CN100374443C - Hydrophilic polymer-thunder good vine extract binding substance and its medicinal composition - Google Patents

Hydrophilic polymer-thunder good vine extract binding substance and its medicinal composition Download PDF

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CN100374443C
CN100374443C CNB2004100296153A CN200410029615A CN100374443C CN 100374443 C CN100374443 C CN 100374443C CN B2004100296153 A CNB2004100296153 A CN B2004100296153A CN 200410029615 A CN200410029615 A CN 200410029615A CN 100374443 C CN100374443 C CN 100374443C
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binding substances
triptolide
polyoxyethylene glycol
ester
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嵇世山
朱德权
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Jenkem Technology Co Ltd
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BEIJING JIANKAI SCIENCE AND TECHNOLOGY Co Ltd
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Abstract

The present invention relates to hydrophilic polymers-thunder god vine extractives or derivative compositions(I), (II), wherein P represents hydrophilic polymers, preferably polyethylene glycol; L, X and Z represent linking groups, and D represents the thunder god vine extractives or derivatives thereof. The compositions improve the water solubility of the thunder god vine extractives or the derivatives thereof, reduce toxicity and extend the circulating half life of the thunder god vine extractives or the derivatives thereof in the biosome.

Description

The binding substances of hydrophilic polymer-Radix Tripterygii Wilfordii extract and pharmaceutical composition thereof
Invention field
The present invention relates to the binding substances of hydrophilic polymer and Radix Tripterygii Wilfordii extract or derivatives thereof and the pharmaceutical composition that comprises this binding substances.
Background technology
Trypterygine (Tripterygium wilfordii) claim herba fibraureae recisae again, belongs to the Celastraceae tripterygium plant.The sixties, Fujian at first was used for the treatment of trypterygine lepra reaction and rheumatoid arthritis, obtained satisfied curative effect.The discovered in recent years trypterygine also has certain curative effect to cancer and infection that organ transplantation caused.Trypterygine ingredient complexity, its effective constituent is: triptolide (triptolide), Triptodiolide (tripdiolide), Triptonide (triptonide), hypolide methylether (hypolide methyl ether), Triptonide lactone (triptonolide), Triptolide 12,13-chlorohydrin (tripcheorolide), thunder rattan lactone triol (triptriolide), wilforonide (wilforonide), wilforine (tripterygine), wilfordine (wilfordine), tripterigine alkali (wilforgine), wilforine alkali (wilforine), wilfortrine (wilfortrine), the hot alkali (wilforzine) of trypterygine, wilfordic acid (wilfordic acid), hydroxywilfordic acid (hydroxy wilfordic acid), trypterygine (tripterin or celustrol), Tripterysium Glucosides etc.
Triptolide, second element all have tangible anti-tumor activity.The white corpuscle that to Leukemia Patients exsomatizes has obvious suppression or killing action.0.1 and 0.25mg/kg has obvious activity to mouse L1210, P388, increase in life span is more than 159%, and makes part animal long-term surviving.Triptolide is all to show than the obvious growth restraining effect to three domestic stomach cancer cells that detect.But the solvability of triptolide is relatively poor.Water-soluble in order to improve, US6569893 has disclosed the amino acid derivative of triptolide.US 6,620, and 843 have reported the succinate derivative (PG490-88) of triptolide.
Trypterygine toxicity is bigger, is commonly called as Graceful Jessamine Herb.Trypterygine has certain toxic side effect, and experimentation on animals shows that the most responsive target organ of trypterygine toxicity is stomach and intestine system, hematopoiesis system and reproductive tract, and is the most common with digestive tract reaction.The degeneration of rat testicle germinal epithelium, spermatogonium division are subjected to suppress, androgone at different levels reduces and disappearance.Studies show that in a large number triptolide is its main active ingredient, also is main toxic component, and effective dose is almost suitable with toxicity dose, and this hinders the further popularization of Chinese medicine trypterygine aspect clinical application greatly.
Improving the water miscible while of Radix Tripterygii Wilfordii extract, reduce its toxicity, improve the pharmacology transformation period of medicine, strengthen the probability of its stability and arrival target site, change route of administration and improve bioavailability and the high molecular weight water soluble polymer bonding becomes purpose of the present invention.
At present, polyethyleneglycol derivative is widely used in the physiology transformation period with prolong drug of combining with protein, peptide and other treatment medicine, reduces 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, be widely used, as PEG-intron  and PEGasys , the key compound 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.Polyoxyethylene glycol is quite clear in the intravital metabolic process of people, is a kind of safe, drug modified agent of having no side effect.
When combining with medicine, commonly used to a kind of technology that is called as Pegylation (PEGylation), be to have a suitable functional group after the end group of polyoxyethylene glycol is chemically activated, this functional group has activity to wanting at least one functional group in the bonded medicine, can form stable key with it.
Therefore, the objective of the invention is to combine with Radix Tripterygii Wilfordii extract with hydrophilic polymer by similar method, improve the solvability of Radix Tripterygii Wilfordii extract thus, reduce its toxicity, prolong the circulating half-life of Radix Tripterygii Wilfordii extract in organism, to guarantee suitable drug level and slow-release function is provided.
Summary of the invention
According to one aspect of the present invention, provide the binding substances of the hydrophilic polymer-Radix Tripterygii Wilfordii extract or derivatives thereof of general formula (I):
PL-D) n
(I)
Wherein:
P is a water-soluble polymers, is selected from the group of being made up of polyoxyethylene glycol, polypropylene glycol, polyvinyl alcohol, polyamino acid, polypropylene morpholine and their multipolymer;
N is-integer that maximum is no more than the end group active function groups number on the P;
L is a linking group, is selected from the group of being made up of ester group, carbonate group, amide group, acid amides ester group, ether, amido, amino acid ester group; And
D is the Radix Tripterygii Wilfordii extract or derivatives thereof.
In a preferred embodiment of the invention, described Radix Tripterygii Wilfordii extract is including but not limited to triptolide (triptolide), Triptodiolide (tripdiolide), Triptonide (triptonide), hypolide methylether (hypolidemethyl ether), Triptonide lactone (triptonolide), Triptolide 12,13-chlorohydrin (tripcheorolide), thunder rattan lactone triol (triptriolide), wilforonide (wilforonide), wilforine (tripterygine), wilfordine (wilfordine), tripterigine alkali (wilforgine), wilforine alkali (wilforine), wilfortrine (wiIfortrine), the hot alkali (wilforzine) of trypterygine, wilfordic acid (wilfordic acid), hydroxywilfordic acid (hydroxy wilfordicacid), trypterygine (tripterin or celustrol), Tripterysium Glucosides etc.
In a preferred embodiment of the invention, the preferred polyoxyethylene glycol of water-soluble polymers or its multipolymer.
In a preferred embodiment of the invention, described binding substances is hydrophilic polymer-triptolide binding substances that following general formula is represented:
Figure C20041002961500071
Wherein:
P represents water-soluble polymers, preferred polyoxyethylene glycol or its multipolymer;
N is an integer, and maximum is no more than the end group active function groups number on the P;
L is a linking group, connects the end group active function groups of Radix Tripterygii Wilfordii extract and water-soluble polymers, preferably but be not limited to: ester group, carbonate group, amide group, acid amides ester group, ether, amido, amino acid ester group.
The binding substances of the hydrophilic polymer-many carboxyls oligopeptides-Radix Tripterygii Wilfordii extract or derivatives thereof of general formula (II) expression is provided according to another aspect of the present invention:
Figure C20041002961500081
Wherein:
P is a hydrophilic polymer, is selected from the group of being made up of polyoxyethylene glycol, polypropylene glycol, polyvinyl alcohol, polyamino acid, polypropylene morpholine and their multipolymer;
M is the integer of 2-12;
J is the integer of 1-6;
R iFor being selected from by H, C 1-12The group of the group that alkyl, substituted aryl, aralkyl, assorted alkyl and substituted alkyl are formed;
X is a linking group, is selected from (the CH by O 2) kCO, O (CH 2) kOCO, O (CH 2) kNHCO, NR (CH 2) kOCO, NR (CH 2) kNHCO, NR (CH 2) kThe group that CO forms, wherein k is the integer of 1-6;
Z is a linking group, is selected from the group of being made up of ester group, carbonate group, amide group, acid amides ester group, ether, amido, amino acid ester group, amino acid amide base;
D is the Radix Tripterygii Wilfordii extract or derivatives thereof, preferred triptolide.
According to another aspect of the present invention, it provides the pharmaceutical composition that comprises above-mentioned binding substances.
An advantage of the invention is that the modification by hydrophilic polymer can provide protection to the bound drug of Radix Tripterygii Wilfordii extract; improved its stability and water-soluble; reduced toxicity; and prolonged the circulating half-life of trypterygine activity extract in organism, guaranteed suitable drug level and slow-release function is provided.
Embodiment
Binding substances of the present invention can be prepared as follows: hydrophilic polymer is carried out modification, introduce active function groups, and then combine with active group (as the hydroxyl on the triptolide) on the Radix Tripterygii Wilfordii extract.
Now describe with the example of polyoxyethylene glycol as hydrophilic polymer.But it should be understood that water-soluble polymers of the present invention is not limited in polyoxyethylene glycol or its multipolymer, also can use for example polypropylene glycol, polyvinyl alcohol, polyamino acid, polypropylene morpholine and their multipolymer.
The structural formula of polyoxyethylene glycol (PEG) can be shown in (III):
Wherein:
Figure C20041002961500091
R is H or C 1-12Alkyl,
L 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.R most preferably is methyl, and promptly formed compound is methoxy poly (ethylene glycol) (mPEG).
Certainly, except the straight chain polyoxyethylene glycol, the polyoxyethylene glycol of side chain or other structures also can be used for this invention and uses.Such as Y shape branch, U-shaped branch, star and many fork ramose polyoxyethylene glycol or the like also can be used for the molecular structure alteration to Radix Tripterygii Wilfordii extract.
For polyoxyethylene glycol, generally adopt molecular weight to be represented, be 150～60,000 dalton as long as make the molecular weight of the polyoxyethylene glycol that forms binding substances, this is equivalent to l is about 3～1300.More preferably, l is 28,112,225 and 450, and this is 1325,5000,10,000 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 l 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.
In a preferred embodiment of the invention, described Radix Tripterygii Wilfordii extract is including but not limited to triptolide (triptolide), Triptodiolide (tripdiolide), Triptonide (triptonide), hypolide methylether (hypolidemethyl ether), Triptonide lactone (triptonolide), Triptolide 12,13-chlorohydrin (tripcheorolide), thunder rattan lactone triol (triptriolide), wilforonide (wilforonide), wilforine (tripterygine), wilfordine (wilfordine), tripterigine alkali (wilforgine), wilforine alkali (wilforine), wilfortrine (wilfortrine), the hot alkali (wilforzine) of trypterygine, wilfordic acid (wilfordic acid), hydroxywilfordic acid (hydroxy wilfordicacid), trypterygine (tripterin or celustrol), Tripterysium Glucosides etc.Their chemical structure is as follows:
Triptolide (triptolide)
Figure C20041002961500102
Triptodiolide (tripdiolide)
All include hydroxyl in these structures, can combine with the polymkeric substance that passes through terminal groups modification, to reach effective protection of drug molecule and rationally to utilize by modes such as ester group, carbonate group, acid amides ester groups.Especially, ester group can discharge active constituents of medicine by biodegradable mode in organism.
Hydrophilic polymer of the present invention-Radix Tripterygii Wilfordii extract binding substances can carry out administration with pure compound form or appropriate drug composition, and the reagent that also can adopt any acceptable administering mode or be used for similar applications carries out.Therefore, another aspect of the present invention provides the pharmaceutical composition that comprises described binding substances.
The administering mode that adopts can be selected in through port, the nose, rectum, transdermal or drug administration by injection mode, its form is solid, semisolid, lyophilized powder or liquid preparation form administration, for example, tablet, suppository, pill, soft hard-gelatin capsules, powder, solution, suspensoid or aerosol etc., the preferred presented in unit dosage form that adopts the simple administration that is applicable to exact dosage desired.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.
Can adopt the pharmaceutical composition of liquid form administration for example can dissolve, be scattered in the carrier by the medicinal adjuvant of means such as dissolving, dispersion with binding substances of the present invention (about 0.5 to about 20%) and selectivity existence, the example of carrier 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, (Mack Publishing 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: the methoxy poly (ethylene glycol)-triptolide of ester group bonding (1) synthetic
Figure C20041002961500121
Figure C20041002961500122
100 milligrams of triptolides, 1.0 gram methoxy poly (ethylene glycol) acetate (Mw5000), 36 milligrams of 4-dimethylaminopyridines are dissolved in 15 milliliters of anhydrous methylene chlorides, add 80 milligrams of dicyclohexylcarbodiimide again.The reaction of solution room temperature stirred overnight.Remove by filter precipitation, solution concentration, resistates adds 15 milliliters of Virahols and 30 milliliters of ether, filtration washing, product vacuum-drying.Get triptolide-14-methoxy poly (ethylene glycol) acetic ester (1).Productive rate: 0.9 gram.Fusing point: 55-57 ℃.
Embodiment 2: the polyoxyethylene glycol-triptolide of ester group bonding (2) synthetic
Figure C20041002961500131
Figure C20041002961500132
100 milligrams of triptolides, 1.0 gram polyoxyethylene glycol oxalic acid (Mw10000), 36 milligrams of 4-dimethylaminopyridines are dissolved in 15 milliliters of anhydrous methylene chlorides, add 80 milligrams of dicyclohexylcarbodiimide again.The reaction of solution room temperature stirred overnight.Remove by filter precipitation, solution concentration, resistates adds 15 milliliters of Virahols and 30 milliliters of ether, filtration washing, product vacuum-drying.Get triptolide-14-polyoxyethylene glycol acetate diester (2).Productive rate: 0.9 gram.Fusing point: 57-59 ℃.
Embodiment 3: many carboxyls of polyoxyethylene glycol oligopeptides-triptolide (3) of ester group bonding synthetic
Figure C20041002961500141
1.0 (wherein, m is 3 to gram methoxy poly (ethylene glycol) L-glutamic acid tripeptides (Mw10500), R iBe H, j equals 2), 150 milligrams of triptolides, 60 milligrams of 4-dimethylaminopyridines are dissolved in 15 milliliters of anhydrous methylene chlorides, add 120 milligrams of dicyclohexylcarbodiimide again.
The reaction of solution room temperature stirred overnight.Remove by filter precipitation, solution concentration, resistates adds 15 milliliters of Virahols and 30 milliliters of ether, filtration washing, product vacuum-drying.Get triptolide-14-methoxy poly (ethylene glycol) L-glutamic acid tripeptide ester (3).Productive rate: 0.85 gram.Fusing point: 58-60 ℃.
Embodiment 4: the glycine of ester group bonding-triptolide binding substances (4) synthetic
Figure C20041002961500151
200 milligrams of t-boc-glycine (t-Boc-Gly-OH), 300 milligrams of triptolides, 120 milligrams of 4-dimethylaminopyridines are dissolved in 30 milliliters of anhydrous methylene chlorides, add 250 milligrams of dicyclohexylcarbodiimide again.The reaction of solution room temperature stirred overnight.Remove by filter precipitation, organic phase is used anhydrous sodium sulfate drying again with the acetate buffer solution washing of the pH5.7 of 0.5M 2 times, concentrate the white plates solid.Add 8 milliliters of methylene dichloride dissolvings again, added 6 milliliters of trifluoroacetic acid hydrolysis 30 minutes.Concentrating under reduced pressure adds 20 milliliters of methylene dichloride, and anhydrous sodium sulfate drying is used in the acetate buffer solution of the pH5.7 of 0.5M washing 2 times again, concentrate the white plates solid, vacuum-drying.Get triptolide-14-glycinate (4).Productive rate: 280 milligrams.H?NMR(CDCl 3)：5.08(d，14-CH)，3.54(d，12-CH)，0.96(d，17-CH 3)，0.85(d，16-CH 3)。
Embodiment 5: many carboxyls of polyoxyethylene glycol oligopeptides of the glycine linking group of ester group bonding and triptolide binding substances (5) synthetic
1.0 (wherein, m is 3 to gram methoxy poly (ethylene glycol) L-glutamic acid tripeptides (Mw10500), R iBe H, j equals 2), 170 milligrams of triptolide glycinates (4) (embodiment 4), 10 milligrams of 4-dimethylaminopyridines are dissolved in 20 milliliters of anhydrous methylene chlorides, add 120 milligrams of dicyclohexylcarbodiimide again.The reaction of solution room temperature stirred overnight.Remove by filter precipitation, solution concentration, resistates adds 15 milliliters of Virahols and 30 milliliters of ether, filtration washing, product vacuum-drying.Get triptolide-14-methoxy poly (ethylene glycol) L-glutamic acid tripeptides-glycinate (5).Productive rate: 0.95 gram.Fusing point: 60-62 ℃.
Embodiment 6: the methoxy poly (ethylene glycol)-triptolide of carbonate group bonding (6) synthetic
1 gram methoxy poly (ethylene glycol) (molecular weight 5000) and 200 milligrams of solid phosgenes are dissolved in 15 milliliters of anhydrous acetonitriles, drip 0.5 milliliter of anhydrous pyridine.Stirred 2 hours under nitrogen protection, rotary evaporation is removed unnecessary solvent, and residual solid is added 40 milliliters of ether, and throw out filters, vacuum-drying.Add 10 milliliters of anhydrous methylene chloride dissolvings again.Add 100 milligrams of triptolides, 0.2 gram 4-dimethylaminopyridine.Nitrogen protection was stirred 6 hours down, filtered, and unnecessary solvent is removed by rotary evaporation, and resistates adds 15 milliliters of Virahols and 30 milliliters of ether.Product filters collects vacuum-drying.Get triptolide-14-methoxy poly (ethylene glycol) carbonic ether (6).Productive rate: 0.85 gram (77%), fusing point: 57-59 ℃.
Embodiment 7: methoxy poly (ethylene glycol)-triptolide that the carboxylic acid amide esters base key closes (7) synthetic
Figure C20041002961500181
2 gram methoxy poly (ethylene glycol) second ammonia (mPEG-NH 2Molecular weight 5000) and 400 milligrams of solid phosgenes be dissolved in 30 milliliters of anhydrous acetonitriles, drip 1 milliliter of anhydrous pyridine.Stirred 2 hours under nitrogen protection, rotary evaporation is removed unnecessary solvent, and residual solid is added 40 milliliters of ether, and throw out filters, vacuum-drying.Productive rate: 1.9 grams (95%).NMR (DMSO): 3.5 (br m, the hydrogen among the PEG), 3.24 (s, 3 hydrogen), 3.18 (t, 2 hydrogen).
1 gram is by previous step synthetic polyethyleneglycol derivative (mPEG-N=C=O), and 100 milligrams of triptolides and 0.2 gram 4-dimethylaminopyridine are dissolved in 40 milliliters of anhydrous acetonitriles.Add 0.5 milliliter of new triethylamine that steams.Nitrogen protection at room temperature, stirred overnight, unnecessary solvent is removed by rotary evaporation, and resistates adds 100 milliliters of Virahols.Product filters collects vacuum-drying.Productive rate: 0.95 gram (91%).Get triptolide-14-methoxy poly (ethylene glycol) carboxylic acid amide esters (7).Fusing point: 58-60 ℃.Fusing point: 57-59 ℃.
Embodiment 8: the preparation of the lyophilized injectable powder of binding substances of the present invention
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 2 grams of embodiment 5
0.9% salt brine solution to 100 milliliter
The binding substances of embodiment 5 is dissolved in 0.9% salt brine solution, obtains 100 milliliters used for intravenous injection solution, with its membrane filtration filtration of material by 0.2 μ m, freezing under aseptic condition, dry, packing obtains lyophilized injectable powder.

Claims (14)

1. the binding substances of the hydrophilic polymer of general formula (I)-Radix Tripterygii Wilfordii extract or derivatives thereof:
PL-D) n
(I)
Wherein:
P is a water-soluble polymers, is selected from the group of being made up of polyoxyethylene glycol, polypropylene glycol, polyvinyl alcohol, polyamino acid, polypropylene morpholine and their multipolymer;
N is an integer, and maximum is no more than the end group active function groups number on the P;
L is a linking group, is selected from the group of being made up of ester group, carbonate group, amide group, acid amides ester group, ether, amido, amino acid ester group, amino acid amide ester; And
D is the Radix Tripterygii Wilfordii extract or derivatives thereof, is selected from the group that triptolide, Triptodiolide and thunder rattan lactone triol are formed.
2. binding substances as claimed in claim 1, wherein, described hydrophilic polymer is a polyoxyethylene glycol, described polyoxyethylene glycol is straight chain polyoxyethylene glycol, branched chair polymacrogol or Y shape branch, U-shaped branch, star or pitch the ramose polyoxyethylene glycol more.
3. binding substances as claimed in claim 2, the molecular weight of wherein said polyoxyethylene glycol is at 150-60, between 000.
4. binding substances as claimed in claim 1, wherein, described binding substances has following general formula:
Figure C2004100296150002C1
Wherein, described L is a linking group, is selected from the group of being made up of ester group, carbonate group, acid amides ester group, ether, amino acid ester group, amino acid amide ester.
5. binding substances as claimed in claim 1, wherein, described binding substances be selected from by:
Triptolide-14-methoxy poly (ethylene glycol) acetic ester (1);
Triptolide-14-polyoxyethylene glycol acetate diester (2);
Triptolide-14-methoxy poly (ethylene glycol) carbonic ether (6); With
Triptolide-14-methoxy poly (ethylene glycol) carboxylic acid amide esters (7)
The group of forming.
6. the binding substances of the hydrophilic polymer-many carboxyls oligopeptides-Radix Tripterygii Wilfordii extract or derivatives thereof of general formula (II) expression:
Wherein:
P is a hydrophilic polymer, is selected from the group of being made up of polyoxyethylene glycol, polypropylene glycol, polyvinyl alcohol, polyamino acid, polypropylene morpholine and their multipolymer;
M is the integer of 2-12;
J is the integer of 1-6;
R iFor being selected from by H, C 1-12The group of the group that alkyl, substituted aryl, aralkyl, assorted alkyl and substituted alkyl are formed;
X is a linking group, is selected from (the CH by O 2) kCO, O (CH 2) kOCO, O (CH 2) kNHCO, NR (CH 2) kOCO, NR (CH 2) kNHCO, NR (CH 2) kThe group that CO forms, wherein k is the integer of 1-6;
Z is a linking group, is selected from the group of being made up of ester group, carbonate group, amide group, acid amides ester group, ether, amido, amino acid ester group, amino acid amide base;
D is the Radix Tripterygii Wilfordii extract or derivatives thereof, is selected from the group that triptolide, Triptodiolide and thunder rattan lactone triol are formed.
7. binding substances as claimed in claim 6, wherein, described hydrophilic polymer is a polyoxyethylene glycol, described polyoxyethylene glycol is straight chain polyoxyethylene glycol, branched chair polymacrogol or Y shape branch, U-shaped branch, star or pitches the ramose polyoxyethylene glycol more.
8. binding substances as claimed in claim 7, wherein, the molecular weight of described polyoxyethylene glycol is at 150-60, between 000.
9. binding substances as claimed in claim 6, wherein, the amino acid among the described linking group Z is glycine.
10. binding substances as claimed in claim 6, wherein, described Radix Tripterygii Wilfordii extract is a triptolide.
11. binding substances as claimed in claim 6, wherein, described binding substances is
Triptolide-14-methoxy poly (ethylene glycol) L-glutamic acid tripeptide ester (3); Perhaps
Triptolide-14-methoxy poly (ethylene glycol) L-glutamic acid tripeptides-glycinate (5).
12. contain binding substances and pharmacology acceptable carrier or vehicle pharmaceutical composition just like claim 1-5 or 6-11.
13. pharmaceutical composition as claimed in claim 12, the pharmaceutical composition that wherein, described pharmaceutical composition is in the through port, nose, rectum, transdermal or injection system carry out administration.
14. pharmaceutical composition as claimed in claim 12, wherein, described pharmaceutical composition is tablet, suppository, pill, soft or hard-gelatin capsules, powder, solution, suspensoid or aerosol.
CNB2004100296153A 2004-03-29 2004-03-29 Hydrophilic polymer-thunder good vine extract binding substance and its medicinal composition Expired - Fee Related CN100374443C (en)

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