The poly conjugate of any embodiment according to a first aspect of the present invention, wherein said active medicine weight is that these are many The 3～60% of coalescence polymer weight, i.e. comprise 3～the active medicine of 60% and the macromole of surplus in this poly conjugate Polymer.Such as, described active medicine weight is the 10～50% of this poly conjugate weight, such as 10～40%, such as 10 ～35%.
The poly conjugate of any embodiment according to a first aspect of the present invention, wherein said macromolecule polyalcohol aminoacid Polymer.In one embodiment, formed the aminoacid of this amino acid polymer be aspartic acid or aspartic acid with Glutamic acid combination.
The poly conjugate of any embodiment according to a first aspect of the present invention, it has a below formula:
Wherein:
R is the side chain of hydrogen or natural amino acid；
N is the integer of 2～100；
PA is amino acid polymer, and the aminoacid forming this amino acid polymer is aspartic acid, or forms this poly-ammonia The aminoacid of base acid polymer is aspartic acid and glutamic acid combination.
The poly conjugate of any embodiment according to a first aspect of the present invention, wherein said R ' is hydrogen.
The poly conjugate of any embodiment according to a first aspect of the present invention, wherein said R ' is selected from following aminoacid Side chain: alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, serine, Soviet Union Propylhomoserin, cysteine, tyrosine, agedoite, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine.
The poly conjugate of any embodiment according to a first aspect of the present invention, wherein said n is the integer of 5～75.
The poly conjugate of any embodiment according to a first aspect of the present invention, wherein said n is the integer of 5～60.
The poly conjugate of any embodiment according to a first aspect of the present invention, wherein said n is the integer of 5～50.
The poly conjugate of any embodiment according to a first aspect of the present invention, wherein said n is an integer, and it is the fullest Foot active medicine weight is 3～the scope of 60% of this poly conjugate weight, and such as meeting active medicine weight is this poly The 10～50% of conjugate weight, such as 10～40%, such as 10～35%.
The poly conjugate of any embodiment, wherein forms the amino of described polyamino acid according to a first aspect of the present invention Acid includes its D type aminoacid, L-type aminoacid, DL mixed amino-acid.
The poly conjugate of any embodiment, wherein forms described polyamino acid polymers according to a first aspect of the present invention Aminoacid be aspartic acid and glutamic acid combination.At this in the case of combination, the mole percent of aspartic acid is big In 40%, it is greater than 50%, is greater than 60%, be greater than 70%.It has been unexpectedly discovered that form described poly-ammonia The aminoacid of base acid polymer uses aspartic acid, or uses aspartic acid and the combination of both glutamic acid and glutamic acid wherein Mole percent less than in the case of 60%, made poly conjugate has the stability of excellence, wherein The E ring of SN38 is stable, it is not easy to open loop and lose biologic activity.
The poly conjugate of any embodiment, the mean molecule of wherein said polyamino acid according to a first aspect of the present invention Amount is 5000～100000 dalton, such as 10000～80000 dalton, such as 10000～50000 dalton, such as 10000～40000 dalton.
The poly conjugate of any embodiment according to a first aspect of the present invention, wherein said active medicine weight is that these are many Coalescence polymer weight 3～60%, i.e. comprise in this poly conjugate 3～the active medicine of 60% and bridge joint aminoacid and The macromolecule polyalcohol of surplus.Such as, described active medicine weight is the 10～50% of this poly conjugate weight, such as 10～ 40%, such as 10～35%.
The poly conjugate of any embodiment according to a first aspect of the present invention, it can use water for injection, 0.9% chlorination Sodium injection, 5% glucose injection are as solvent for injection when being administered.
Further, second aspect present invention provides poly conjugate described in preparation any one of first aspect present invention Method, including following steps:
I) macromolecule polyalcohol is provided so that it is be dissolved in solvent to form solution；
Ii) in step i) gained solution, add active medicine and make it dissolve；
Iii) to step ii) gained solution adds catalyst and condensing agent, make macromolecule polyalcohol and active medicine enter Row condensation reaction, to form macromolecule polyalcohol and both active medicines poly conjugate by chemical bonds；
Iv) separation and Extraction gained poly conjugate.
Method according to a second aspect of the present invention, wherein described in step i), solvent is organic solvent, such as but not limited to Dimethylformamide, dimethyl sulfoxide etc..
Method according to a second aspect of the present invention, wherein step iii) described in catalyst be 4-(dimethylamino) pyridine (it can be abbreviated as DMAP).Its consumption can be generally 0.01～4 times of active medicine mole, such as 0.5～2 times, such as 0.8～1.5 times, such as 1.0～1.2 times.
Method according to a second aspect of the present invention, wherein step iii) described in condensing agent be dicyclohexylcarbodiimide (Dicyclohexylcarbodiimide, it can be abbreviated as DCC).Its consumption can be generally the 0.5 of active medicine mole ～4 times, such as 0.8～1.5 times, such as 1.0～1.2 times.
Method according to a second aspect of the present invention, wherein step iv) described in separation and Extraction by dialysis or ultrafiltration Method is carried out, and the method can easily remove unconjugated free active medicine.This dialysis or ultra-filtration and separation are extracted Method is to well known to a person skilled in the art.
In the methods of the invention, condensing agent DCC and catalyst DMAP reaction condition is used can to make carboxylic acid type polyamino acid The free carboxy of such as poly-aspartic-acid and the amino condensation in active pharmaceutical ingredients molecular structure, thus form active drug Thing SN38 and such polyamino acid are through the poly conjugate of chemical bonds.Well known by persons skilled in the art can make the present invention Active medicine also can be used for the present invention with described macromolecule polyalcohol by other method of chemical bonds.
Have been found that by the inventive method, at least give poly conjugate of the present invention have than live accordingly in it The deliquescent advantage that property medicine is significantly higher in terms of dissolubility.Such as, the inventive method is passed through so that gained of the present invention The dissolubility of SN38 poly conjugate (being converted to SN38 meter) ratio have significantly higher dissolubility in the former medical instrument of SN38.
Further, third aspect present invention provides a kind of pharmaceutical composition, wherein comprises first aspect present invention and appoints Poly conjugate described in one embodiment, and optional pharmaceutically acceptable adjuvant.
Pharmaceutical composition according to a third aspect of the present invention, it can be arbitrary pharmaceutical dosage forms in pharmaceuticals industry, Such as but not limited to, oral formulations such as tablet, capsule, granule, oral solution, oral mixed suspension liquor etc., injection system Agent such as injection with small volume, high-capacity injection, aseptic powdery preparation (such as lyophilization injectable powder etc.), suck preparation example As through nasal inhalation preparation (such as suction powder agent or suction solution) etc..
The concrete dosage form that this pharmaceutical composition presents is depended in the selection of described adjuvant.Such as, when this drug regimen When thing is tablet, capsule, granule etc., wherein can optionally include diluent (such as starch, lactose, microcrystalline Cellulose Deng), disintegrating agent (such as sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose etc.), binding agent (such as Hydroxypropyl methyl cellulose, polyvinylpyrrolidone, Polyethylene Glycol etc.), lubricant or fluidizer (such as magnesium stearate, Talcum Powder, stearic acid, silica sol etc.).Can also optionally include correctives, coloring agent, coating materials etc..
The most such as, when this pharmaceutical composition is oral solution, oral mixed suspension liquor etc., solvent example can wherein be comprised Such as the Polyethylene Glycol etc. that water, ethanol, glycerol, propylene glycol, molecular weight are 200～600.Can also optionally include correctives, Toner etc..
The most such as, when this pharmaceutical composition is injection with small volume, high-capacity injection etc., wherein can comprise solvent Such as water, ethanol, glycerol, propylene glycol, molecular weight are the Polyethylene Glycol etc. of 200～600, it is also possible to optionally comprise osmotic pressure and adjust Joint agent such as sodium chloride, glucose etc..
The most such as, when this pharmaceutical composition is aseptic powdery preparation etc., wherein can comprise excipients such as mannitol, Glucose, dextran, sodium chloride, sucrose, lactose etc..
These are the formula of pharmaceutical composition of the present invention of pharmaceutical dosage forms and preparation method can pass through people in the art The known method of member and experience realize.Such as tablet, wet granule compression tablet, dry granulation tabletting, powder can be passed through straight Connect the methods such as tabletting to prepare.The most such as lyophilization injectable powder, appropriate mannitol can be added according to formulation requirements and use Water for injection dissolves, the most freeze-dried and obtain.
The pharmaceutical composition of any embodiment according to a third aspect of the present invention, it is medicinal composition for injections, and It can use water for injection, 0.9% sodium chloride injection, 5% glucose injection as solvent for injection when being administered.
Further, fourth aspect present invention provides treatment tumor or the method for cancer, and the method includes to there is a need to The poly conjugate of first aspect present invention any embodiment of administration effective dose or third party of the present invention The step of the pharmaceutical composition of face any embodiment.
Method according to a fourth aspect of the present invention, wherein said tumor or cancer are colorectal cancer.In one embodiment, Described colorectal cancer is advanced CRC.In one embodiment, described poly conjugate is used for and 5-fluorouracil and Ya Ye Acid therapeutic alliance does not previously accept the late stage colorectal cancer patients of chemotherapy；Or, described poly conjugate is used for as single drug, Treatment is through the patient containing 5-fluorouracil chemotherapy regimen Endodontic failure.
Any embodiment of the either side of the present invention, can be combined with other embodiment, as long as they are not There will be contradiction.Additionally, in any embodiment of either side of the present invention, it is real that arbitrary technical characteristic goes for other Execute this technical characteristic in scheme, as long as they do not have contradiction.
Arbitrary technical characteristic that any embodiment of either side of the present invention or this either side is had is equally applicable Other any embodiment or any embodiment of other either side, as long as they will not be conflicting, certainly mutually Between where applicable, if necessary can make individual features suitably to modify.Make into one with feature the most to various aspects of the present invention The description of step.
All documents recited in the present invention, their full content is incorporated herein by, and if these literary compositions Offer expressed implication and the present invention inconsistent time, be as the criterion with the statement of the present invention.Additionally, the present invention use various terms and Phrase has and well known to a person skilled in the art general sense, nonetheless, the present invention remain desirable at this these terms and Phrase is described in more detail and explains, the term mentioned and phrase are if any inconsistent with common art-recognized meanings, with institute of the present invention table The implication stated is as the criterion.
Gained poly conjugate of the present invention has the character of excellence, such as, have the chemical stability of excellence and excellent life Thing effect.Such as, in test example 1 of the present invention, the whole samples to preparation example 1-preparation example 14 carry out study on the stability, knot Fruit display: the whole macromolecule polyalcohol of preparation example 1-preparation example 10 gained-bridge joint aminoacid-SN38 poly conjugate, its August hundred Point content is all in the range of 96.8～98.5%, and during August, E ring open loop catabolite increases percent all 23.2～38.6% model In enclosing, display has excellent chemical stability；Preparation example 11 gained whole poly conjugate, its, percentage composition all existed in August In the range of 89.2～92.6%, during August, E ring open loop catabolite increase percent is all in the range of 142.2～176.5%, table These poly conjugate main constituent content bright reduces fast, and catabolite increase is the most；Preparation example 12-preparation example 14 gained is the most Coalescence compound, its, percentage composition was all in the range of 93.1～94.3% in August, and during August, to increase percent equal for E ring open loop catabolite In the range of 237.1～282.7%, show that these poly conjugate main constituent content have reduction, and catabolite increases non- Chang Duo.The most such as, the result of test example 2 of the present invention shows: preparation example 1～10 gained whole poly conjugate is relative to free The percent of SN38 dosage is all in the range of 68～77%, and preparation example 11～14 gained whole poly conjugate is relative to free The percent of SN38 dosage is all in the range of 84～96%, and such as preparation example 11 gained whole poly conjugate is relative to free The percent of SN38 dosage is all in the range of 93～96%.
In the present invention, term " poly conjugate " or also referred to as " conjugate ", " polymer " etc., refer to oneization Learn material, including active medicine and macromolecule polyalcohol two parts, described active drug moiety and described macromolecular polymeric Thing part passes through chemical bonds, such as, combined by ester bond or amido link, and therefore, poly conjugate of the present invention is essentially Also it is a kind of compound, i.e. poly conjugate of the present invention is also referred to as compound.Term " poly " has those skilled in the art Known to implication, such as it can be regarded as polymer, polymer, polymer substance, macromolecular compound, aggretion type macromole Deng.
For polyamino acid, described aminoacid can be selected from: carboxylic acid type aminoacid, amino-type aminoacid or its group Close, such that it is able to form the polyamino acid such as carboxylic acid type polyamino acid or amino-type polyamino acid.Carboxylic acid type aminoacid is selected from: sky Aspartic Acid (Asp), glutamic acid (Glu) or they are with the combination of arbitrary ratio；Amino-type aminoacid can be selected from: ornithine (Orn), lysine (Lys), arginine (Arg), hydroxylysine (Hyl) or they are with the combination of arbitrary ratio.These aminoacid Their D type, L-type, DL mixed type can be included.The preparation method of polyamino acid is to well known to a person skilled in the art, such as (the Journal of Environmental such as US5610264 discloses the synthetic method of poly-aspartic-acid, S.Roweton Polymer Degradation, Vol.5, No.3,1997:175) also disclose the synthetic method of a kind of poly-aspartic-acid.Class As, other polyamino acid also has many documents to disclose their synthetic method, and by controlling these synthetic methods Condition, it can be advantageous to obtain the polyamino acid with the desired degree of polymerization, i.e. can advantageously obtain and there is desired molecular weight Or the polyamino acid of molecular weight ranges.Furthermore it is also possible to use the pharmaceutically acceptable salt such as sodium salt (example of these polyamino acid Such as poly-aspartic-acid), hydrochlorate (such as poly ornithine) etc..Additionally, these polyamino acid are also commercially available, such as may be used Easily to buy the poly-amino with the desired degree of polymerization or molecular weight or molecular weight ranges from Sigma-Aldrich company Acid, such as, can buy molecular weight that product article No. is P6762 15000～50000 dalton from Sigma-Aldrich company Poly-ASPARTIC ACID.In the present invention, if not otherwise indicated, polyamino acid used is buied from market.
The SN38 that the present invention uses, can buy the most from the market, such as, can purchase from Sigma-Aldrich company , can also buy from Hubei Yuancheng Pharmaceutical Co., Ltd..The most if not otherwise specified, SN38 used is purchased from the latter.
In one embodiment of the invention, instant invention overcomes SN38, the aggretion type macromole that research design is novel The poly SN38 poly conjugate formed with camptothecin material such as SN38 chemical combination.
In an embodiment of poly conjugate of the present invention, can be in conjunction with multiple on an aggretion type macromole SN38。
SN38 has the biologic activity similar with irinotecan.Irinotecan is the derivant of semi-synthetic camptothecine, is The antineoplastic agent of energy specificity suppression DNA topoisomerase I.It is SN-38 by carboxylesterase metabolism in great majority tissue, and The specific activity irinotecan that the latter acts on the topoisomerase I of purification is higher, and thin to several Mus and human tumor cell line Cellular toxicity is also better than irinotecan.SN-38 or irinotecan can induce single stranded DNA to damage, thus blocking dna replication fork, thus Produce cytotoxicity.This cytotoxicity is time dependence, and specific effect is in the S phase.
In vitro in experiment, do not find that irinotecan and SN-38 effectively can be known by P-glycoprotein [sup] MDR [/sup] Not, and demonstrate that the cell line to CAVe drug resistance still has cytotoxicity.
It addition, in testing in vivo, irinotecan shows the anti-tumor activity of wide spectrum (P03 pancreas conduit to Mus tumor model Adenocarcinoma, MA-16/C breast carcinoma, C38 and C51 adenocarcinoma of colon) and have anti-human xenograft tumours activity (Co-4 adenocarcinoma of colon, MX-1 breast carcinoma, St-15 and SC-6 adenocarcinoma of stomach), the irinotecan tumor (Changchun to express P-glycoprotein [sup] MDR [/sup] New alkali and the P388 leukemia of Adriamycin resistant) also there is anti-tumor activity.
This product is in addition to having anti-tumor activity, and maximally related pharmacotoxicological effect is acetylcholine esterase inhibition.
After using this medicine, the intensity (such as leukopenia and diarrhoea) of main side effects and parent drug and its metabolism The area under curve of product SN-38 is correlated with.In single therapy, (leukocyte and neutrophilic granulocyte drop to haematics toxicity Low spot) or degree and irinotecan and the area under curve value significant correlation of its metabolite SN-38 of diarrhoea.Irinotecan and The pharmacokinetic properties of SN-38 (its active metabolite) is studied in I clinical trial phase, and 60 example patients receive The Drug therapy of recommended dose scheme, i.e. 30 minutes intravenous drip this product 100-750mg/m2.The kinetics right and wrong of irinotecan Dose dependent.The patient registered in clinical studies accepts different irinotecan dosage regimen, and its pharmacokinetics is homogeneous Seemingly.Its blood plasma evanescent mode be two Room and three Room.In three-compartment model, mean plasma half-life is 12 in the first stage Minute, second stage is 2.5 hours, and terminal stage is 14.2 hours.Using recommended dose 350mg/m2At the end of quiet, she Standing and reach peak serum concentration for health and SN-38, respectively 7.7ug/mL, 56ug/mL, its area under curve is respectively 34ug/h/ ML, 451ug/h/mL, its Vdss is very big, and keeps relative stability, for the function of dosage, average out to 157L/m2.Machine Body total body clearance meansigma methods is 15L/h/m2, and stable in the different treatment cycle holding of same patient.SN-38 is in Different Individual Its drug metabolism Parameters variation is the biggest.The 24 hourly average homaluria rates of irinotecan and SN-38 are respectively using dosage 19.9% and 0.25%.II phase clinical research test about irinotecan pharmacokinetics is carried out in 72 example tumor patients. The parameter that the pharmacokinetic parameter that limited samples model calculates and I phase are studied is sufficiently close to.In experiment in vitro, irinotecan It is respectively 65% and 95% with the plasma protein binding rate of SN-38.When the bilirubin of patient is 1.5-3 times of Upper Limit of Normal Value Time, irinotecan clearance rate reduces about 40%.Irinotecan 200mg/m is given in these patients2Time, its plasma drug level Irinotecan 350mg/m is given with the cancer patient of normal hepatocytes function2Shi Xiangtong.Share with 5-fluorouracil/folinic acid, do not change Become the pharmacokinetic properties of irinotecan.
In one embodiment of the invention, the poly conjugate of the present invention is by carboxylic acid type polyamino acid and SN38ization Close and obtain.Such as, it is to be formed ester with 20-hydroxyl on SN38 molecule through bridge joint amino acid compound by carboxylic acid on polyamino acid molecule Bonded composition.Such as, as a example by poly-aspartic-acid passes through the poly conjugate of Formation of glycine with SN38, a kind of exemplary Chemical bonding pattern be:
In formula, PA represents that poly-aspartic-acid, R ' are hydrogen (i.e. bridge joint aminoacid are glycine), according to ingredient proportion and control Reaction condition processed can easily adjust size or the scope of n.
Wherein the amino of SN38 intermediate can with DCC as condensing agent chemical condensation react in poly-aspartic-acid Carboxyl reaction, two intermolecular slough H2O molecule forms amido link (-CON-), multiple free on poly-aspartic-acid peptide chain Carboxyl can be bonded desired amount according to the actual conditions (such as inventory, reaction temperature, response time etc.) of condensation reaction SN38 intermediate, such as in the poly conjugate being made up of polyamino acid and SN38 intermediate two branch obtained, in SN38 The weight of mesosome can account for this poly conjugate weight 3～60% (such as 10～50%, such as 10～40%, such as 10～ 35%), gained poly conjugate and alkali substance reaction then can be made to form pharmaceutically acceptable salt, such as, form sodium salt. The most confirmed by ultraviolet method and HPLC method with chemical bonding rather than physical bond (such as hydrogen bond) shape in the present invention The poly conjugate become.The representative instance of above-mentioned carboxylic acid type polyamino acid includes but not limited to D-ASP (Aspartic Acid, Asp), ASPARTIC ACID, DL-aspartic acid, and combinations thereof aspartic acid and any structure of such as arbitrary configuration The carboxylic acid type polyamino acid that the glutamic acid of type is such as polymerized with 0-99% mixed proportion with arbitrary proportion.
In one embodiment of the invention, the poly conjugate of the present invention is by carboxyl type polyamino acid and SN38ization Close and obtain.Such as, it is to be existed with 20-hydroxyl on SN38 molecule by bridge joint aminoacid by the free carboxy on polyamino acid molecule Formed under the effect of reaction reagent.
In the method preparing material of the present invention, the various raw materials used by reaction are that those skilled in the art are according to existing Knowledge can prepare, or can be by what method known to document prepared, or can be by commercially available 's.Intermediate used in reaction scheme of the present invention, raw material, reagent, reaction condition etc. all can be according to people in the art The existing knowledge of member can be made suitably to change.
Poly conjugate of the present invention can use with other active ingredient combinations, as long as it does not produce other detrimental effects, The most do not produce anaphylaxis.
Poly conjugate of the present invention can be as unique drug use, or can be with one or more other physiologically actives Material upper and of the present invention has the collaborative and/or Drug combination of potentiation.Therapeutic alliance can be by by each treatment group Point simultaneously, order or separate administration and realize.
Term used herein " pharmaceutical composition " means to include comprising each product specifying composition of specified amount, Yi Jizhi Any product connect or indirectly produce from each combination specifying composition of specified amount.In the present invention, term " pharmaceutical composition " Can exchange with " compositions " and use.
The actual dose level of each active component in pharmaceutical composition of the present invention can be changed, in order to the active matter quality of gained Effectively can obtain required therapeutic response for concrete patient, compound and administering mode.Dosage level must be according to concrete activity The activity of material, route of administration, the order of severity of the treated patient's condition and the patient's condition of patient to be treated and medical history are selected. But, the way of this area is, the dosage of active substance from less than obtain required therapeutic effect and from the beginning of the level that requires, by Cumulative add dosage, until obtaining required effect.
When for the invention described above treatment and/or prevention or other treatment and/or prevention, treat and/or prevent effectively The poly conjugate a kind of of the present invention of amount can be applied in a pure form.Or, described poly conjugate can be with containing this purpose Poly conjugate and one or more medicines can accept the pharmaceutical composition of excipient and are administered.Word " is treated and/or prevents effectively Amount " poly conjugate of the present invention refer to be applicable to reasonable effect/Hazard ratio treatment obstacle of any therapeutic treatment and/or prevention The poly conjugate of q.s.It is to be understood that total consumption per day of poly conjugate of the present invention and pharmaceutical composition must be by leading Examine doctor to make decision in the range of reliable medical judgment.For any concrete patient, concrete treatment effective dose water Flat must be according to many factors depending on, described factor includes the order of severity of treated obstacle and this obstacle；Used is concrete The activity of poly conjugate；The concrete pharmaceutical composition used；The age of patient, body weight, general health, sex and drink Food；The administration time of concrete pharmaceutical composition, route of administration and the excretion rate used；The treatment persistent period；With used The other medicines that pharmaceutical composition is applied in combination or uses simultaneously；And similar factor known to medical field.Such as, this area Way is, the dosage of pharmaceutical composition, from the beginning of the level required less than obtaining required therapeutic effect, is gradually increased dosage, Until obtaining required effect.It is, in general, that poly conjugate of the present invention is used for the dosage of mammal particularly people with described The gauge of camptothecine compounds SN38 can between 0.0001～1000mg/kg body weight/day, such as between 0.001～ 500mg/kg body weight/day, such as between 0.001～100mg/kg body weight/day.
Use pharmaceutical carrier familiar to the person skilled in the art to can be prepared as the poly of the present invention containing effective dose to combine The pharmaceutical composition of thing.Therefore the present invention also provides for comprising formulated together with one or more nontoxic drug acceptable carriers The pharmaceutical composition of poly conjugate of the present invention.Described pharmaceutical composition can become with solid or liquid form confession by particular formulation especially Oral administration, confession parental injection or confession rectally.
Described pharmaceutical composition can be configured to many dosage forms, it is simple to being administered, such as, oral formulations is (such as tablet, capsule Agent, solution or suspension)；Injectable preparation (such as injectable solution or suspension, or injectable dried powder, Add injection water before the injection can use immediately).In described pharmaceutical composition, carrier includes: the binding agent that oral formulations uses (such as starch, it is common that Semen Maydis, Semen Tritici aestivi or rice starch, gelatin, methylcellulose, sodium carboxymethyl cellulose and/or polyvinyl pyrrole Alkanone), diluent, lubricant (such as silicon dioxide, Talcum, stearic acid or its salt, it is common that magnesium stearate or calcium stearate, and/ Or Polyethylene Glycol), and if it is required, possibly together with disintegrating agent, such as starch, agar, alginic acid or its salt, it is common that sodium alginate, And/or effervescent mixture, cosolvent, stabilizer, suspending agent, coloring agent, correctives etc., the anticorrosion that injectable preparation uses Agent, solubilizing agent, stabilizer etc.；The substrate of topical formulations, diluent, lubricant etc..Pharmaceutical preparation can be with oral administration or gastrointestinal External square type (such as intravenous, subcutaneous, intraperitoneal or local) is administered, if some drugs is unstable under the conditions of stomach, Enteric coated tablets can be configured to.
More specifically, the pharmaceutical composition of the present invention can by oral, rectum, parenteral, pond, intravaginal, peritoneum In, locally (as by powder, ointment or drop), buccal give the mankind and other mammals, or as mouthspray Agent or nasal mist give.In terms used herein " parenteral " refers to include intravenous, intramuscular, intraperitoneal, breastbone, subcutaneous With intra-articular injection and the administering mode of transfusion.
Be suitable for the pharmaceutical composition of parental injection can include physiologically acceptable sterile, aqueous or non-aqueous liquor, Dispersant, suspensoid or Emulsion, and for reconstructing the sterile powders of sterile injectable solution agent or dispersant.The most aqueous or The example of nonaqueous carrier, diluent, solvent or vehicle include water, ethanol, polyhydric alcohol (propylene glycol, Polyethylene Glycol, glycerol etc.), Vegetable oil (such as olive oil), injectable organic ester such as ethyl oleate and their suitable mixture.
These pharmaceutical compositions also can contain adjuvant, such as preservative, wetting agent, emulsifying agent and dispersant.By various anti- Bacteriocin and antifungal, such as parabens, chlorobutanol, phenol, sorbic acid etc., it can be ensured that prevent the work of microorganism With.It is also expected to include isotonic agent, such as saccharide, sodium chloride etc..By using the material that can postpone to absorb, such as aluminum monostearate And gelatin, the prolongation that can reach injectable drug form absorbs.
Suspensoid the most also can contain suspending agent, such as ethoxylation i-octadecanol, polyoxyethylene mountain Pears alcohol and polyoxyethylene sorbitan esters, microcrystalline Cellulose, inclined aluminium hydroxide, bentonite, agar and Tragacanth or this The mixture etc. of a little materials.
In some cases, for extending the effect of medicine, it is desirable to slow down and subcutaneously or intramuscularly inject the absorption of medicine.This can lead to Cross and use the crystal of poorly water-soluble or the liquid suspension of amorphous substance to realize.So, the infiltration rate of medicine depends on Its dissolution velocity, and dissolution velocity can be depending on crystal size and crystal formation.Or, the delay of the medicament forms of parenteral Absorb by by this medicine dissolution in or be suspended in oil vehicle in realize.
Injectable depot formulations form can be by forming medicine in biodegradable polymer is such as polylactide-polyglycolide Prepared by the microcapsule matrix of thing.Can be according to the ratio of medicine and polymer and the character of the concrete polymer used, to medicine Rate of release is controlled by.The example of other biological degradable polymer includes poe class and polyanhydrides.Injectable reservoir Preparation also can be prepared in the liposome compatible with bodily tissue or microemulsion by pharmaceutical pack being embedded in.
Injectable formulation can be such as by filtering with bacteria filter or by mixing the biocide of aseptic solid composite form Carrying out sterilizing, described solid composite can be dissolved or dispersed in sterilized water or other sterile injectable medium before use.
The compounds of this invention or its pharmaceutical composition can be by oral method or parenteral administration modes.Oral administration is permissible Being tablet, capsule, coating materials, parenteral preparation has injection and suppository etc..These preparations are the skills according to this area Prepared by the method that art personnel are familiar with.It is conventional adjuvant to manufacture the adjuvant used by tablet, capsule, coating materials, Such as starch, gelatin, arabic gum, Silicon stone, Polyethylene Glycol, the solvent used by liquid dosage form such as water, ethanol, propylene glycol, plant Oil (such as Semen Maydis oil, Oleum Arachidis hypogaeae semen, olive oil etc.).Preparation containing the compounds of this invention also have other adjuvant, such as surface live Property agent, lubricant, disintegrating agent, preservative, correctives and pigment etc..In tablet, capsule, coating materials, injection and suppository Dosage containing poly conjugate of the present invention calculates with camptothecine compounds SN38 amount present in unit dosage form.At list In unit's dosage form, the general content of reactive compound of the present invention is 0.01-5000mg, and preferred unit dosage form contains 0.1-500mg, more Preferably unit dosage form contains 1-500mg.Specifically, the solid dosage forms for oral administration that the present invention can provide includes glue Wafer, tablet, pill, powder and granule.In this type of solid dosage forms, reactive compound can be with at least one inert medicine Acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or following material mix: a) filler or extender；B) viscous Mixture such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and Radix Acaciae senegalis；C) wetting agent is the sweetest Oil；D) disintegrating agent such as agar, calcium carbonate, Rhizoma Solani tuber osi or tapioca, alginic acid, some silicate and sodium carbonate；E) solution resistance Stagnant dose such as paraffin；F) accelerator such as quaternary ammonium compound is absorbed；G) wetting agent such as spermol and glyceryl monostearate；H) adsorbent Such as Kaolin and bentonite；And i) lubricant such as Pulvis Talci, calcium stearate, magnesium stearate, solid polyethylene glycol, dodecyl Sodium sulfate and their mixture.In the case of capsule, tablet and pill, described dosage form also can comprise buffer agent.
The solid composite of similar type uses excipients such as lactose and high molecular weight polyethylene glycol etc., it is possible to as soft Implant in capsule and hard capsule.
The solid dosage forms of tablet, dragee (dragees), capsule, pill and granule can with coating and shell material such as Prepare together with enteric coating material other clothing materials known with field of medicine preparations.These solid dosage formss can optionally contain opacifier, and Its composition also can make its simply or preferentially at certain position of intestinal optionally with delayed mode release of active ingredients.Can use The example of embedding composition include polymer substance and wax class.If be suitable for, active substance also can be above-mentioned with one or more Excipient is made into microencapsulated form.
Liquid dosage form for oral administration includes pharmaceutically acceptable Emulsion, solution, suspensoid, syrup and elixir. Liquid dosage form also can be containing inert diluent commonly used in the art in addition to containing active substance, such as water or other solvents, solubilising Agent and emulsifying agent such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-fourth two Alcohol, dimethylformamide, oils (particularly Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, Semen Maydis oil, germ oil, olive oil, Oleum Ricini and Semen Sesami Oil), glycerol, tetrahydrofurfuryl alcohol, Polyethylene Glycol and the fatty acid ester of sorbitan and their mixture.Orally administered composition removes Comprise and outside inert diluent, also can comprise adjuvant, such as wetting agent, emulsifying agent and suspending agent, sweeting agent, correctives and flavouring agent.
Compositions for rectum or vagina administration is preferably suppository.Suppository can by by poly conjugate of the present invention with suitable Non-irritating excipient or carrier such as cocoa butter, Polyethylene Glycol or suppository wax mixing prepare, they are at room temperature solid Body, but be the most then liquid, therefore can melt in rectal cavity or vaginal canal and discharge reactive compound.
Poly conjugate of the present invention and pharmaceutical composition thereof further contemplate for topical.For administering locally to poly of the present invention The dosage form of conjugate includes powder, spray, ointment and inhalant.Aseptically can by active substance and pharmacy The carrier accepted and any required preservative, buffer agent or propellants.Ophthalmic preparation, eye ointment, powder and solution Agent is contemplated within the scope of the present invention.
Poly conjugate of the present invention can also be administered by liposomal form.As it is known in the art, liposome generally uses phospholipid Or other lipid materials prepare.Liposome is formed by the single or multiple lift aquation liquid crystal being scattered in water-bearing media.Any energy Enough formed liposome nontoxic, physiologically acceptable and metabolizable lipid all can use.The chemical combination of the present invention of liposomal form Thing in addition to the compounds of the present invention, also can contain stabilizer, preservative, excipient etc..Preferably lipid is natural and synthesis Phospholipid and phosphatidylcholine (lecithin), they can use individually or together.The method forming liposome is that this area is public Know.See for example Prescott, Ed., MethSN38s in Cell Biology, Volume XIV, Academic Press,New York,N.Y.(1976),p.33。
Surprisingly, it was found that poly conjugate of the present invention biological and/or physically and/or chemically aspect demonstrate Challenging beneficial effect.
Accompanying drawing explanation
Fig. 1: use the test of pesticide effectiveness of human colon carcinoma HCT116 cell: with the rheological parameters' change with time of body weight after tail intravenously administrable.
Fig. 2: use human colon carcinoma HCT116 cell the test of pesticide effectiveness: with after tail intravenously administrable gross tumor volume through time-varying Change.
Detailed description of the invention
Example is prepared and test example further illustrates the present invention below by concrete, it should be understood, however, that, these examples Son is only used for specifically describing in more detail being used, and is not to be construed as limiting in any form the present invention.
The present invention to test used in material and test method carry out generality and/or concrete description.Though It is so to it is known in the art that still the present invention is still at this for realizing many materials that the object of the invention used and operational approach Describe in detail as far as possible.It will be apparent to those skilled in the art that hereinafter, if not specified, material therefor of the present invention and Operational approach is well known in the art.
A, the method for test poly conjugate
Method of testing 1: ultraviolet visible spectrophotometry
Ultraviolet-can is carried out for SN38, poly-aspartic-acid, poly-aspartic-acid three kinds of materials of-SN38 poly conjugate See that spectrophotometric scans, result show in the wave-length coverage of 250～400nm poly-aspartic-acid will not to poly conjugate or The absorbance of SN38 has contribution, and at this region poly-aspartic-acid-SN38 poly conjugate and both original shape medicine SN38 Typical absorption spike length coincide.These results indicate that three kinds of materials have unique spectrum row in spectrophotometric FAXIA For and spectral contribution so that by HPLC is legal and three kinds of materials of quantitative analysis are possibly realized.
It addition, the present inventor also finds in further test, for gathering that aspartic acid-glutamic acid combination obtains Aminoacid, for SN38, they are respectively provided with the ultraviolet similar with above-mentioned poly-aspartic-acid, SN38 and poly conjugate thereof-can Seeing spectrophotography spectral scan TuPu method, three class materials have unique spectrum behavior and light in spectrophotometric FAXIA Spectrum contribution so that and quantitative analysis three class material legal by HPLC is possibly realized.
Method of testing 2: high performance liquid chromatography (HPLC method)
Chromatographic column: Ai Jieer Venusil XBP C44.6*250mm, 5um, 300A
Guard column core: Féraud door C4
The Na2HPO4 aqueous solution of mobile phase A: 5mM, regulates pH7.0
Mobile phase B: acetonitrile
Column temperature: 40 DEG C
Flow velocity: 1ml/min
Detector: DAD (during mensuration SN38 and poly conjugate etc. thereof at 266nm wavelength)
Sample concentration: 1mg/ml
Sample size: 10ul
Condition of gradient elution:
According to above HPLC method, test following four kinds of materials and chromatographic behavior thereof: (A) SN38, (B) poly-aspartic-acid, (C) mixture of poly-aspartic-acid-SN38 poly conjugate, (D) poly conjugate and free SN38.
Result shows:
(A), in the high-efficient liquid phase chromatogram of SN38 (25 μ g/ml), at display SN38 about 18.3min, peak is gone out；
(B), in the high-efficient liquid phase chromatogram of poly-aspartic-acid (PA, 75 μ g/ml), at about 5.2min, little chromatograph is shown Peak, the reason that chromatographic peak is little is that PA absorbs weak at detection wavelength 254nm；
(C) (PA-SN38, preparation example 1 product, 100 μ g/ml, wherein comprise poly-aspartic-acid-SN38 poly conjugate SN38 concentration suitable with SN38 concentration in (A) SN38 sample solution above) high-efficient liquid phase chromatogram in, at about 18.3min Place goes out small chromatographic peak (free SN38 < 0.15%) to be detected, but shows a peak area and (A) figure at about 5.2min In suitable chromatographic peak.This shows, in this PA-SN38 poly conjugate, without free SN38, (area normalization method calculates substantially Obtaining its peak area percent and be less than 0.15%, i.e. dissociate SN38 < 0.15%), the inventive method can obtain highly purified PA- SN38 poly conjugate (purity in terms of SN38 is more than 99%)；And PA-SN38 synthesizes stable compound with chemical bonded refractory, Can not separate under chromatographic condition, and owing to the powerful polarity of polyamino acid makes the chromatograph of this PA-SN38 poly conjugate Retention behavior is close with PA, goes out peak at PA.It can in addition contain combine measurement result by this HPLC method to calculate this many coalescences The percentage composition of SN38 in compound, i.e. active medicine content, the active medicine content results of preparation example 1 is 23.1% (w/w)；
(D) poly-aspartic-acid-SN38 poly conjugate and physical mixture (PA-SN38,100 μ g/ of free SN38 ml；SN38,25 μ g/ml) high-efficient liquid phase chromatogram in, at about 18.4min, the SN38 being consistent with SN38 addition detected Chromatographic peak, and at about 5.2min, the PA-SN38 chromatographic peak being consistent with PA-SN38 addition detected.This shows, this PA- SN38 poly conjugate has independent chromatographic behavior with free both SN38, and the two does not interfere with each other.
(E) (C) poly-aspartic-acid-SN38 poly conjugate sample is placed 10 hours at 60 DEG C, measure simultaneously, knot Really show that the PA-SN38 peak detected at about 5.2min diminishes, and a chromatographic peak occurs at about 4.5min, use liquid- The detection of matter combined instrument shows that this peak is the E ring open loop catabolite of SN38 in poly conjugate.
Above HPLC method equally adopts in SN38 the most poly-with the poly conjugate that other macromolecule polyalcohol is formed (aspartic acid-glutamic acid) polymer, the most substantially need not make significantly change and can realize these many HPLC condition The qualitative and quantitative analysis of coalescence compound (the most about occurs that E ring open loop is degraded at main peak at 5.2min and about 4.5min Product all can have deviation accordingly, and this deviation causes mainly due to macromolecule polyalcohol used difference, can't be right Measurement result has an impact).
B, the preparation example part of poly conjugate
The chemosynthesis of preparation example 1, poly-aspartic-acid-glycine-SN38 poly conjugate
Use known method to obtain poly-DL-aspartic acid (20000Da), prepare as macromolecule polyalcohol Poly conjugate.Use glycine as bridge joint aminoacid.Schematically synthetic route is as follows:
(the many coalescences of poly-aspartic-acid-SN38 Compound)
Synthesis step: take poly-ASPARTIC ACID 800.0mg (molecular weight 28000Da), be dissolved in 5ml dimethylformamide In.Taking intermediate 03 206.7mg (0.30mol) again and add in above-mentioned dimethyl formamide solution, stirring makes 03 dissolving.Separately take Dicyclohexylcarbodiimide 62.5mg (0.30mol) and 4-(dimethylamino) pyridine 37.0mg (0.30mol), all adds above-mentioned two In methylformamide solution, under the conditions of room temperature (23-25 DEG C), magnetic agitation 12 hours, add tetrabutyl ammonium fluoride 156.7mg, continues stirring 6 hours.NaHCO by the 0.5M of 100ml3Solution joins in above-mentioned reaction solution, magnetic agitation 1 Hour, above-mentioned alkaline solution is poured in bag filter, after dialysing 45 hours with deionized water, solution passes through 0.2 μ filter membrane, cold Freeze and be dried, obtaining poly-aspartic-acid-amphotericin B poly conjugate 820.4mg.
After measured, this preparation example obtain poly-aspartic-acid-SN38 poly conjugate hydrogen nuclear magnetic resonance (1H-NMR) Collection of illustrative plates (not shown), shows the spectral line being consistent with this poly conjugate.
After measured, this preparation example obtain poly-aspartic-acid-SN38 poly conjugate nuclear magnetic resonance of carbon (13C-NMR) Collection of illustrative plates (not shown), shows the spectral line being consistent with this poly conjugate.
After measured, efficient liquid phase (HPLC) ultraviolet of the poly-aspartic-acid-SN38 poly conjugate that this preparation example obtains Detection (UV) collection of illustrative plates (not shown), consistent with expected result.
After measured, efficient liquid phase (HPLC) mass spectrum of the poly-aspartic-acid-SN38 poly conjugate that this preparation example obtains Detection (MS) figure spectrogram shows some fragments formed by SN38 (not shown).This shows that SN38 is present in this poly and combines In thing, and it is eluted out in HPLC system with macromolecule polyalcohol part.
After measured, the end-product that this preparation example obtains, combined state active medicine content=23.1% (w/w), free activity < 0.15% (can use the peak area at SN38 peak in HPLC figure to be multiplied by 100% institute divided by the peak area at PA-SN38 peak to medicament contg Obtain percent to calculate).
The chemosynthesis of preparation example 2, poly-aspartic-acid-glycine-SN38 poly conjugate
With reference to the method for preparation example 1, but macromolecule polyalcohol uses poly-D-ASP instead, and (molecular weight 5000Da) enters OK, use glycine as bridge joint aminoacid.Gained poly conjugate collects rate 85.8% with small molecule active medicine.Gained produces After measured, combined state active medicine content=17.9% (w/w), dissociate thing active medicine content < 0.18%.
The chemosynthesis of preparation example 3, poly-aspartic-acid-glycine-SN38 poly conjugate
With reference to the method for preparation example 1, but macromolecule polyalcohol uses poly-ASPARTIC ACID (molecular weight 100000Da) instead Carry out, use glycine as bridge joint aminoacid.Gained poly conjugate collects rate 88.3% with small molecule active medicine.Gained After measured, combined state active medicine content=31.1% (w/w), dissociate product active medicine content < 0.25%.
Preparation example 4, the chemosynthesis of poly-(glutamic acid/aspartic acid)-glycine-SN38 poly conjugate
With reference to the method for preparation example 1, but macromolecule polyalcohol uses poly-(glutamic acid/aspartic acid) instead, and (glutamic acid accounts for The 35% of total amino acids mole, molecular weight 20000Da) carry out, use glycine as bridge joint aminoacid.Gained poly combines Thing collects rate 82.4% with small molecule active medicine.Products therefrom after measured, combined state active medicine content=24.5% (w/ W), free active medicine content < 0.22%.
Preparation example 5, the chemosynthesis of poly-(glutamic acid/aspartic acid)-glycine-SN38 poly conjugate
With reference to the method for preparation example 1, but macromolecule polyalcohol uses poly-(glutamic acid/aspartic acid) instead, and (glutamic acid accounts for The 23.5% of total amino acids mole, molecular weight 20000Da) carry out, use glycine as bridge joint aminoacid.The many coalescences of gained Compound collects rate 82.4% with small molecule active medicine.Products therefrom after measured, combined state active medicine content=24.5% (w/ W), free active medicine content < 0.22%.
Preparation example 6, the chemosynthesis of poly-(glutamic acid/aspartic acid)-glycine-SN38 poly conjugate
With reference to the method for preparation example 1, but macromolecule polyalcohol uses poly-(glutamic acid/aspartic acid) instead, and (glutamic acid accounts for The 35.8% of total amino acids mole, molecular weight 20000Da) carry out, use glycine as bridge joint aminoacid.The many coalescences of gained Compound collects rate 84.8% with small molecule active medicine.Products therefrom after measured, combined state active medicine content=18.7% (w/ W), free active medicine content < 0.20%.
The chemosynthesis of preparation example 7, macromolecule polyalcohol-bridge joint aminoacid-SN38 poly conjugate
With reference to the method for preparation example 1, but bridge joint amino acids Glycine changes lysine into.Gained poly conjugate is with little point Sub-active medicine collects rate 86.3%.After measured, combined state active medicine content=15.9% (w/w), dissociate products therefrom work Property medicament contg < 0.15%.
The chemosynthesis of preparation example 8, macromolecule polyalcohol-bridge joint aminoacid-SN38 poly conjugate
With reference to the method for preparation example 6, but macromolecule polyalcohol uses poly-(glutamic acid/aspartic acid) instead, and (glutamic acid accounts for The 15.5% of total amino acids mole, molecular weight 10000Da), bridge joint amino acids Glycine changes glutamic acid into.Gained poly combines Thing collects rate 84.3% with small molecule active medicine.Products therefrom after measured, combined state active medicine content=28.4% (w/ W), free active medicine content < 0.15%.
The chemosynthesis of preparation example 9, macromolecule polyalcohol-bridge joint aminoacid-SN38 poly conjugate
With reference to the method for preparation example 6, but macromolecule polyalcohol uses poly-(glutamic acid/aspartic acid) instead, and (glutamic acid accounts for The 7.5% of total amino acids mole, molecular weight 25000Da), bridge joint amino acids Glycine changes alanine into.Gained poly combines Thing collects rate 87.3% with small molecule active medicine.Products therefrom after measured, combined state active medicine content=32.7% (w/ W), free active medicine content < 0.15%.
The chemosynthesis of preparation example 10, poly-aspartic-acid-glycine-SN38 poly conjugate
With reference to 18 support methods of CN1429121A (Chinese Patent Application No. 01809441.4) description embodiment, different It is to use the macromolecule polyalcohol used by embodiment of the present invention 1-3 respectively, obtains 3 kinds of poly conjugate samples.The many coalescences of gained Compound collects rate all in the range of 80～90% with small molecule active medicine.After measured, combined state active medicine contains products therefrom Amount is all in the range of 10～30%, and free active medicine content is respectively less than 0.5%.This example products therefrom has the E ring of excellence Stability, shows that different process gained poly conjugate is obtained in that the technology of the present invention effect equally.
Example 1 made above～preparation example 10 gained whole poly conjugate, all can represent by below general formula, according to combination The parameter meters such as state active medicine content, each matter theory inventory, unconjugated SN38 and unconjugated macromolecule polyalcohol Calculate, finally obtain their n value all in the range of 5～75
Preparation example 11, prepare macromolecule polyalcohol-SN38 poly conjugate
Respectively refer to the method for embodiment 1-10 and art methods (such as in Chinese Patent Application No. Method described in 201310688394X), different is only to make macromolecule polyalcohol directly be connected with 20 hydroxyls of SN38, And do not use the bridge joint aminoacid of centre, obtain 10 kinds of poly conjugate samples.Gained poly conjugate is with small molecule active medicine Thing collects rate all in the range of 80～90%.After measured, combined state active medicine content is all 10～30% scope for products therefrom In, free active medicine content is respectively less than 0.5%.
Preparation example 12, prepare poly conjugate
The method respectively referring to embodiment 1-3, macromolecule polyalcohol except for the difference that used is polyglutamic acid, obtains 3 kinds Poly conjugate sample.Gained poly conjugate collects rate all in the range of 80～90% with small molecule active medicine.Gained produces After measured, combined state active medicine content is all in the range of 10～30%, and free active medicine content is respectively less than 0.5% for thing.
Preparation example 13, prepare poly conjugate
The method respectively referring to embodiment 4-6, macromolecule polyalcohol except for the difference that used is poly-(glutamic acid/Radix Asparagi Propylhomoserin) and glutamic acid account for the 50.3% of total amino acids mole, 68.2%, 85.4% respectively, obtain 3 kinds of poly conjugate samples Product.Gained poly conjugate collects rate all in the range of 80～90% with small molecule active medicine.Products therefrom after measured, in conjunction with State active medicine content is all in the range of 10～30%, and free active medicine content is respectively less than 0.5%.
Preparation example 14, prepare poly conjugate
Poly is prepared according to 18 support methods of CN1429121A (Chinese Patent Application No. 01809441.4) description embodiment Conjugate PG-glycyl-(7-ethyl-10-OH-CPT).Gained poly conjugate collects rate with small molecule active medicine 82.7%.After measured, combined state active medicine content is 15.4% to products therefrom, free active medicine content < 0.25%.
The preparative-scale of above-mentioned each preparation example can easily amplify and each performance parameter does not haves substantially change, energy Effectively repeat.
C, test example part
Test example 1: investigate the chemical stability of poly conjugate of the present invention
Place 8 months under the conditions of making the present invention the most each preparation example gained various poly conjugate be placed in 35 DEG C, use this Invent HPLC method mentioned above and measure the content of wherein poly conjugate, measure the E ring of SN38 in poly conjugate molecule simultaneously Open loop catabolite is relative to the percentage contents of main constituent.
For SN38 poly conjugate, with percentage composition time during August relative to 0 month as evaluation index；For E ring open loop Catabolite, to increase percent as evaluation index time during its August relative to 0 month.These indexs are used to combine to evaluate poly The stability of thing.
Test example 2: biological experiment
Test example 21:
Although irinotecan is used clinically for colorectal cancer, but it is also effective for pulmonary carcinoma, its metabolite SN38 Also there is same anticancer spectrum.With reference to CN101507820A (Chinese Patent Application No. 200910127655.4) description embodiment 8 Institute's support method, the TGD (it reflects tumor growth delay) of test preparation example 1-14 gained whole poly conjugate.It addition, use The free SN38 of various dose, is measured in the same method TGD, describes dose-effect curve with free SN38 Yu TGD.According to this dosage-effect The amount answering profile lookup required poly conjugate in the case of reaching same effect (is converted as SN38 contained in poly conjugate Amount), and calculate in the case of reaching same effect poly conjugate dosage relative to the percent of free SN38 dosage, this number If value less than 100%, shows to reach required poly conjugate dose ratio in the case of identical biological effect and dissociates SN38 agent Measure little, and this numerical value is the lowest shows that the biology effect of poly conjugate is the best.
Test example 22:The test of pesticide effectiveness of use human colon carcinoma HCT116 cell:
The poly-aspartic-acid-SN38 poly conjugate (sample 1) of gained in preparation example 1 is used to carry out following experiment.
With 10% hyclone containing inactivation, the penicillin of 100U/ml and the streptomycin of 100 μ g/ml and 2mM paddy ammonia The McCoy's 5a culture medium of amide 37 DEG C, the incubator of 5%CO2 cultivates HCT116 cell.Cell cultivates initial concentration Be 1 × 106/milliliter, every 3 to 4 days after cell covers with sub-bottle pass on.The tumor cell being in exponential phase is used for The inoculation of in-vivo tumour.The HCT116 tumor cell resuspended with the McCoy's 5a culture fluid of serum-free connects with 5 × 106/100 μ l Plant in the right side of laboratory animal side of body flank subcutaneous.The animal selecting gross tumor volume more uniform when tumor length to about 120mm3 is divided Group is administered, totally 4 groups, often group 8.
The measurement of tumor and experimental index: use slide gauge that tumor is measured twice a week, measure the length of tumor Footpath and minor axis, its volume computing formula is: volume=0.5 × major diameter × minor axis2.Relative tumour volume is calculated according to gross tumor volume (relative tumor volume, RTV) and relative tumour volume increase ratio (%, T/C).RTV=Vt/V0, wherein Vt is for dividing The gross tumor volume average of the t days after group administration, V0 is the gross tumor volume average on the packet same day.T/C=TRTV/CRTV × 100, its Middle TRTV is treatment group RTV, and CRTV is solvent control group RTV.Inhibition rate of tumor growth (%, TGI) is calculated as follows: (1-T/C) × 100%.
With tail intravenously administrable, measure gross tumor volume and the rheological parameters' change with time of body weight of following 4 groups:
1: solvent control group (qwk × 2)；2: positive controls irinotecan 80mg/kg (qwk × 2)；3: poly-aspartic Acid-SN38 poly conjugate (sample 1) 50mg/kg, single dose；4: poly-aspartic-acid-SN38 poly conjugate (sample Product 1) 40mg/kg (qwk × 2).Result of the test is shown in Fig. 1 and Fig. 2 respectively.
Test-compound poly-aspartic-acid-SN38 poly conjugate (sample 1) 40mg/kg (qwk × 2) group and poly-Tianmen Winter propylhomoserin-SN38 poly conjugate (sample 1) 50mg/kg group all shows the strongest significant antitumous effect, and tumor is raw Long suppression ratio was respectively for 93.1% and 90.7% (comparing P < 0.001 with solvent control group).And effect is replaced than Yi Li significantly Kang Qiang.
D, compositions example part
Compositions example 1: preparation lyophilization injectable powder
Formula: poly conjugate 50 weight portion, mannitol 200 weight portion
Preparation method: add to poly conjugate and mannitol, in appropriate water for injection, make dissolving, with 1M hydrochloric acid solution or 1M hydrogen The pH value of sodium hydroxide solution regulation solution is to 5.0～5.5, and mending and injecting water to solid content in medicinal liquid is 7.5%.Successively Degerming with 0.45um and 0.22um filtering with microporous membrane, aseptically medicinal liquid is dispensed in cillin bottle (every bottled amount folding The amount being counted as SN38 is 50mg), and to jump a queue, put in freezer dryer, lyophilization to water content is less than 3%, tamponade, i.e. ?.
Compositions example 2: preparation lyophilization injectable powder
Formula: poly conjugate 50 weight portion, lactose 250 weight portion
Preparation method: add to poly conjugate and lactose, in appropriate water for injection, make dissolving, with 1M hydrochloric acid solution or 1M hydrogen-oxygen The pH value of change sodium solution regulation solution is to 4.5～5.0, and mending and injecting water to solid content in medicinal liquid is 10%.Use successively 0.45um and 0.22um filtering with microporous membrane is degerming, and medicinal liquid is aseptically dispensed in cillin bottle (every bottled amount conversion The amount becoming SN38 is 50mg), and to jump a queue, put in freezer dryer, lyophilization to water content is less than 3%, and tamponade to obtain final product.
Compositions example 3: prepare injection
Formula: poly conjugate 50 weight portion, citric acid 10 weight portion, water for injection 1000 weight portion
Preparation method: add to poly conjugate and citric acid, in appropriate water for injection, make dissolving, with 1M hydrochloric acid solution or 1M hydrogen The pH value of sodium hydroxide solution regulation solution is to 3.5～4.0, and benefit adds to the full amount of water for injection.Micro-with 0.45um and 0.22um successively Hole membrane filtration is degerming, and medicinal liquid is aseptically dispensed in ampoule bottle (every bottled amount is converted to the amount of SN38 50mg), sealing by fusing, to obtain final product.

Claims (10)

1. a poly conjugate, active medicine therein is SN38, i.e.
The 20-hydroxyl of this active medicine is via an aminoacid with macromolecule polyalcohol even Connect；Described macromolecule polyalcohol is amino acid polymer.
Poly conjugate the most according to claim 1, wherein:
The 20-hydroxyl of active medicine is connected with described macromolecule polyalcohol via an aminoacid, a described amino acid whose carboxylic Base forms ester bond with the 20-hydroxyl of active medicine, and an amino acid whose amino is connected with macromolecule polyalcohol；
The 20-hydroxyl of active medicine is connected with described macromolecule polyalcohol via an aminoacid, a described amino acid whose carboxylic Base forms ester bond with the 20-hydroxyl of active medicine, and an amino acid whose amino forms amide with the carboxyl on macromolecule polyalcohol Key；
One or more active drug molecule is combined on each macromolecule polyalcohol molecule；
Described active medicine weight is the 3～60% of this poly conjugate weight；Such as, described active medicine weight is this poly The 10～50% of conjugate weight, such as 10～40%, such as 10～35%；And/or
The aminoacid forming amino acid polymer is aspartic acid or aspartic acid and glutamic acid combination.
Poly conjugate the most according to claim 1, it has a below formula:
Wherein:
R is the side chain of hydrogen or natural amino acid；
N is the integer of 2～100；
PA is amino acid polymer, and the aminoacid forming this amino acid polymer is aspartic acid, or forms this polyamino acid The aminoacid of polymer is aspartic acid and glutamic acid combination.
Poly conjugate the most according to claim 3, wherein said R ' is hydrogen；Or selected from following amino acid whose side chain: third Propylhomoserin, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, serine, threonine, half Guang Propylhomoserin, tyrosine, agedoite, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine.
Poly conjugate the most according to claim 3, wherein:
Described n is the integer of 5～75, or n is the integer of 5～60, or n is the integer of 5～50；
Described n is an integer, and active medicine weight is 3～the scope of 60% of this poly conjugate weight, such as 10～ 50%, such as 10～40%, such as 10～35%；
The aminoacid forming described polyamino acid includes its D type aminoacid, L-type aminoacid, DL mixed amino-acid；And/or
The aminoacid forming described polyamino acid polymers is aspartic acid and glutamic acid combination.
Poly conjugate the most according to claim 1, wherein:
The mean molecule quantity of wherein said polyamino acid is 5000～100000 dalton, such as 10000～80000 dalton, Such as 10000～50000 dalton, such as 10000～40000 dalton；And/or
It can use water for injection, 0.9% sodium chloride injection, 5% glucose injection as solvent for injection when being administered.
7. the method for poly conjugate described in preparation any one of claim 1-6, including following steps:
I) macromolecule polyalcohol is provided so that it is be dissolved in solvent to form solution；
Ii) in step i) gained solution, add active medicine and make it dissolve；
Iii) to step ii) gained solution adds catalyst and condensing agent, make macromolecule polyalcohol and active medicine contract Close reaction, to form macromolecule polyalcohol and both active medicines poly conjugate by chemical bonds；
Iv) separation and Extraction gained poly conjugate.
Method the most according to claim 7, wherein:
Described in step i), solvent is organic solvent, such as but not limited to dimethylformamide, dimethyl sulfoxide etc.；
Step iii) described in catalyst be 4-(dimethylamino) pyridine (it can be abbreviated as DMAP)；Its consumption can be generally alive 0.01～4 times of property medicine mole, such as 0.5～2 times, such as 0.8～1.5 times, such as 1.0～1.2 times
Step iii) described in condensing agent be dicyclohexylcarbodiimide；Its consumption can be generally active medicine mole 0.5～4 times, such as 0.8～1.5 times, such as 1.0～1.2 times；And/or
Step iv) described in separation and Extraction be to be carried out by dialysis or the method for ultrafiltration.
9. a pharmaceutical composition, wherein comprises the poly conjugate described in any one of claim 1-6, and optional pharmacy Acceptable adjuvant；Further, this pharmaceutical composition is medicinal composition for injections, and its can use water for injection, 0.9% sodium chloride injection, 5% glucose injection are as solvent for injection when being administered.
10. treatment tumor or the method for cancer, the method includes to the claim of administration effective dose in need Poly conjugate described in any one of 1-6 or the step of the pharmaceutical composition of claim 9.
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