CN107137715A - Prodrug and preparation is conjugated in a kind of 9-hydroxy-risperidone polyethylene glycol - Google Patents
Prodrug and preparation is conjugated in a kind of 9-hydroxy-risperidone polyethylene glycol Download PDFInfo
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- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
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Abstract
The invention of prodrug (PEG 9-hydroxy-risperidones) is conjugated in a kind of new drug 9-hydroxy-risperidone polyethylene glycol, is related to it and prepares and apply, described PEG 9-hydroxy-risperidones have shown in below formula:Including carrier (polyethylene glycol, PEG), linking arm (AA) and 9-hydroxy-risperidone, wherein carrier is single armed polyethylene glycol or both arms and four arm polyethylene glycol, the degree of polymerization 10~500；Linking arm is amino acid or the oligopeptides being made up of amino acid.Transformed by carrying out PEGylation modification to 9-hydroxy-risperidone, extend drug half-life, can reach 1 times a week or even monthly 1 time, improve and use compliance；The water solubility of medicine is added, enable to make normal injection agent, it is to avoid using the super difficult technique of nanocrystalline durative action preparation, reduction production difficulty and application risk.This preparation technology is simple to operate, environmental protection, with low cost, it is easy to industrialized production.Formula is as follows：Single armed：Both arms：Four arms：
Description
Technical field
The invention belongs to medicine and the field of chemical synthesis, and in particular to prodrug is conjugated in a kind of new drug 9-hydroxy-risperidone polyethylene glycol
Invention, the application also provide 9-hydroxy-risperidone polyethylene glycol be conjugated prodrug preparation method and application.
Background technology
9-hydroxy-risperidone (Paliperidone) is the atypical antipsychotics of Johnson companies of U.S. exploitation listing,
Belong to the 5-HT antagonists of benzo Isoxazole derivative class.9-hydroxy-risperidone (Paliperidone) be also 9-hydroxy-risperidone (9-
Hydroxy-risperidone), it is the major active metabolite product of Risperidone (Risperidone), its pharmacological characteristic and profit
Train ketone similar, antipsycholic action is mainly played by antagonism 5-hydroxytryptamine receptor and dopamine D Z acceptors, with other atypia
Anti-semen antibody is compared, and has shown higher receptor affinity, and therapeutic effect is good.
The chemical name of 9-hydroxy-risperidone：(±) -3-2- [4- (fluoro- 1, the 2- benzos isoxazole -3- bases of 6-) -1- piperidyls] second
Base] -6,7,8,9- tetrahydrochysene -9- hydroxy-2-methyl -4H- pyridos [1,2-a] pyrimidin-4-ones, molecular formula is C23H27FN4O3, change
Learn structural formula：
Schizophrenia is the unknown common mental disease of one group of cause of disease, with perception, thinking, emotion, will and behavior etc.
Many obstacles, are characterized with the uncoordinated of cerebration or be divorced from reality.How intact the usual Consciousness of patient, intelligence is,
Delaying the course of disease, some patientss can develop into the decline of cerebration more.The easy recurrent exerbation of schizophrenia, course of disease delay, patient
The characteristics of poor compliance, also brings certain difficulty to clinical treatment.
9-hydroxy-risperidone half-life period is very short, it is impossible to make common oral preparation, the 9-hydroxy-risperidone sustained release tablets that in the market is only deposited by
Poor in patient's compliance, using effect is not good.It is that a kind of palm fibre of 9-hydroxy-risperidone puts Esterification product that palm fibre, which puts sour 9-hydroxy-risperidone, is utilized
Its slightly solubility and nanometer crystal technique, Janssen Pharmaceutica have developed new 2 generation antipsychotic drug-palm fibre and puts sour 9-hydroxy-risperidone injection
Liquid (kind think of reaches@), is that the current country uniquely can be quick in acute stage for the treatment of schizophrenia acute stage and maintenance phase
Recurrence can effectively be prevented in long term maintenance therapy again by working, and monthly inject the new antipsychotic drug of 1 time.Palm fibre is put
Sour 9-hydroxy-risperidone is a kind of prodrug, into resolving into 9-hydroxy-risperidone and work after in vivo.
But, palm fibre puts sour 9-hydroxy-risperidone parenteral solution (kind think of reaches) to be white to linen suspension, there is following defect：
(1) research and development difficulty is big, and preparation equipment requires high, and nanocrystalline particles size and distribution is difficult to control to, and it is special to be needed in terms of production
Nanocrystal technology and corresponding special installation, current domestic production equipment are difficult to reach and the detection device without response；(2) matter
Control requires high, in terms of quality in addition to it need to control parenteral solution conventional project, also needs to control weight suspension ability and consistence test, particle diameter point
The special items such as cloth, release, storage stability, uniformity of dosage units；(3) it is expensive, every (1ml：100mg) import 2000
Yuan；(4) dosage need to be controlled strictly, it is proposed that patient reaches 150mg, a Zhou Houzai in the kind think of of initial treatment first day injection
Secondary injection 100mg, the injection site of preceding 2 doses of initial treatment medicines is deltoid muscle.Maintaining treatment dosage is monthly 75mg, according to
The tolerance situation and/or curative effect of patient, can increase or decrease injection dosage monthly in the range of 25-150mg.2nd dose of medicine
After thing, monthly the position of 1 injection can be deltoid muscle or gluteus.Every month can adjust the dosage of maintaining treatment.Adjust
During whole dosage, the long-acting release feature that kind think of reaches need to be considered, whole effects produced by dosage adjustment may need some months
Time can just embody；(5) administering mode is complicated：Only use that (first 2 times are deltoid muscle, later can be with for intramuscular injection
It is gluteus or deltoid muscle), per injection must all be operated by the health workers of specialty, during injection, should slowly inject flesh
Meat deep.It is careful not to enter drug injection in blood vessel.Every dose of medicine all should disposably be injected and finished, it is impossible to fractional injection.No
By drug injection to intravascular or subcutaneous；(6) composition of parenteral solution is complicated, has used surfactant Polysorbate 20
It is (kind to think up to composition to be Polysorbate 20, Macrogol 4000, Citric Acid Mono, disodium hydrogen phosphate, a water biphosphate
Sodium, sodium hydroxide and water for injection).
Palm fibre puts why sour 9-hydroxy-risperidone parenteral solution (kind think reach at@) makes the durative action preparation of such complexity except medicine in itself
Outside physicochemical property, the also consideration of pharmacoeconomics：(1) 9-hydroxy-risperidone molecule half-life period itself is very short, it is impossible to make common mouth
Formulation；(2) the oral absolute bioavailability of 9-hydroxy-risperidone sustained release tablets is low (28% or so)；(3) palm fibre puts sour 9-hydroxy-risperidone and use up
Pipe half-life period effectively extends, but water-soluble very poor；(4) nanometer crystal technique, is especially distributed by nanocrystalline different-grain diameter and combines
Slightly solubility reaches the purpose of sustained release, is a technology content very high proprietary technology, it is difficult to imitated；(5) although palm fibre puts sour handkerchief profit
The potential risk that piperazine ketone parenteral solution (kind to think to reach@) has medicine intravasation to be likely to form thrombus, but due to mental patient's medication
Particularity, the product or income are much larger than risk.
Polyethylene glycol (PEG) is that a few of U.S. FDA approval can be used for one of synthetic polymer of intravenously administrable,
PEG modification techniques are the novel medicine feeding technologies developed rapidly in recent years, are mainly used in injection delivery systems.
The above mentioned problem existed for 9-hydroxy-risperidone, using the hydroxyl in 9-hydroxy-risperidone, passes through polyethyleneglycol modified technology
Prepare 9-hydroxy-risperidone polyethylene glycol be conjugated prodrug, make its substantially increase it is water miscible simultaneously, also significantly extend 9-hydroxy-risperidone
Half-life period.Polyethylene glycol 9-hydroxy-risperidone can make Aqueous injection agent, after injection enters in vivo, can exist by design requirement
9-hydroxy-risperidone is discharged with certain hydrolysis rate in vivo, schizophrenia acute stage is produced and maintains the response to treatment of phase, both
It can reach that palm fibre puts long-acting, the slow release effect of sour 9-hydroxy-risperidone parenteral solution (kind to think to reach@), turn avoid its production cost height, use
Inconvenient shortcoming, reduces the medical expense of patient, improves medication compliance.Polyethylene glycol 9-hydroxy-risperidone makes lyophilized, injection
Auxiliary material needed for liquid is relatively fewer, and composition is simple, it is to avoid use surfactant (solubilization) Polysorbate 20, reduces
Adverse reaction；Preparation technology is easy to the production of domestic industry metaplasia, it is to avoid use nanocrystal technology and special production equipment, production
Cost is greatly lowered.
The content of the invention
Prodrug is conjugated it is an object of the invention to provide a kind of new 9-hydroxy-risperidone prodrug, i.e. 9-hydroxy-risperidone polyethylene glycol
(PEG- 9-hydroxy-risperidones) and preparation method.Compared with 9-hydroxy-risperidone and palmitic acid 9-hydroxy-risperidone, it considerably increases water solubility,
The 9-hydroxy-risperidone of activity is decomposed into vivo, plays drug effect, and by design, can make 1 day, 1 week, 2 weeks, 1
The even longer time moon injects the newtype drug with slow releasing function once.
Prodrug (PEG- 9-hydroxy-risperidones) is conjugated with following structure in 9-hydroxy-risperidone polyethylene glycol：
Single armed：
Both arms：
Four arms：
In aforementioned prodrugs structure, n is 20~500 integer in single armed, both arms PEG- 9-hydroxy-risperidones, represents polyethylene glycol
The degree of polymerization.(AA)w、(AA)vThe small molecule oligopeptides of identical or different amino acid or amino acid condensation formation is represented, connection is used as
Group.W, v are 0-12 integers, and represented amino acid quantity, preferably w, v are 1.
In aforementioned prodrugs structure, a, b, c, d are 10~200 integers in four arm PEG- 9-hydroxy-risperidones, represent polyethylene glycol
The degree of polymerization.(AA)w、(AA)v、(AA)x、(AA)yRepresent the small molecule of identical or different amino acid or amino acid condensation formation
Oligopeptides, is used as linking group.W, v, x, y are 0-12 integers, and represented amino acid quantity, preferably w, v, x, y are 1.
PEG- 9-hydroxy-risperidones are synthesized by certain technological means, following structure of illustrating：
Single armed：
Both arms：
Four arms：
Present invention citing PEG- 9-hydroxy-risperidone structural formulas, there is single armed, both arms, four arms, as implied above (to include but is not limited to such as
On structure), for ease of understanding, the embodiment of the present invention synthesized both arms PEG- 9-hydroxy-risperidones and four arm PEG- 9-hydroxy-risperidones and four
Arm PEG- glycine 9-hydroxy-risperidones.
The preparation of PEG- 9-hydroxy-risperidones：9-hydroxy-risperidone reacts into ester with polyethylene glycol acetic acid direct polycondensation.
PEG- glycine 9-hydroxy-risperidones：9-hydroxy-risperidone and glycine reactant into ester, then 9-hydroxy-risperidone glycinate again with
Polyethylene glycol acetic acid is combined.
There is provided include PEG- 9-hydroxy-risperidones or pharmaceutically acceptable drug regimen for another aspect of the present invention
Thing, in some embodiments, pharmaceutical composition may be constructed parenteral solution, freeze-dried powder, subcutaneous injection agent, implant etc..This
The advantage of invention is the PEG- 9-hydroxy-risperidones prepared relative to palmitic acid 9-hydroxy-risperidone, with good dissolubility energy, stably
Property and longer Half-life in vivo, realize the target of long-acting slow-release, at the same avoid nanometer crystal technique puzzlement and suspend breast
The potential preparation risk of agent.
Another aspect of the present invention is pharmaceutically acceptable there is provided PEG- 9-hydroxy-risperidones or with pharmaceutic adjuvant composition
Dosage form, the treatment applied to schizophrenia acute stage and maintenance phase.
Embodiment
Following examples are used for illustrating the present invention, but are not limited to the present invention.
Embodiment 1 (preparation of both arms PEG- 9-hydroxy-risperidones)：
By both arms polyethylene glycol acetic acid (mean molecule quantity 2000, breadth coefficient<1.05) 20.0g (10.0mmol), two rings
Hexyl carbodiimide (DCC) 4.9g (24.0mmol), is dissolved in 200mL anhydrous methylene chlorides at room temperature, stirring, adds handkerchief profit
Piperazine ketone 9.4g (22.0mmol) and 0.12g (1.0mmol) DMAP, normal-temperature reaction 16h, filters out insoluble matter, by solvent rotary evaporation
Remove, addition 100mL isopropanols (IPA) recrystallization, filtering, product vacuum is dried, and obtains both arms polyethylene glycol -9-hydroxy-risperidone ester
16.7g。
1H-NMR (400MHz, CDCl3)δ：7.75-7.68 (m, 2H), 7.25-7.21 (m, 2H), 7.07-7.01 (m, 2H),
5.80 (t, J=5.4Hz, 2H), 4.22 (s, 4H), 4.06-3.72 (m, 4H), 3.77-3.72 (m, 4H) 3.65-3.58 (m,
188H), 3.33-3.23 (m, 4H), 3.18-3.10 (m, 2H), 2.86-2.78 (m, 4H), 2.72-2.63 (m, 4H), 2.55-
2.36 (m, 4H), 2.30-1.92 (m, 22H).
Embodiment 2 (preparations of four arm PEG- 9-hydroxy-risperidones)：
By four arm polyethylene glycol acetic acid (mean molecule quantities 20000, breadth coefficient<1.05) 20.0g (1.0mmol), 1- (3-
Dimethylaminopropyl) -3- ethyl-carbodiimide hydrochlorides (EDCI) 0.92g (4.8mmol), be dissolved at room temperature 200mL without
In water dichloromethane, stirring adds 9-hydroxy-risperidone 1.88g (4.4mmol) and 0.01g (0.1mmol) DMAP, normal-temperature reaction 16h,
Insoluble matter is filtered out, solvent rotary evaporation is removed, addition 100mL isopropanols (IPA) recrystallization, filtering, product vacuum is dried, obtained
Four arm polyethylene glycol -9-hydroxy-risperidone ester 15.8g.
1H-NMR (400MHz, CDCl3)δ：7.63-7.59 (m, 4H), 7.25-7.21 (m, 4H), 7.20-7.11 (m, 4H),
4.58-4.50 (m, 8H), 4.25 (s, 8H), 4.16-4.08 (m, 8H), 3.93-3.02 (m, 1830H), 3.01-2.87 (m,
8H), 2.50-2.48 (m, 8H), 2.38-2.05 (m, 44H), 1.90-1.73 (m, 8H).
Embodiment 3 (preparations of four arm PEG- glycine 9-hydroxy-risperidones)：
Four arm polyethylene glycol-acetic acid (mean molecule quantity 20000, breadth coefficient<1.04) the sharp piperazine of 20.0g (1.0mmol), handkerchief
Ketone-glycinate 3.88g (8.0mmol), DMAP (DMAP) 0.98g (8.0mmol), I-hydroxybenzotriazole
(HOBT) 1.08g (8.0mmol), is dissolved in 200ml dichloromethane, dicyclohexylcarbodiimide is added dropwise under nitrogen protection
(DCC) 1.65g (8.0mmol) dichloromethane (16mL) solution, drop finishes, and nitrogen protection reaction is stayed overnight.It is filtered to remove solids
Matter, excess of solvent rotary evaporation is removed, and residue addition 200ml isopropanols (IPA) recrystallization, filtering, product is vacuum dried,
Obtain four arm polyethylene glycol-glycine -9-hydroxy-risperidone 17.2g.
1H-NMR (400MHz, CDCl3)δ：7.74-7.65 (m, 4H), 7.21-7.15 (m, 4H), 7.12-7.05 (m, 4H),
4.58-4.52 (m, 8H), 4.40-4.35 (m, 8H), 4.16 (s, 8H), 3.93-3.05 (m, 1852H), 3.12-2.78 (m,
8H), 2.55-2.43 (m, 8H), 2.32-2.03 (m, 44H), 1.92-1.78 (m, 8H).
Experiment 1：The solubility comparative test of PEG- 9-hydroxy-risperidones and palmitic acid 9-hydroxy-risperidone
According to 2015 editions《Chinese Pharmacopoeia》, deliquescent investigate is carried out to embodiment：Accurately weigh the sample (production of embodiment
Thing) and 9-hydroxy-risperidone, palmitic acid 9-hydroxy-risperidone it is each appropriate, be separately added into after a certain amount of purified water, shaken every 5min strengths
30s, and observed, it is completely dissolved if being visible by naked eyes particles of solute in 30min and being considered as, the results are shown in Table 1.
The solubility comparative test result of table 1, PEG- 9-hydroxy-risperidones and 9-hydroxy-risperidone
Drawn from above-mentioned experimental result, it is readily soluble in 9-hydroxy-risperidone polyethylene glycol conjugate water of the invention, with respect to the sharp piperazine of handkerchief
For ketone and palmitic acid, water-soluble substantially increase.
Experiment 2：The stability test of injection PEG- 9-hydroxy-risperidones
Sample (product of embodiment 1,2,3) is soluble in water, and it is 2mg/ml's (in terms of 9-hydroxy-risperidone) to be configured to concentration
The aqueous solution, adds mannitol in right amount, is filtered with 0.22 micron membrane filter, filtrate is sub-packed in 10ml cillin bottles (5ml/ branch), freeze
Dry, gland obtains embodiment 4,5,6.Sample after lyophilized is placed 10 days under illumination, hot conditions respectively, acceleration environment (temperature
40 DEG C of degree, humidity 75%) June is placed, with reference to the detection method of 9-hydroxy-risperidone raw material, detected whether using high performance liquid chromatograph
There is free 9-hydroxy-risperidone, as a result table 2.
Instrument：Shimadzu LC-16 high performance liquid chromatographs
Detection wavelength：275nm
Column temperature：35℃
Flow velocity：1.2ml/min
Mobile phase：
Mobility A:0.01mol/L acetic acid amine aqueous solutions 1000ml adds 1ml formic acid；Mobile phase B：700ml acetonitriles are taken, are added
300ml isopropanols, plus 1ml formic acid.Mobile phase A：B=25：75
Retarder thinner：Tetrahydrofuran-dimethylformamide=5:95
Table 2, injection PEG- 9-hydroxy-risperidone stability test results --- free 9-hydroxy-risperidone amount (%)
From above-mentioned experiment, injection PEG- 9-hydroxy-risperidones accelerate 6 months, the sign for free 9-hydroxy-risperidone occur, but
It is the security of the quality (clarity of solution) and clinic that do not influence product.
Test 3 injection PEG- 9-hydroxy-risperidones and compared with the hydrolysis experiment that kind think of reaches
Made respectively of the sample of embodiment 4,5,6 and palmitic acid 9-hydroxy-risperidone parenteral solution (kind think of reaches, comparison example) to having a competition
Test：
1) the genial think of of the sample of Example 4,5,6 is reached, and 6 parts are prepared respectively, is taken appropriate (equivalent to 10mg 9-hydroxy-risperidones/appearance
Measuring bottle) it is placed in 25ml volumetric flasks；
2) above-mentioned all samples add 10mL 0.0025mol/L sodium hydroxide (0.01%) aqueous dissolution, in 40 DEG C of water
The aqueous hydrochloric acid solution that 2mL 0.02mol/L are added after solution 0,5,10,30,60,90,150min terminates hydrolysis, solubilizer (tetrahydrochysene furan
Mutter-dimethylformamide=5:95) scale is diluted to, is shaken up；
3) hydrolysate -9-hydroxy-risperidone is determined with HPLC, detection method is with experiment 2.
Table 3, different sample hydrolysis result of the tests
From above-mentioned experiment, injection PEG- 9-hydroxy-risperidones can be hydrolyzed under certain environment, discharge effectively
Composition 9-hydroxy-risperidone, and the kind hydrolysis rate for thinking to reach is considerably slower than embodiment 4,5,6, analysis reason is that the Hydrolytic Mechanism of the two is deposited
In certain difference, embodiment is polyethylene glycol 9-hydroxy-risperidone direct hydrolysis, and it is by palmitic acid 9-hydroxy-risperidone that kind think of, which reaches,
Granule size is first dissolved, then release 9-hydroxy-risperidone is hydrolyzed.In a word, by the way that 9-hydroxy-risperidone is carried out into structural modification -- it is poly-
PEGylation, can control its hydrolysis rate according to certain requirement, so as to reach the effect slowly discharged, be allowed to be expected to turn into
The 1 times a week or even monthly parenteral solution of 1 time.
Claims (8)
1. prodrug is conjugated in a kind of 9-hydroxy-risperidone polyethylene glycol（PEG- 9-hydroxy-risperidones）, it is characterised in that by polyethyleneglycol modified handkerchief profit
Piperazine ketone turns into 9-hydroxy-risperidone polyethylene glycol and prodrug is conjugated,
The molecular structure of compounds formula includes following structure：
Single armed：
Both arms：
Four arms：
Wherein（AA）For difunctional linker.
2. in the PEG- 9-hydroxy-risperidone structures described in claim 1（AA）w、（AA）v、（AA）x、（AA）yComprising but be not limited only to sweet
Propylhomoserin, alanine, lysine, phenylalanine, isoleucine, proline, valine, histidine, leucine, tryptophan, Soviet Union's ammonia
Acid, methionine, preferably glycine, represent the small molecule oligopeptides of identical or different amino acid condensation formation, as linking group,
W, v, x, y can be 0-12 integers, preferably 1, represented amino acid quantity, w, v, x, y can be with identical, can also be different.
3. in the PEG- 9-hydroxy-risperidone structures described in claim 1, the n in single armed and both arms is 20~500 integer.
4. in the PEG- 9-hydroxy-risperidone structures described in claim 1, a, b, c, d are 10~200 integer, equal generation in four arm configurations
The degree of polymerization of table polyethylene glycol, a, b, c, d can be with identical, can also be different.
5. the 9-hydroxy-risperidone polyethylene glycol conjugate prodrug described in claim 1（PEG- 9-hydroxy-risperidones）Preparation method：To parent
Aqueous polyethylene glycol is modified, and is introduced active function groups carboxyl, is directly combined with 9-hydroxy-risperidone；Or 9-hydroxy-risperidone first with
Amino acid or oligopeptides react into ester, and then 9-hydroxy-risperidone amino-acid ester is combined with the carboxyl of polyglycolic acid again.
6. polyethyleneglycol modified 9-hydroxy-risperidone conjugate as claimed in claim 1（PEG- 9-hydroxy-risperidones）Or constituted with pharmaceutic adjuvant
Composition, can make parenteral solution, freeze-dried powder, liquid, implant etc. is subcutaneously injected.
7. such as claim 1-6 polyethyleneglycol modified 9-hydroxy-risperidone conjugate（PEG- 9-hydroxy-risperidones）Or constituted with pharmaceutic adjuvant
Composition, its half-life period can extend several times or decades of times, and 1 time can be injected weekly and is even monthly injected 1 time.
8. the polyethyleneglycol modified 9-hydroxy-risperidone conjugate as described in claim 1-6（PEG- 9-hydroxy-risperidones）Or and pharmaceutic adjuvant
The pharmaceutically acceptable dosage form of composition, the treatment applied to schizophrenia acute stage and maintenance phase.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110124048A (en) * | 2019-04-23 | 2019-08-16 | 湖南华腾制药有限公司 | Multi-arm polyethylene glycol matrine conjugate, preparation method and application |
| CN115260190A (en) * | 2022-08-30 | 2022-11-01 | 南开大学 | Prapidone prodrug, preparation method and application thereof |
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| US20040096507A1 (en) * | 2002-11-08 | 2004-05-20 | Sunbio Inc. | Novel hexa-arm polyethylene glycol and its derivatives and the methods of preparation thereof |
| WO2010039861A2 (en) * | 2008-09-30 | 2010-04-08 | The Regents Of The University Of Michigan | Dendrimer conjugates |
| CN101724144A (en) * | 2008-11-03 | 2010-06-09 | 北京键凯科技有限公司 | Novel multi-arm polyethylene glycol, preparation method and application thereof |
| WO2011042450A1 (en) * | 2009-10-06 | 2011-04-14 | Ascendis Pharma As | Carrier linked paliperidone prodrugs |
| CN102917592A (en) * | 2010-03-16 | 2013-02-06 | 萨拉戴克斯生物医学公司 | Risperidone immunoassay |
| CN104736566A (en) * | 2012-08-21 | 2015-06-24 | 奥索临床诊断有限公司 | Antibodies to paliperidone haptens and use thereof |
| CN104755479A (en) * | 2012-08-21 | 2015-07-01 | 詹森药业有限公司 | Haptens of risperidone and paliperidone |
| CN104548125A (en) * | 2014-12-30 | 2015-04-29 | 北京大学 | Preparation and application of PEG-PTX-NCs (pegylation-paclitaxel-nanocrystals) |
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| CN110124048A (en) * | 2019-04-23 | 2019-08-16 | 湖南华腾制药有限公司 | Multi-arm polyethylene glycol matrine conjugate, preparation method and application |
| CN110124048B (en) * | 2019-04-23 | 2022-06-17 | 湖南华腾制药有限公司 | Multi-arm polyethylene glycol matrine conjugate, preparation method and application thereof |
| CN115260190A (en) * | 2022-08-30 | 2022-11-01 | 南开大学 | Prapidone prodrug, preparation method and application thereof |
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