CN1448420A - Hydrophilic polymer and tanshinones medicine conjugation agent and medicine composition containing same - Google Patents
Hydrophilic polymer and tanshinones medicine conjugation agent and medicine composition containing same Download PDFInfo
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- CN1448420A CN1448420A CN 02108778 CN02108778A CN1448420A CN 1448420 A CN1448420 A CN 1448420A CN 02108778 CN02108778 CN 02108778 CN 02108778 A CN02108778 A CN 02108778A CN 1448420 A CN1448420 A CN 1448420A
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- tanshinone
- hydrophilic polymer
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Abstract
Tanshinone medicine, such as tanshinone IIa, tanshinone IIb, tanshinone I, srytotanshinone, neotanshinone A, neotanshinone B, neotanshinone C, etc is made to combine with hydrophilic polymer to raise the water solubility of tanshinone medicine and increase the circular half time of tanshinone medicine in body. The present invention can raise the medicine convenience and treating effect via carrying medicine molecule with non-toxic and no-immunogenicity water soluble polyglycol.
Description
Technical field
The present invention relates to a kind of novel hydrophilic polymer and the binding substances of tanshinone medicine and the pharmaceutical composition that comprises this binding substances.
Background technology
TANSHINONES and derivative thereof are the extraction compositions that comes from the natural phant labiate red sage root (Salviamiltiorrhiza Bunge).Its maternal plant red sage root is extensive use of in traditional Chinese medicine.This class medicine comprises: Tanshinone I Ia (Tabnshinone IIa), Tanshinone I Ib (Tanshinone IIb), Tanshinone I (Tanshinone I), Cryptotanshinone (cryptotanshinone) and danshenxinkun (neotanshinone) A, B and C etc.The chemical structure of these tanshinone derivatives is as follows:
Tanshinone I Ia is wherein representative compound, and its biological activity shows treatment blood circulation function.Especially obvious in treatment heart disease and stroke effect, and the damage of liver had therapeutic action.Simultaneously it also demonstrates antibiotic, anti-inflammatory, anti-oxidant activity.To Bacillus tuberculosis H
37R
vBacterial strain has stronger activity.But Tanshinone I Ia itself has low water solubility and short physiology transformation period.Therefore in the actual market drug use, use its derivative, as Tanshinone I Ia sodium sulfonate more.After the injection, myocardial ischemia and myocardial infarction are had obvious effect, and the thrombus dissolving effect is strong, and heart is had repairing effect.Though it is water-soluble that this sodium sulfonate derivative has improved, its physiology transformation period is still shorter, can not realize the common raising of two kinds of performances.
Be head it off, now use polyethyleneglycol derivative widely, make itself and the combining of protein, peptide or other treatment medicine, with physiology transformation period of prolong drug, reduce its immunogenicity and toxicity.In clinical use, PEG and derivative thereof have obtained using widely in a lot of commercial medicines as the carrier of making pharmaceutical preparation, and the trial that PEG is bonded to drug molecule has also been obtained significant progress in last decade, in many approval medicines, extensively be used, as PEG-intron
, the key compound of a kind of alpha-interferon and polyoxyethylene glycol has just shown longer circulating half-life and better result of treatment.The key compound of taxol and polyoxyethylene glycol has also reduced toxicity accordingly and has prolonged biological activity.They are quite clear in the intravital metabolic process of people, are a kind of safe, the drug modified agent that has no side effect.
When combining with medicine, commonly used to a kind of technology that is called as polyoxyethylene glycol (PEGylation) change, be to have a suitable functional group after one of the polyoxyethylene glycol two ends or two end groups are chemically activated, this functional group has activity to wanting at least one functional group in the bonded medicine, can form stable key with it, and be degraded under can suitable in vivo situation and remove, and discharge activeconstituents.
Therefore, the purpose of this invention is to provide the binding substances of a kind of hydrophilic polymer and tanshinone medicine, to improve to the water-soluble of natural product TANSHINONES and derivative thereof and physiology transformation period.
Summary of the invention
According to an aspect of the present invention, it provides a kind of hydrophilic polymer of representing with following formula and the binding substances of tanshinone medicine:
P-X-Tan is wherein: P is a water-soluble polymers; X is a linking group; And Tan is the tanshinone medicine.
According to the preferred embodiment of the invention, it provides the chemical structural formula as shown in the formula represented hydrophilic polymer and Tanshinone I Ia:
Wherein: Y represents O or N-X-P independently; P is a soluble polymer; And X is a linking group.
Simultaneously, purpose of the present invention also can provide a kind of hydrophilic polymer of representing with following formula and the binding substances of tanshinone medicine:
Wherein: P is a water-soluble polymers; Arg represents arginine or poly arginine; Tan is a tanshinone derivative; And n is the integer of 1-12.
In above-mentioned binding substances, described tanshinone medicine is preferably Tanshinone I Ia, Tanshinone I Ib, Tanshinone I, Cryptotanshinone and danshenxinkun A, B and C.
Water-soluble polymers in the binding substances of the present invention is selected from polyoxyethylene glycol, polypropylene glycol, polyvinyl alcohol, polypropylene morpholine and their multipolymer, and wherein preferably molecular weight is 300 to 60,000 polyoxyethylene glycol.
Described linking group is hydrazone group, imido grpup or ester group preferably.
According to another aspect of the present invention, it provides and comprises the pharmaceutical composition of above-mentioned binding substances as activeconstituents.
Can improve the absorption of natural tanshinone medicine according to binding substances of the present invention, prolong action time, heighten the effect of a treatment, reduce dosage and avoid some toxic side effect.
Embodiment
Used hydrophilic polymer for example is polyoxyethylene glycol, polypropylene glycol, polyvinyl alcohol, polypropylene morpholine or their multipolymer in binding substances of the present invention, wherein especially preferably polyoxyethylene glycol and multipolymer thereof.These hydrophilic polymers are by the modification to free hydroxy-terminal, to contain diazanyl, azanol base, phenylhydrazino, Urea,amino-, aminoguanidine etc., be the acidic amino acid oligopeptides perhaps, particularly L-glutamic acid oligopeptides and arginine oligopeptides etc. be attached on the parent of this polymkeric substance, make this polymkeric substance that tie point with drug molecule can be provided, thus with natural drug activeconstituentss such as TANSHINONES in carbonyl, amino, hydroxyl etc. link together.Particularly, can in a hydrophilic polymer one oligopeptides modification structure, connect one or more drug molecule, to guarantee suitable drug level and slow-release function is provided to the natural drug activeconstituents of this micromolecular.
In binding substances of the present invention, owing to the non-wetting ability such as medicines such as TANSHINONES itself, the binding substances of formed hydrophilic polymer-drug molecule will form the micro-sphere structure of rolling into a ball with some molecular aggregates ingredients in the aqueous solution.This structure has kept good characteristics such as hydrophilic polymer good hydrophilicity, flexibility, anti-macrophage phagocytic, and the sustained-release and controlled release to drug molecule is provided simultaneously, prolong drug, especially natural drug molecule greatly, dwell period in vivo.
Another advantage of the present invention is except remaining with the common solvability of hydrophilic polymer such as polyoxyethylene glycol or derivatives thereof, non-immunogenic and feature such as nontoxic, if use oligopeptides group will provide a plurality of POLs to drug molecule, guaranteed that the effective blood drug concentration of drug molecule and substep discharge.
Be example with the polyethyleneglycol derivative now, being connected of hydrophilic polymer and drug molecule among the present invention is described.
Comprised in the structure of polyethyleneglycol derivative that polymkeric substance props up chain portion and end group functional group part, is described below respectively.
Polyoxyethylene glycol (PEG), its general structure is shown in I:
Wherein: R is H or C
1-12Alkyl, n is any integer, characterizes its polymerization degree.
When R was low alkyl group, R can be any low alkyl group that contains 1-6 carbon atom, as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, n-pentyl or n-hexyl.When R was cycloalkyl, R was preferably the cycloalkyl that contains 3-7 carbon atom, as cyclopropyl, cyclobutyl and cyclohexyl.Preferred cycloalkyl is a cyclohexyl.Its exemplary compounds is methoxy poly (ethylene glycol) (mPEG).Similar thing of other polyoxyethylene glycol or ethylene glycol copolymer also can be used for this invention to be used, as polypropylene glycol, polyvinyl alcohol, polypropylene morpholine etc.
For polyoxyethylene glycol, generally adopt molecular weight to be represented, be 300～60,000 dalton as long as make the molecular weight of the polyoxyethylene glycol that forms binding substances, this is equivalent to n is about 6～1,300.More preferably, n is 28,112 and 450, and this is 1,325,5,000 and 20,000 corresponding to molecular weight respectively.Owing to, preferably use the molecular weight characterization polyethylene glycol polymer, rather than represent the unit of repetition certainly in the PEG polymkeric substance with Integer n usually by its molecular-weight average but not repeat the potential unhomogeneity of the initial PEG compound that the unit limits certainly.The initial PEG compound of various molecular weight can or can obtain from commercial source by the preparation of the currently known methods in this area.
All containing functional groups such as carbonyl, amino, carboxyl, hydroxyl in use many medicines, the especially natural medicinal ingredients at present; they all combine with compositions such as monose, polysaccharide, nucleosides, polymerized nucleoside, phosphoryls in vivo usually, to be formed on activated pharmacology structure in the organism.
Therefore, hydrophilic polymer can be by identical mode and these drug molecule combinations, substituting biological organic molecule, and overcome biological organic molecule in vivo the physiology transformation period short, the defective that duration of efficacy is short.
In the molecular structure of TANSHINONES and derivative thereof, its active function groups is a carbonyl.The derivative of many ammonia, available general expression NH
2-X represents, can with this type of aldehyde ketone generation nucleophilic reaction, dehydration then forms the compound that contains the two keys of C=N.The most frequently used aminoderivative has following several:
NH
2-X
-NH
2Hydrazine or hydrazine
-OH oxyammonia
-NHC
6H
5Phenylhydrazine
-NHC
6H
3(NO
2)
22,4 dinitrophenyl hydrazine
-NHCONH
2Urea,amino-
-NHCOCH
2N+ (CH
3)
3The Cl Ji draws (Girard, A.) reagent
-CNNH
2Guanidine aldehyde ketone and above reagent react, available following general formula is represented:
The nucleophilic addition of this type is an acidic catalyst reaction.If carry out acidic hydrolysis, get final product can be original aldehyde and ketone.Therefore can keep through the tanshinone derivative degradation in vivo after the modification, the tanshinone derivative that is discharged still has original physiologically active.
In binding substances of the present invention, hydrophilic polymer all has free hydroxyl group usually.Therefore, when combining with the tanshinone medicine, need carry out modification to this free hydroxyl group, formation can be carried out the reactive activity end group with carbonyl or the hydroxyl on the tanshinone medicine.Therefore the purposes that realizes at needs can adopt following several method that terminal functionality is carried out modification.Below the introducing of active group will be described with polyoxyethylene glycol as the example of hydrophilic polymer.Amination
Polyoxyethylene glycol after the amination, the amino bigger by reactive behavior has replaced hydroxyl, is even more important reacting to form in the key compound with a molecule that contains the carboxylic acid group.
Carboxylated
After polyoxyethylene glycol is carboxylated, can improve the reactivity of PEG, make PEG form key compound with another molecular reaction that contains amino or hydroxyl.
If adopt each seed amino acid, the terminal functionality of carboxyl will be obtained to contain equally as reaction raw materials.Especially, if use acidic amino acid or contain the polymkeric substance of acidic amino acid, will obtain to contain the terminal functionality of a plurality of pendant carboxylic groups.This kind structure will help improving the load factor to micromolecular various natural medicinal ingredients, and can obtain slow release effect by stepwise degradation.Hydrazidesization
On the basis of acid polyethylene glycol compound, further do the hydrazine processing.Make it form hydrazine or phenylhydrazine analog derivative, make PEG can with contain carbonyl, carboxyl, sulfonic molecule and form key compound.
Other
Same, also can carry out modification to it by methods such as acyl chlorides, maleimide, pyridine disulphide, can obtain the synthetic method of being correlated with easily in this area.
In addition, on this hydrophilic polymer, also can connect targeted molecular, as antibody etc., so that directed transhipment binding substances of the present invention.
In binding substances of the present invention, tanshinone drug molecule part is preferably by isolating active constituents of medicine in the natural phant, as Tanshinone I Ia, Tanshinone I Ib, Tanshinone I, Cryptotanshinone and danshenxinkun A, B and C etc.
Binding substances of the present invention can the pure compound form or the appropriate drug composition carry out administration, the reagent that can adopt any acceptable administering mode or be used for similar purposes carries out.Composition can comprise conventional pharmaceutical carrier or vehicle and as the binding substances of the present invention of activeconstituents (one or more), in addition, also can comprise other medicament, carrier, assistant agent etc.
Usually, according to required administering mode, pharmaceutically acceptable composition will comprise the suitable pharmaceutical excipient of about 1 to about 99 weight % binding substances of the present invention and 99 to 1 weight %.Preferred composition comprises the binding substances of the present invention of about 5 to 75 weight %, and all the other are suitable pharmaceutical excipient.
Preferred route of administration is a drug administration by injection, adopts conventional per daily dose scheme, and this scheme can be adjusted according to the severity of disease.Binding substances of the present invention or its pharmacy acceptable salt also can be mixed with the injection agent, for example use about 0.5 to about 50% activeconstituents to be scattered in the medicinal adjuvant that can adopt the liquid form administration, example is water, salt solution, dextrose hydrate, glycerine, ethanol etc., thereby forms solution or suspensoid.
If necessary, pharmaceutical composition of the present invention also can comprise a spot of auxiliary substance, as wetting agent or emulsifying agent, pH buffer reagent, antioxidant etc., for example: citric acid, Arlacel-20, Emulphor FM, Yoshinox BHT etc.
The actual fabrication method of such formulation is that those skilled in the art is known or conspicuous, for example can be referring to Remington ' s Pharmaceutical Sciences, the 18th edition, (MackPublishing Company, Easton, Pennsylvania, 1990).In any case according to technology of the present invention, employed composition will contain the binding substances of the present invention for the treatment of significant quantity, to be used for the treatment of corresponding disease.
Embodiment
Below in conjunction with case description binding substances of the present invention and preparation method thereof, it does not limit the present invention, and scope of the present invention is defined by the claims.
Embodiment 1
Methoxy poly (ethylene glycol) is connected by imido grpup with Tanshinone I Ia
2.5 gram methoxy poly (ethylene glycol) amine (Methoxy-PEG-NH
2, molecular weight 5,000) and 150 milligrams of Tanshinone I Ia be dissolved in 20 ml methanol, add 0.1 milliliter of trifluoroacetic acid in the mixed solution.Solution lucifuge heating reflux reaction 2 hours, reaction solution is removed by rotary evaporation, and resistates impouring Virahol (IPA) filters collecting precipitation, vacuum-drying.Product spent ion exchange resin purifying.Productive rate: 1 gram (40%), fusing point: 53-55 ℃.
Embodiment 2
Methoxy poly (ethylene glycol) is connected by hydrazone group with Tanshinone I Ia
2.5 gram methoxy poly (ethylene glycol) acyl trap (Methoxy-PEG-CO-NH-NH
2, molecular weight 5,000) and 150 milligrams of Tanshinone I Ia be dissolved in 20 ml methanol, add 0.1 milliliter of trifluoroacetic acid in the mixed solution.Solution lucifuge heating reflux reaction 2 hours, reaction solution is removed by rotary evaporation, and resistates impouring Virahol (IPA) filters collecting precipitation, vacuum-drying.Productive rate: 2.25 grams (90%), fusing point: 53-55 ℃.
Embodiment 3
Polyoxyethylene glycol is connected by hydrazone group with Tanshinone I Ia
5 gram polyoxyethylene glycol hydrazides (PEG-(CO-NH-NH
2)
2, molecular weight 20,000) and 150 milligrams of Tanshinone I Ia be dissolved in 50 ml methanol, add 0.1 milliliter of trifluoroacetic acid in the mixed solution.Solution lucifuge heating reflux reaction 2 hours, reaction solution is removed by rotary evaporation, and resistates impouring Virahol (IPA) filters collecting precipitation, vacuum-drying.Productive rate: 4.6 grams (92%), fusing point: 58-60 ℃.
Embodiment 4
Methoxy poly (ethylene glycol)-L-glutamic acid oligopeptides is connected by hydrazone group with Tanshinone I Ia
10 gram methoxy poly (ethylene glycol)-L-glutamic acid, 6 peptides (Methoxy-PEG-(glutamic acid)
6, molecular weight 21,200) be dissolved in 150 milliliters of anhydrous methylene chlorides, add 10 milliliters of anhydrous hydrazines and 820 milligrams of dicyclohexyl carbonyl diimines (DCC) in the solution, stirred 5 hours under the room temperature.Steaming desolventizes, and resistates is dissolved in 20 milliliter 1, the 4-dioxane.Sedimentation and filtration is removed, and filtrate concentrates, 100 milliliters of Virahols of impouring, and precipitation is collected, vacuum-drying.
3 gram methoxy poly (ethylene glycol)-hydrazide group L-glutamic acid 6 peptides (Methoxy-PEG-(Glutamate-NH-NH
2)
6, molecular weight 21,300 is made by back) and 320 milligrams of Tanshinone I Ia be dissolved in 50 ml methanol, adding 0.2 milliliter of trifluoroacetic acid in the solution.Solution lucifuge heating reflux reaction 2 hours, reaction solution is removed by rotary evaporation, and resistates impouring Virahol (IPA) filters collecting precipitation, vacuum-drying.Productive rate: 2.7 grams (90%), fusing point: 60-62 ℃.
Embodiment 5
The bonding of methoxy poly (ethylene glycol)-arginine derivative and Tanshinone I Ia
2.5 gram methoxy poly (ethylene glycol) arginine (Methoxy-PEG-Arginine, molecular weight 5,000) and 150 milligrams of Tanshinone I Ia are dissolved in 40 milliliters of second eyeballs, add 0.5 milliliter of anhydrous pyridine in the mixed solution.Stirring reaction spends the night under the solution nitrogen protection, and solvent is removed by rotary evaporation, in the resistates impouring ether, filters collecting precipitation, vacuum-drying.Productive rate: 2.25 grams (90%), fusing point: 54-56 ℃.
Embodiment 6
The methoxy poly (ethylene glycol) carboxy derivatives is connected by ester group with Tanshinone I Ib
10 gram methoxy poly (ethylene glycol) amine (Methoxy-PEG-NH
2, molecular weight 5,000) and 1 the gram succinyl oxide be dissolved in 80 milliliters of methylene dichloride, add 0.5 milliliter of anhydrous pyridine.Stirred overnight under the nitrogen protection, solvent is removed by rotary evaporation, in the resistates impouring Virahol, filters collecting precipitation, vacuum-drying.Productive rate: 9.0 grams (90%).
5 gram methoxy poly (ethylene glycol) acid (MPEG-COOH, molecular weight 5,000 is by the previous step preparation), 0.2 gram hydroxybenzotriazole (HOBT), 0.2 gram 4-dimethylaminopyridine dimethyl aminopyridine (DMAP) is dissolved in 50 milliliters of methylene dichloride.Solution adds 0.32 gram dicyclohexyl carbonyl diimine (DCC) again.Stirred overnight at room temperature under the nitrogen protection.Solution concentration, resistates are dissolved in 20 milliliter 1, in the 4-dioxane, remove by filter precipitation, and filtrate concentrates, and 100 milliliters of Virahols of resistates impouring filter, ether washing, vacuum-drying.Productive rate: 4.25 grams (85%), fusing point: 52-54 ℃.
Embodiment 7
Methoxy poly (ethylene glycol)-L-glutamic acid oligopeptides is connected by ester group with Tanshinone I Ib
5 gram methoxy poly (ethylene glycol)-L-glutamic acid, 6 peptide acid (Methoxy-PEG-(glutamicacid)
6, molecular weight 21,200), 0.31 gram Tanshinone I ib, 0.2 gram hydroxybenzotriazole (HOBT), 0.2 gram 4-dimethylaminopyridine (DMAP) be dissolved in 50 milliliters of methylene dichloride.Solution adds 0.32 gram dicyclohexyl carbonyl diimine (DCC) again.Stirred overnight at room temperature under the nitrogen protection.Solution concentration, resistates are dissolved in 20 milliliter 1, in the 4-dioxane, remove by filter precipitation, and filtrate concentrates, and 100 milliliters of Virahols of resistates impouring filter, ether washing, vacuum-drying.Productive rate: 2.7 grams (90%), fusing point: 59-61 ℃.
Embodiment 8
Present embodiment illustrates the preparation of drug combination process of representative parenteral administration, and described composition comprises binding substances of the present invention.
Composition
Binding substances 2g of the present invention
0.9% salt brine solution is to 100mL
Binding substances of the present invention is dissolved in 0.9% salt brine solution, obtains the intravenous solution of 100mL,, under aseptic condition, pack its membrane filtration filtration of material by 0.2 μ.
Claims (13)
1, with the hydrophilic polymer of following formula and the binding substances of drug molecule:
P-X-Tan is wherein: P is a water-soluble polymers; X is a linking group; And Tan is the tanshinone derivative drug molecule.
2, a kind of hydrophilic polymer of representing with following formula and the binding substances of tanshinone derivative:
Wherein: P is water-soluble polymers independently; Arg is arginine or poly arginine; Tan is the tanshinone derivative drug molecule; N is the integer of 1-12.
3, a kind of with represented hydrophilic polymer of following formula and the binding substances of Tanshinone I Ia:
Wherein: Y is independent O or N-X-P; P is a water-soluble polymers; And X is a linking group.
4, as the described binding substances of one of claim 1-3, wherein, described water-soluble polymers is selected from polyoxyethylene glycol, polypropylene glycol, polyvinyl alcohol, polypropylene morpholine and their multipolymer.
5, binding substances as claimed in claim 4, wherein, described water-soluble polymers is a polyoxyethylene glycol.
6, binding substances as claimed in claim 5, wherein, the molecular weight of polyoxyethylene glycol is 300～60,000.
7, as the described binding substances of one of claim 1-3, wherein, the free hydroxyl group on the described hydrophilic polymer can be used C
1-12Alkoxyl group, cycloalkyloxy or aralkoxy end-blocking.
8, as the described binding substances of one of claim 1-3, wherein, the portability targeted molecular is transported this binding substances with orientation on described hydrophilic polymer.
9, binding substances as claimed in claim 8, wherein, described targeted molecular is an antibody.
10, as the described binding substances of one of claim 1-3, wherein, linking group X is hydrazone group, imido grpup, hydroxylamino, ester group.
11, pharmaceutical composition, it comprises as described binding substances of one of claim 1-10 and pharmacology is acceptable carrier or vehicle.
12, composition as claimed in claim 11, it also can comprise other therapeutic activity composition.
13, composition as claimed in claim 11, it is the formulation of injection agent, solution, tablet, suspensoid or aerosol.
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|---|---|---|---|
| CN 02108778 CN1252130C (en) | 2002-04-01 | 2002-04-01 | Hydrophilic polymer and tanshinones medicine conjugation agent and medicine composition containing same |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005044837A1 (en) * | 2003-11-07 | 2005-05-19 | Beijing Jenkem Technology Co., Ltd. | The conjugates of a hydrophilic polymer-buxus's extracts and the pharmaceutical compositions of thereof |
| WO2005092898A1 (en) * | 2004-03-29 | 2005-10-06 | Beijing Jenkem Technology Co., Ltd. | The conjugates of a hydrophilic polymer-tripterygium's extracts and the pharmaceutical compositions thereof |
| CN100387585C (en) * | 2006-04-26 | 2008-05-14 | 秦引林 | Tanshinone I derivatives and pharmaceutical application thereof |
| CN102127037A (en) * | 2011-01-11 | 2011-07-20 | 上海交通大学 | Tanshinone compounds and applications thereof |
| CN104140404A (en) * | 2014-07-16 | 2014-11-12 | 中国药科大学 | Compounds with effect of directly inhibiting thrombin and applications |
| WO2016078577A1 (en) * | 2014-11-20 | 2016-05-26 | 杭州本生药业有限公司 | Tanshinone i compound modified by polymer or nano micelle thereof, and preparation method and use thereof |
| US9855338B2 (en) | 2005-12-05 | 2018-01-02 | Nitto Denko Corporation | Polyglutamate-amino acid conjugates and methods |
| CN111107873A (en) * | 2017-09-05 | 2020-05-05 | 默沙东公司 | Compounds for reducing the viscosity of biologicals |
| US11845798B2 (en) | 2017-05-02 | 2023-12-19 | Merck Sharp & Dohme Llc | Formulations of anti-LAG3 antibodies and co-formulations of anti-LAG3 antibodies and anti-PD-1 antibodies |
-
2002
- 2002-04-01 CN CN 02108778 patent/CN1252130C/en not_active Expired - Fee Related
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005044837A1 (en) * | 2003-11-07 | 2005-05-19 | Beijing Jenkem Technology Co., Ltd. | The conjugates of a hydrophilic polymer-buxus's extracts and the pharmaceutical compositions of thereof |
| CN1867578B (en) * | 2003-11-07 | 2010-04-28 | 北京键凯科技有限公司 | The conjugates of a hydrophilic polymer-buxus's extracts and the pharmaceutical compositions of thereof |
| CN101306203B (en) * | 2003-11-07 | 2010-12-01 | 天津键凯科技有限公司 | Hydrophilic polymer-boxwood extract conjugate and its medicine composition |
| WO2005092898A1 (en) * | 2004-03-29 | 2005-10-06 | Beijing Jenkem Technology Co., Ltd. | The conjugates of a hydrophilic polymer-tripterygium's extracts and the pharmaceutical compositions thereof |
| US9855338B2 (en) | 2005-12-05 | 2018-01-02 | Nitto Denko Corporation | Polyglutamate-amino acid conjugates and methods |
| CN100387585C (en) * | 2006-04-26 | 2008-05-14 | 秦引林 | Tanshinone I derivatives and pharmaceutical application thereof |
| CN102127037A (en) * | 2011-01-11 | 2011-07-20 | 上海交通大学 | Tanshinone compounds and applications thereof |
| CN104140404A (en) * | 2014-07-16 | 2014-11-12 | 中国药科大学 | Compounds with effect of directly inhibiting thrombin and applications |
| WO2016078577A1 (en) * | 2014-11-20 | 2016-05-26 | 杭州本生药业有限公司 | Tanshinone i compound modified by polymer or nano micelle thereof, and preparation method and use thereof |
| US11845798B2 (en) | 2017-05-02 | 2023-12-19 | Merck Sharp & Dohme Llc | Formulations of anti-LAG3 antibodies and co-formulations of anti-LAG3 antibodies and anti-PD-1 antibodies |
| CN111107873A (en) * | 2017-09-05 | 2020-05-05 | 默沙东公司 | Compounds for reducing the viscosity of biologicals |
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|---|---|
| CN1252130C (en) | 2006-04-19 |
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