CN103992417A - Accessory for coating medicinal compound and preparation method thereof - Google Patents
Accessory for coating medicinal compound and preparation method thereof Download PDFInfo
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- CN103992417A CN103992417A CN201410063279.8A CN201410063279A CN103992417A CN 103992417 A CN103992417 A CN 103992417A CN 201410063279 A CN201410063279 A CN 201410063279A CN 103992417 A CN103992417 A CN 103992417A
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- 0 C*C(C)OCC(C(*C)OC(COCC(C(C1)*C(*C)CC1[C@@]1N=O)=C1N)C1O)[C@]1O Chemical compound C*C(C)OCC(C(*C)OC(COCC(C(C1)*C(*C)CC1[C@@]1N=O)=C1N)C1O)[C@]1O 0.000 description 8
- KCFNOFMKQYSRQE-SXVYVOEYSA-N CCC(CCC1CC(C2)N)CC1[C@H]2N Chemical compound CCC(CCC1CC(C2)N)CC1[C@H]2N KCFNOFMKQYSRQE-SXVYVOEYSA-N 0.000 description 1
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Abstract
The invention discloses a preparation method of an accessory for coating a medicinal compound. The method comprises synthesis of succinylated glucan, synthesis of an aminated folacin analogue, and synthesis of a folacin-dextran conjugate namely the accessory. The invention also discloses the accessory produced by the method, and a medicinal compound containing the accessory and a preparation method thereof.
Description
Technical field
The present invention is the invention of No. 201210543504.9 division of Chinese patent application, enjoys the applying date on December 14th, 2012.
The invention belongs to field of pharmaceutical preparations, particularly, the present invention relates to the preparation method for the auxiliary material of packaging medicine compound, this auxiliary material is except promoting the physico-chemical property of medicine of its parcel, even can be with collaborative onsets such as taxols, and can improve the tolerance of medicine.In addition, the invention still further relates to the auxiliary material producing by the method and comprise pharmaceutical composition of this auxiliary material and preparation method thereof etc.
Background technology
Most of cancer therapy drugs of current clinical use, as taxol, Docetaxel (docetaxel), the solubleness in physiological saline such as Zorubicin is poor, cannot directly use clinically, needs some auxiliary materials to coordinate.For example,
prepare taxol with the mixture of polyoxyethylenated castor oil and ethanol,
(taxotere) prepared with polysorbate and ethanol, but all can cause strong side effect, as anaphylaxis, Toxicity of Kidney, nerve and cardiac toxic etc.; Nearest
be that carrier is prepared taxol with serum albumin, toxic side effect also obviously reduces, but no matter serum albumin is to extract or DNA restructuring acquisition, purifying difficulty is large, cause cost high, a dosage just needs US $ 5,100, and need at least 3 doses a course for the treatment of, cannot promote in China.
Japanese Patent JP2010126533A has disclosed, together with taxol is conjugated in covalency such as dextran, and then by the non-covalent fixing folic acid in drug particles surface that is adsorbed on, to reach the object of targeting anti-tumor, but the inventor finds, taxol is as drug activity compound, put together with dextran, especially with dextran on the side reaction of a large amount of groups, due to the change of chemical structure, can significantly reduce the drug effect of taxol, if eliminate the close by product of structure, need complicated purge process (as chromatography is crossed post), cost can fall, and folic acid is adsorbed on surface, easily wash-out.Chinese patent 20121002970.5 discloses covalently bound folic acid-dextran-ferric oxide nanometer particle, it has targeting effect, it does not report the antitumous effect (reality does not have substantially) of this particle itself, and the inventor finds that it is first to synthesize dextran-ferric oxide nanometer particle, and then carry out folic acid and put together, combined coefficient is low, and auxiliary material is lost the adaptability of medicine.
For this reason, the inventor is through arduous research, and in conjunction with some fortune, chance on by some linking groups folic acid is directly covalently bound in dextran, although lost to a certain extent the targeting of folic acid to tumour, at present its external toxicity (activity) that there is no antitumor cell after tested, but but can very stably noncovalently wrap medicines such as taxol, solubility and stability are all good, and needn't change the chemical structure of taxol, also without using complicated purifying process (as, column chromatography).More unexpectedly be, although this auxiliary material itself does not have the toxicity of extracorporeal anti-tumor cell, but can combined with taxol onset, improve the antineoplastic effect in body, and can improve the drug tolerance of animal subject, making in clinical use can larger dose ground administration, thereby further improves antitumous effect.
Summary of the invention
The object of the present invention is to provide the preparation method of the new auxiliary material for packaging medicine compound, the method is without complicated purifying process, especially when the auxiliary material of preparation is for packaging medicine compound, possesses good medicine adaptability, even can with the collaborative onset of the medical compounds such as taxol, improve curative effect and drug tolerance, the pharmaceutical composition solubility and the stability that are wrapped to form are all good.In addition, the present invention also provides the auxiliary material producing by the method and has comprised pharmaceutical composition of this auxiliary material and preparation method thereof etc.
Particularly, aspect I, the invention provides the preparation method for the auxiliary material of packaging medicine compound, it comprises,
(1) press procedural style I ambroid acidylate dextran, wherein the molecular-weight average of dextran is 5～30KDa, and more preferably 10～20KDa, as 10KDa, 15KDa or 20KDa
(2) press the synthetic aminated folacin of procedural style II
(3) synthesize folic acid-dextran conjugate by the product of flow process step (1) and step (2) formula III for
Aspect II, the invention provides the auxiliary material for packaging medicine compound, its preparation method by the present invention I aspect prepares and obtains.
Aspect III, the invention provides the application in the pharmaceutical composition (preferably injection is more preferably lyophilized injectable powder) that the auxiliary material of the present invention II aspect contains fat-soluble medicine compound (preferably taxol) in preparation.
Aspect IV, the invention provides the present invention II aspect auxiliary material parcel medical compounds and pharmaceutical composition, preferred wherein said composition is injection, more preferably wherein said composition is lyophilized injectable powder.
Be preferably fat-soluble medicine compound at the pharmaceutical composition Chinese traditional medicine compound aspect the present invention IV, be more preferably taxol.
Aspect V, the invention provides the preparation method of the pharmaceutical composition of the present invention IV aspect, it comprises,
(4) medical compounds is mixed to (preferably with high-speed homogenization machine mix) and enter in the solution containing the auxiliary material of the present invention II aspect, form the solution that contains nano-scale particle; With,
(5) optionally add pharmaceutically acceptable auxiliary material (as, N.F,USP MANNITOL) and/or be dried (as, lyophilize) to the product of step (4).
Preferably the method for the present invention V aspect does not comprise chromatographic step.
Preferably, in the method aspect the present invention V, medical compounds is fat-soluble medicine compound, preferably taxol.
Preferably, in the method aspect the present invention V, the nano-scale particle in step (4) is that particle diameter is less than the 200nm particle of (being preferably less than 180nm).
Preferably, in the method aspect the present invention V, the medical compounds in step (4) and the weight ratio of auxiliary material are 0.5～2: 1～10, are preferably 0.8～1.2: 3～6, and as 1: 4.
The not detailed part of above I, II, III, IV and/or V aspect, can explain according to following aspect.
In first aspect, the invention provides the method for packaging medicine compound, it comprises,
(1) by procedural style I by dextran (preferably its molecular-weight average is 5～30KDa, and more preferably 10～20KDa, as 10KDa, 15KDa or 20KDa) ambroid acidylate dextran
(2) press the synthetic aminated folacin of procedural style II
(3) synthesize folic acid-dextran conjugate by the product of flow process step (1) and step (2) formula III for
(4) medical compounds is mixed in the solution of the folic acid-dextran conjugate obtaining containing step (3), forms the solution containing nano-scale particle; With,
(5) optionally add pharmaceutically acceptable auxiliary material and/or be dried to the product of step (4).
The method of first aspect present invention is carried out the sequence of steps of synthesizing the step of major auxiliary burden (folic acid-dextran conjugate) and medical compounds parcel, medical compounds and auxiliary material present the form of non-covalent combination in theory, do not change the molecular structure of medical compounds, thereby make the strong adaptability of the method for various medical compounds, especially for medical compoundss such as taxols, collaborative onset can be played to improve the effect of curative effect, and drug tolerance can be improved.Preferably, in the method for first aspect present invention, medical compounds is fat-soluble medicine compound, can be to be fat-soluble medical compounds under specific pH, is more preferably taxol.
Chemical reaction and the physical process of the each step of method of first aspect present invention arrange rationally, thereby can complete the purifying of each step by means such as lower-cost filtration, crystallization and/or dialysis, make final product still can reach other purity of pharmaceutical grade.Therefore, preferably, in the method for first aspect present invention, do not comprise chromatographic step.Needn't buy so expensive tomography devices and filler, also without carrying out the processes such as chromatography column balance, wash-out and/or regeneration consuming time and careful, the process that has facilitated whole parcel to prepare.
In the step (4) of the method for first aspect present invention, preferably medical compounds is mixed in the solution of the folic acid-dextran conjugate obtaining containing step (3) with high-speed homogenization machine.Conventionally, the mixed reagent of medical compounds and auxiliary material carries out with agitator etc., and high-speed homogenization machine is generally used for the fragmentation of biological substance, but, only the inventor studies discovery, uses in the present invention commercially available high-speed homogenization machine, but makes the medical compoundss such as taxol and this auxiliary material of folic acid-dextran conjugate more easily mix and is rolled into nano level particle, speed is fast, and parcel efficiency high (using less auxiliary material just can wrap up more medical compounds).Thereby preferably, in the method for first aspect present invention, the nano-scale particle in step (4) is the particle that particle diameter is less than 200nm, is more preferably the particle that particle diameter is less than 180nm; Also preferably in the method for first aspect present invention, the weight ratio of the medical compounds in step (4) and folic acid-dextran conjugate is 0.5～2: 1～10, more preferably 0.8～1.2: 3～6, and as 1: 4 etc.
The method of first aspect present invention finally can further be processed, to be prepared into pharmaceutical preparation, and for example injection (injection), preferably lyophilized injectable powder.Therefore, preferably in the method for first aspect present invention, in step (5), can add other pharmaceutically receivable auxiliary materials to the product of step (4), as N.F,USP MANNITOL, thereby can be prepared into injection, further, can carry out lyophilize, thereby be prepared into lyophilized injectable powder.
In second aspect, the invention provides the preparation method for the auxiliary material of packaging medicine compound, it comprises,
(1) ambroid acidylate dextran;
(2) synthetic aminated folacin;
(3) synthesize folic acid-dextran conjugate with the product of step (1) and step (2).
Preferably the method for second aspect present invention comprises,
(1) by procedural style I by dextran (preferably its molecular-weight average is 5～30KDa, and more preferably 10～20KDa, as 10KDa, 15KDa or 20KDa) ambroid acidylate dextran
(2) press the synthetic aminated folacin of procedural style II
(3) synthesize folic acid-dextran conjugate by the product of flow process step (1) and step (2) formula III for
The auxiliary material of the method for second aspect present invention can wrap up a large amount of different types of medical compoundss, do not change the molecular structure of compound, adaptability is good, especially also can improve drug tolerance for the medical compounds energy synergys such as taxol energy, therefore be preferred for wrapping up fat-soluble medicine compound, more preferably for wrapping up taxol.
The chemical reaction of the each step of method of second aspect present invention arranges rationally, thereby can complete the purifying of each step by means such as lower-cost filtration, crystallization and/or dialysis, makes final auxiliary material still can reach other purity of pharmaceutical grade.Therefore, preferably, in the method for second aspect present invention, do not comprise chromatographic step.Save like this cost, facilitated preparation flow.
In addition, in the third aspect, the present invention also provides the auxiliary material for packaging medicine compound, and its method by second aspect present invention is prepared and obtained.This auxiliary material purity is high, and medical compounds adaptability is good, especially for the medical compounds energy synergys such as taxol and can and can improve drug tolerance, and the pharmaceutical composition solubility being wrapped to form and stability all good.
Thereby, in fourth aspect, the present invention further provides the application in the pharmaceutical composition that the auxiliary material of third aspect present invention contains fat-soluble medicine compound (preferably taxol) in preparation.Preferably wherein, the method for preparation is the method for packaging medicine compound, is more preferably the method for first aspect present invention, especially by method that in the method for first aspect present invention, step (4) and (5) form.
And, aspect the 5th, the present invention also further provide third aspect present invention auxiliary material parcel medical compounds (preferably fat-soluble medicine compound, as taxol) and medicine.Preferably wherein, the method for packaging medicine compound is the method for first aspect present invention, for example, by method that in the method for first aspect present invention, step (4) and (5) form.
Beneficial effect of the present invention is, method and auxiliary material possess good medicine adaptability, without complicated purifying process, can reduce production costs, thereby can produce the medicine that Chinese afford to use; Be prepared into after pharmaceutical composition, especially be prepared into after antitumor drug with the medical compounds such as taxol, improve curative effect thereby can work in coordination with onset, thereby and reduce toxic side effect and improve drug tolerance, thereby can reduce the medication frequency, thereby further reduce patient's treatment cost; In addition, the pharmaceutical composition solubility and the stability that are wrapped to form are all good, thereby are convenient to accumulating, further reduce costs, and can not increase because of redissolving after long-time storage the probability that untoward reaction occurs.
For the ease of understanding, the present invention has quoted open source literature, and these documents are in order more clearly to describe the present invention, its in full content all include in and carry out reference herein, just look like their in full in this article entire teachings gone over.
Below will be described in detail the present invention by specific embodiment and accompanying drawing.It needs to be noted, these descriptions are only exemplary descriptions, do not form limitation of the scope of the invention.According to the discussion of this specification sheets, many variations of the present invention, change have been all obviously concerning one of ordinary skill in the art.
Brief description of the drawings
Fig. 1 has shown the inhibition to tumor growth after medication, wherein legend be from top to bottom expressed as successively empty carrier,
lyophilized injectable powder 125mg/kg of the present invention, 100mg/kg, 75mg/kg and 50mg/kg.
Embodiment
Carry out example by specific embodiment below, wherein agents useful for same all can be bought by market channel, if any not using up part, can guide with reference to the experiment of corresponding organic chemical synthesis handbook and SFDA.
Embodiment 1: the preparation of folic acid-dextran conjugate
1, succinylation dextran synthetic
Synthetic route is as follows:
Get 10.0g dextran (molecular-weight average 20KDa, Mw/Mn=1.3, can be purchased from Shanghai Sunlight reagent company limited) be dissolved in anhydrous dimethyl formamide (DMF), stir and within 20 minutes, form clear soln, then add 1670mg succinyl oxide and 200.0mg4-dimethyl aminopyridine (DMAP), rapid stirring is to all dissolution of solids.Be placed under room temperature (25 DEG C) and make whole reaction solution reaction 24 hours, afterwards reaction solution is put in Spectra/Por3 dialysis tubing (molecular weight cut-off 3,500), be placed in water and dialyse 2 days.Then by the solution lyophilize in dialysis tubing, obtain white succinylation dextran.Nucleus magnetic resonance (NMR) result is as follows: 1H-NMR (d-DMSO): 2.8 (CH
2cH
2-, succinylation dextran), 3.2-3.6 (dextran), 4.4-5.8 (dextran).
2, aminated folacin synthetic
Synthetic route is as follows:
Getting 3g folic acid is dissolved in 120mL dimethyl sulfoxide (DMSO) (DMSO), add wherein 930mg (4.5mmol) N, N '-dicyclohexylcarbodiimide (DCC) and 770mg (6.7mmol) N-hydroxy-succinamide (NHS), reaction solution is placed 12 hours at room temperature (25 DEG C) darkroom place, then by product DCU precipitation is filtered removal, 70) and stir add 1000mL acetone/diethyl ether mixed solution (V: V=30:, collect yellow mercury oxide and with acetone/diethyl ether mixed solution (V: V=30: 70) dry after washing to reaction solution again.
Getting the yellow mercury oxide that 2.78g dries is dissolved in 20mL DMSO again, getting 6.01g quadrol joins in this solution fast, after being mixed, both place 12 hours at room temperature (25 DEG C) darkroom place, 70) and stir add 50mL acetone/diethyl ether mixed solution (V: V=30:, collect yellow mercury oxide and recrystallization purification in DMSO solution, obtain aminated folacin.
3, folic acid-dextran conjugate synthetic
Synthetic route is as follows:
Getting succinylation Dextran 200 0mg prepared by step 1 is dissolved in 40ml dry DMF; add 50mg DMAP and 579.7mg DCC; under room temperature (25 DEG C), place after 12 hours; add again 2mL to contain 1-ethyl-3-(3-dimethyl aminopropyl)-carbodiimide (EDC) solution of aminated folacin prepared by 300mg step 2; reaction solution stirred after 12 hours under room temperature (25 DEG C); reaction solution is put into Spectra/Por3 dialysis tubing (molecular weight cut-off 3; 500), in, be placed in water and dialyse 2 days.Then by the solution lyophilize in dialysis tubing, obtain yellow folic acid-dextran conjugate.Nucleus magnetic resonance (NMR) result is as follows: 1H-NMR (d-DMSO): 2.8 (CH
2cH
2-, succinylation dextran), 3.2-3.6 (dextran), 4.4-5.8 (dextran), 8.6 (folic acid).
Embodiment 2: preparation and the stability test of the lyophilized injectable powder of the taxol of folic acid-dextran conjugate parcel
Get folic acid-dextran conjugate prepared by 1000mg EXAMPLE l, be dissolved in the phosphoric acid buffer (pH=7.4) of 100ml15mM, after dissolving, be placed on magnetic stirring apparatus and stir with 400rpm.In whipping process, 250mg taxol is dissolved in 5mL ethanol, dropwise join in the solution of stirring, add in the FS-1 type high-speed homogenization machine that is placed on (can purchased from Zhong Zheng instrument manufacturing company limited of Jintan City), with peak power homogenate 6 times, each 1 minute, stop 2 minutes, afterwards homogenate is put into Spectra/Por3 dialysis tubing (molecular weight cut-off 3,500) in, the phosphoric acid buffer (pH=7.4) that is placed in 15mM is dialysed 12 hours to remove ethanol, then adds 2500mg N.F,USP MANNITOL to regulate osmotic pressure, and through 0.2 μ m filter membrane degerming.Detect through particle size analyzer, particle diameter < 200 nanometers of the particle in the aqueous solution, obtain the taxol particle solution that folic acid-dextran conjugate wraps up.
Above-mentioned particle solution is placed in to Virtis AdVantage Plus freeze drier (can purchased from Shanghai Dan Ding International Trading Company Ltd) lyophilize, the lyophilize step that the inventor optimizes is: be first refrigerated to-40 DEG C of 120min, be warmed up to again-22 DEG C of 90min, then cool to-40 DEG C and keep 6 hours, whole process continues 9.5 hours; Then be warming up to-11 DEG C, continue to bleed dry 48.6 hours; Finally in 3 hours, rise to 25 DEG C, continue to bleed dry 7 hours.Obtained thus lyophilized injectable powder, water ratio is no more than 3.5%, and sealing is preserved.
Get after this lyophilized injectable powder filling 10ml water for injection containing 25mg taxol, can in 3 minutes, redissolve, show that solubility is good.Solution after redissolution is transparent light yellow transparent liquid, and the pH recording is 7.2, and osmotic pressure is 291 ± 2.4mOsm, and the particle diameter of the particle recording with dynamic light scattering method is less than 120 ± 20 nanometers, shows still can keep the small particle size of particle.
This lyophilized injectable powder is placed 30 days at 40 DEG C, carried out accelerated stability test, then redissolve and identify according to aforesaid method, result is not found noticeable change, shows said preparation good stability.
Embodiment 3: the pharmacodynamic study of the paclitaxel freeze drying powder injection of folic acid-dextran conjugate parcel
Lyophilized injectable powder prepared by embodiment 2 has carried out cytotoxicity test, the non-leaflet lung carcinoma cell in subject cell behaviour source.The lyophilized injectable powder of different concns is joined
in cell culture medium, process after 72 hours, calculate IC50.Result shows, the cytotoxicity of the taxol of folic acid-dextran conjugate parcel of various concentration, close with the taxol of same concentrations that does not pass through any processing, the IC50 calculating is ≌ 10nM, use separately the cytotoxicity of folic acid-dextran conjugate itself very little, IC50 > 0.05mg/ml, visible vitro cytotoxicity mainly comes from taxol, and folic acid-dextran conjugate does not affect the performance of taxol cytotoxic effect substantially.
Use lyophilized injectable powder prepared by the embodiment 2 of different concns (with the content meter of taxol wherein) and existing
nude mice is carried out to drug tolerance test, measure the body weight of nude mice after administration, using the maximal dose that do not affect body weight as tolerance limit, result is
maximum tolerance is 80mg/kg taxol amount, and the tolerance of the maximum of lyophilized injectable powder prepared by embodiment 2 reaches 125mg/kg taxol amount, show after folic acid-dextran conjugate parcel taxol, can strengthen the drug tolerance of animal subject, toxicity reduces greatly, thereby can increase taxol consumption.
The lyophilized injectable powder of preparing with embodiment 2 carries out experimentation on animals, by the lyophilized injectable powder of various dose (50,75,100 and 125mg/kg, with the content meter of taxol wherein) intravenous injection is to having transplanted with it the nude mice of the non-leaflet lung carcinoma cell of people respectively, simultaneously with injection empty carrier (Vehicle, i.e. phosphoric acid buffer (PBS)) and
(80mg/kg, with wherein the content meter of taxol) as a control group, observes the inhibition growth curve of tumour.Result as shown in Figure 1, shows in the time that the dosage of lyophilized injectable powder of the present invention reaches 75mg/kg, and medicine has statistically significantly been better than 80mg/kg's to the growth-inhibiting effect of tumour cell
(its curative effect in 50mg/kg dosage of the present invention is statistically without significant difference), the visible basic no cytotoxicity of folic acid-dextran conjugate as auxiliary material; But after parcel taxol, can work in coordination with the antitumous effect that strengthens taxol, can increase taxol consumption in addition, therefore can obtain the antitumous effect of remarkable excellence.
Claims (10)
1. for the preparation method of the auxiliary material of packaging medicine compound, it comprises,
(1) press procedural style I ambroid acidylate dextran, wherein the molecular-weight average of dextran is 5～30KDa, and more preferably 10～20KDa, as 10KDa, 15KDa or 20KDa
(2) press the synthetic aminated folacin of procedural style II
(3) synthesize folic acid-dextran conjugate by the product of flow process step (1) and step (2) formula III for
2. for the auxiliary material of packaging medicine compound, it is prepared and is obtained by preparation method claimed in claim 1.
3. the application in the pharmaceutical composition (preferably injection, is more preferably lyophilized injectable powder) that auxiliary material claimed in claim 2 contains fat-soluble medicine compound (preferably taxol) in preparation.
Auxiliary material claimed in claim 2 parcel medical compounds and pharmaceutical composition, preferred wherein said composition is injection, more preferably wherein said composition is lyophilized injectable powder.
5. pharmaceutical composition claimed in claim 4, wherein medical compounds is fat-soluble medicine compound, preferably taxol.
6. the preparation method of pharmaceutical composition claimed in claim 4, it comprises,
(4) medical compounds is mixed to (preferably with the mixing of high-speed homogenization machine) and enter in the solution containing the auxiliary material described in claim 2, form the solution containing nano-scale particle; With,
(5) optionally add pharmaceutically acceptable auxiliary material (as, N.F,USP MANNITOL) and/or be dried (as, lyophilize) to the product of step (4).
7. method claimed in claim 6, it does not comprise chromatographic step.
8. method claimed in claim 6, wherein medical compounds is fat-soluble medicine compound, preferably taxol.
9. method claimed in claim 6, wherein the nano-scale particle in step (4) is that particle diameter is less than the 200nm particle of (being preferably less than 180nm).
10. method claimed in claim 6, wherein the medical compounds in step (4) and the weight ratio of auxiliary material are 0.5～2: 1～10, are preferably 0.8～1.2: 3～6, as 1: 4.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410063279.8A CN103992417A (en) | 2012-12-14 | 2012-12-14 | Accessory for coating medicinal compound and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410063279.8A CN103992417A (en) | 2012-12-14 | 2012-12-14 | Accessory for coating medicinal compound and preparation method thereof |
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|---|---|---|---|
| CN201210543504.9A Division CN103120794B (en) | 2012-12-14 | 2012-12-14 | Pharmaceutic adjuvant with collaborative work and anti-tumor application thereof |
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|---|---|
| CN103992417A true CN103992417A (en) | 2014-08-20 |
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ID=51306778
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108135917A (en) * | 2015-09-25 | 2018-06-08 | Zy医疗 | Pharmaceutical preparation based on the particle comprising polysaccharide-vitamin conjugate |
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2012
- 2012-12-14 CN CN201410063279.8A patent/CN103992417A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108135917A (en) * | 2015-09-25 | 2018-06-08 | Zy医疗 | Pharmaceutical preparation based on the particle comprising polysaccharide-vitamin conjugate |
| EP3352796A4 (en) * | 2015-09-25 | 2019-05-01 | ZY Therapeutics Inc. | Drug formulation based on particulates comprising polysaccharide-vitamin conjugate |
| US10517961B2 (en) | 2015-09-25 | 2019-12-31 | ZY Therapeutics, Inc. | Drug formulation based on particulates comprising polysaccharide-vitamin conjugate |
| US10994024B2 (en) | 2015-09-25 | 2021-05-04 | ZY Therapeutics, Inc. | Drug formulation based on particulates comprising polysaccharide-vitamin conjugate |
| CN108135917B (en) * | 2015-09-25 | 2021-07-09 | Zy医疗 | Pharmaceutical formulations based on particles comprising polysaccharide-vitamin conjugates |
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