CN102228696A - Polyethylene glycol-polyvinyl alcohol copolymer-metaxalone prodrug and synthesis method thereof - Google Patents
Polyethylene glycol-polyvinyl alcohol copolymer-metaxalone prodrug and synthesis method thereof Download PDFInfo
- Publication number
- CN102228696A CN102228696A CN 201110162519 CN201110162519A CN102228696A CN 102228696 A CN102228696 A CN 102228696A CN 201110162519 CN201110162519 CN 201110162519 CN 201110162519 A CN201110162519 A CN 201110162519A CN 102228696 A CN102228696 A CN 102228696A
- Authority
- CN
- China
- Prior art keywords
- prodrug
- metaxalone
- polyethylene glycol
- peg
- pva
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention discloses a polyethylene glycol-polyvinyl alcohol copolymer-metaxalone (PEG-PVA-Met) prodrug which is shown as a structural general formula (I), wherein R is a formula which is shown in the specification; n is 10-100; and X is an integer from 3 to 10. Through the PEG-PVA-Met macromolecular prodrug synthesized by the invention, the water solubility of the small molecular drug of metaxalone can be improved, the half-life period of the prodrug is prolonged, and the release of the prodrug in a human body can also be effectively controlled. The prodrug is undoubtedly good for many chronic patients.
Description
Technical field
The present invention relates to metaxalone prodrug and the synthetic method thereof of a kind of polyethylene glycol-ethenol copolymer, belong to technical field of medicine synthesis as carrier.
Background technology
Development along with polymer science and modern medicine, Polymer Materials for Controlled Drug Release (PDDS) has become popular research field, according to the model of action between medicine and the macromolecule carrier, PDDS can be divided into two classes, a kind of be medicine with physics mode by the drug slow delivery systme of macromolecule carrier embedding, the medicament slow release system that promptly adopts encapsulation or complex technique to obtain.Another kind is to adopt the covalent bond interconnection technique that macromolecule carrier is connected with small-molecule drug with covalent chemical bond and the macromolecular prodrug that obtains, also claims polymeric prodrugs.Prodrug is a kind of special medicament forms, and this medicine is keeping nonactive before transhipment arrives action site, just can discharge active medicine after activating by certain conditions at target site.Though low-molecule drug curative effect height in the past is easy to use, many kinds wherein but exist very big side effect.General low-molecule drug all is to enter human body by oral or injection, and in the short time after advancing medicine, the concentration of medicament is considerably beyond the required concentration of treatment in the blood, and too high concentration may make that the people poisons, allergy etc.Simultaneously they rate of metabolism is fast in vivo, the half-life is short, easily drain, so along with the putting off of time, the very fast reduction of the concentration of medicament and affecting the treatment.On the other hand, appointed part also lacks selectivity to low-molecule drug in the body to entering, and this also is that into dose increases, one of reason that curative effect is lower.Advantages such as that macromolecular drug has is long-acting, efficient, low toxicity, slow release, selectivity is good, side effect is little.A kind of effective method that improves curative effect of medication is exactly that the low molecule medicine that will have pharmacologically active changes into inactive derivant (macromolecular prodrug just) by chemical method, and in general the synthetic of macromolecular prodrug is will hang down the molecule medicine by covalent bond to be connected on the suitable macromole.This macromolecular prodrug can become low molecule medicine and macromole by hydrolysis or enzymolysis in human body.Macromolecular prodrug on the one hand can reduce side effects of pharmaceutical drugs effectively, reduces consumption release time that on the other hand can prolong drug, increases dissolubility.If use the targeting poly compound to combine with low-molecule drug, this macromolecular prodrug may accumulate on the cell of pathological changes, and does not influence other normal cell, has both reached the purpose of treatment, can not cause big side effect to the people again.This shows that the macromole medical instrument has very large practical significance.
Rhythm of life that modern society is fast and keen competition, make most of people bear huge life stress, therefore, diseases such as anxiety, lumbago and backache, skelalgia, arthralgia become common health problem, especially sprain, dampen and make the people more painful, cause live in straitened circumstances cisco unity malfunction and study.According to document announcement, there is 70%～85% adult to suffer the puzzlement of backache, worldwide, myalgia becomes second largest disease.
Metaxalone (chemical name: 5-[(3,5-dimethyl benzene oxygen) methyl]-the 2-oxazolidone, metaxalone, be called for short: Met) be the central muscle-relaxing drug, spinal cord polysynaptic pathway capable of blocking has sedation, also has cholinolytic and antipyretic effect.Clinical being mainly used in treated the local myalgia that inflammation, wound etc. cause.Drugs approved by FDA listing in 2002.Metaxalone is a glucuronide at liver metabolism, discharges through kidney.Though metaxalone is as novel nondepolarizing type muscle relaxant, have advantage clearly, but also have some untoward reaction, as drowsiness, anorexia, feel sick, vomiting, dizziness, xerostomia, urine retention, anemia and jaundice, pyuria and renal calculus can appear in severe patient.The poorly water-soluble of metaxalone, the half-life has only 2～3h, makes its application be subjected to certain restriction.
The water-soluble macromolecule material is extraordinary medicine sustained release carrier, if with small-molecule drug by can hydrolysis or the covalent bond of enzymolysis be connected with them and be prepared into macromolecular prodrug, can effectively prolong the half-life of micromolecule medicine, increase dissolubility, improve the therapeutic effect of medicine, reduce side effect etc.
(Polyethylene glycol PEG) has good water-solubility to Polyethylene Glycol, can increase the blood plasma anelasticity, reduces protein immunization, improves therapeutic index, and therefore, PEG becomes the first-selected polymer support of synthetic macromolecule prodrug.The appearance of Pegylation technology in 1989 is polyethyleneglycol modified bioactive molecule, or macromolecular prodrug synthetic provides the necessary technology guarantee.Over more than 30 year, scientist has developed many technology, in order to structure Polyethylene Glycol and medicine, or the junctional complex of other bioactive molecule.Polyethylene Glycol as the advantage of carrier show following some: (1) PEG has amphipathic, both can be water-soluble, can be dissolved in most organic solvents again.(2) nontoxic, no teratogenecity, non-immunogenicity have fine biocompatibility.(3) with other polymer phase ratio, the molecular weight of PEG not only distributes wide, and lower, is suitable as very much the carrier of synthetic macromolecule prodrug.(4) its many advantageous properties can be given biomolecule after the modification.Although Polyethylene Glycol has the clear superiority as the macromolecular carrier of prodrug, but because the peg molecule end of the chain has only 1～2 activity hydroxy, cause its struck capacity low, the active drug molecule that is connected on the polymer chain is few, often is difficult to obtain high charging ratio.The activated group of polyvinyl alcohol is many, and each all has a hydroxyl above the construction unit, all can be connected with medicine, and drug loading can change according to condition, but its rate of dissolution in water is slow, needs suitable heating just can reach quick dissolving.If the copolymer of polyvinyl alcohol and Polyethylene Glycol as pharmaceutical carrier, might both can be guaranteed the polymer good water-solubility, can increase the activated group of polymer support again, prepare the macromolecular prodrug of high drug load, this innovation of the present invention just place.
At the metaxalone poorly water-soluble, problems such as the half-life is short, the inventor utilizes the copolymer of polyvinyl alcohol and Polyethylene Glycol to make carrier, be connected with metaxalone by covalent bond, the synthetic macromolecule prodrug, improve the water solublity of small-molecule drug metaxalone, prolong its half-life, make it in human body, can control the release of its medicine effectively.
Summary of the invention
The object of the present invention is to provide a kind of good biocompatibility, good water solubility, have the polyethylene glycol-ethenol copolymer-metaxalone macromolecular prodrug of controlling slow release function.
Another object of the present invention is to provide the synthetic method of polyethylene glycol-ethenol copolymer-metaxalone prodrug.
Implementation procedure of the present invention is as follows:
Polyethylene glycol-ethenol copolymer-metaxalone prodrug shown in the general structure (I),
Wherein, R is
, n is 10-100, X is the integer of 3-10.
The synthetic method of above-mentioned polyethylene glycol-ethenol copolymer-metaxalone prodrug comprises the steps:
(1) reaction of 5-aryloxy methyl-2-oxazolidone and chloracetyl chloride obtains N-chloracetyl-5-[(3,5-dimethyl benzene oxygen) methyl]-the 2-oxazolidone;
(2) polyethylene glycol-ethenol copolymer and N-chloracetyl-5-[(3,5-dimethyl benzene oxygen) methyl]-2-oxazolidone reaction obtains polyethylene glycol-ethenol copolymer-metaxalone prodrug, be reflected at 40～70 ℃ and carry out, be preferably in 55～65 ℃ and carry out; Reaction dissolvent adopts DMF.
The concrete synthesis step that the present invention adopts is as follows:
(1) N-chloracetyl-5-[(3,5-dimethyl benzene oxygen) methyl]-the 2-oxazolidone
In four-hole bottle, adding 5-aryloxy methyl-2-oxazolidone, triethylamine and toluene stir, and when treating that temperature rises to 50 ℃, drip chloracetyl chloride, react 3 h, are cooled to room temperature, add suitable quantity of water, stir, and crystallization gets white needle-like crystals.
(2) polyethylene glycol-ethenol copolymer-metaxalone (PEG-PVA-Met) prodrug is synthetic
In four-hole bottle, add PEG-PVA, DMF and N-chloracetyl-5-[(3,5-dimethyl benzene oxygen) methyl]-the 2-oxazolidone, 40～70 ℃ were reacted 8-20 hour, were cooled to room temperature then, filtered, and drying obtains white PEG-PVA-Met solid.
The present invention also provides the rate of releasing drug of PEG-PVA-Met in pH=1.1, pH=7.4 and pH=10.0 buffer solution.The result shows: PEG-PVA-Met can slowly release the female medicine metaxalone of micromolecule; PEG-PVA-Met is in pH=1.1 buffer solution, and the rate of release of metaxalone is the slowest; In the buffer solution of pH=10.0, the rate of release of metaxalone is the fastest.Along with buffer solution alkalescence increases, the hydrolysis rate of macromolecular prodrug increases, and is consistent with the hydrolysis situation of amido link.Amido link is hydrolysis easily under alkali condition, and the fracture easily under alkali condition of the amido link in the PEG-PVA-Met macromole just easily discharges the small-molecule drug metaxalone.
The synthetic PEG-PVA-Met macromolecular prodrug of the present invention can not only increase the water solublity of small-molecule drug metaxalone, prolongs its half-life, and can also control the release of its medicine effectively in human body, and this is undoubtedly a lot of chronics' Gospel.
Description of drawings
[0003] Fig. 1 is a synthetic route chart of the present invention;
The DSC collection of illustrative plates of Fig. 2 Met and PEG-PVA-Met;
The IR collection of illustrative plates of Fig. 3 PEG-PVA and PEG-PVA-Met;
The release curve of Fig. 4 PEG-PVA-Met in different buffer solution;
The release curve of Fig. 5 PEG-PVA-Met when Chymetin exists and do not exist.
The specific embodiment
The invention will be further described below in conjunction with specific embodiment.
The reagent specification that the present invention adopts is as follows: polyethylene glycol-ethenol copolymer (on the grand chemical industry company limited of transporting by sea provide, the husband of BASF Aktiengesellschaft produces, polyvinyl alcohol and Polyethylene Glycol mole are than being 3:1, molecular weight 45000); N, dinethylformamide; Acetone (traditional Chinese medicines group, CP); N, and dinethylformamide (DMF Tianjin Fu Yu Fine Chemical Co., Ltd, AR); The chloracetyl metaxalone.
The synthetic synthetic route of polyethylene glycol-vinyl alcohol-metaxalone as shown in Figure 1.
Embodiment 1:PEG-PVA-Na's is synthetic
Adding new steaming of 25ml DMF(in the 50ml three-necked bottle of thermometer, condensing tube is housed successively dewaters), 3.0g PEG-PVA, slowly heating and vigorous stirring are to dissolving (about 110 ℃) fully, be cooled to 60 ℃, add 0.25g sodium, keep 60 ℃ of system temperatures, reaction 4h, sucking filtration is removed insoluble matter, gets the pale red clear solution.
Embodiment 2:N-chloracetyl-5-[(3,5-dimethyl benzene oxygen) methyl]-2-oxazolidone synthetic
In the 100mL four-hole bottle of mechanical agitator, condensing tube, thermometer and Dropping funnel is housed, add 0.002mol 5-aryloxy methyl-2-oxazolidone, 0.002mol triethylamine and 15mL toluene stir.When treating that temperature rises to 50 ℃, drip the mixed liquor of 0.0032mol chloracetyl chloride and 10mL toluene, and the control rate of addition makes reaction temperature be no more than 50 ℃.After dropwising, be heated to backflow, react 3 h, be cooled to room temperature, add 5mL water, stir, crystallization, filtration and with water wash 3 times must white needle-like crystals.Mother solution water extracting twice merges organic layer, the toluene that distilling under reduced pressure is excessive, and crystallization is filtered, and gets target product chloracetyl-metaxalone.
Embodiment 3: polyethylene glycol-vinyl alcohol-metaxalone synthetic
In the mother solution (1) of embodiment 1, add embodiment 2 synthetic 1.8g chloracetyl-metaxalone, stir, and keep 60 ℃ of reaction temperatures, reaction 6h.Reaction finishes; distilling under reduced pressure goes out most of DMF; add precipitant acetone under the vigorous stirring, produce precipitation in a large number, sucking filtration; fully embathe precipitation three times with acetone; in washing liquid, do not contain the chloracetyl metaxalone, put into the dry 2d of exsiccator, get pale solid; be PEG-PVA-Met, weigh 2.8g.
The synthetic PEG-PVA-Met prodrug that obtains has been carried out DSC and IR analysis, and the result is as follows:
As shown in Figure 2, from the DSC thermal analysis curve as can be seen, the fusing point of metaxalone is 124.6 ℃.And in the DSC of synthetic PEG-PVA-Met prodrug collection of illustrative plates, there is not tangible endothermic peak to occur near this temperature, two endothermic peaks of PEG-PVA-Met are 108 ℃ and 215 ℃, it can be said that bright: (1) metaxalone and PEG-PVA are generating the PEG-PVA-Met macromolecular prodrug after the reaction under the condition of determining; (2) illustrate do not have unreacted metaxalone to exist in the product.
From the infrared spectrum curve of Fig. 3 PEG-PVA and PEG-PVA-Met as can be seen, at 3420cm
-1Near strong absworption peak is the hydroxyl stretching vibration absworption peak in the PEG-PVA strand; 2923 cm
-1With 2856 cm
-1Absworption peak is methylene asymmetrical stretching vibration and symmetrical stretching vibration absworption peak near two places; 1457 cm
-1The place is methylene basal plane internal strain vibration absorption peak; 1089 cm
-1The place is C-O-C ehter bond stretching vibration peak in the peg molecule chain; Contrasting two collection of illustrative plates differences is: in the PEG-PVA-Met spectrogram at 3035 cm
-1It is to connect the proton hydrogen stretching vibration peak on the phenyl ring in the medicine metaxalone molecule, 1652 cm that there is absworption peak at the place
-1The place is the carbonylic stretching vibration peak, and showing in the synthetic macromolecular prodrug of institute has amido link to generate 1731 cm
-1Stretching vibration peak for ester carbonyl group in the five-membered ring in the Met molecule.Contrast by two figure as can be seen, Met has been connected on the PEG-PVA copolymer.
The present invention has also studied the influence of differential responses temperature to drug loading, as shown in table 1, during synthesizing polyethylene glycol-polyvinyl alcohol-metaxalone during metaxalone, metaxalone and PEG-PVA rate of charge are the 1:1(mass ratio), along with reaction temperature rises to 60 ℃ from 40 ℃, its drug loading also constantly increasing, reaches maximum 22.8%; After temperature was elevated to 70 ℃, drug loading began to descend.So selecting best reaction temperature is 60 ℃.The reason that the temperature high drug load descends may be: the one, and female medicine metaxalone is failed to be connected with carrier and is just had decomposition partly under alkali condition; The 2nd, solvent itself has some side reactions and takes place under hot conditions.
As can be seen from Table 1, the present invention adopts the PEG-PVA copolymer, and drug loading is compared existing PEG medicine carrying and is greatly improved.
Embodiment 4: the external sustained release experiment of polyethylene glycol-vinyl alcohol polymer-metaxalone prodrug
PEG-PVA-Met is respectively charged into long bag filter (molecular cut off 3500) of 4cm and sealing, puts into pH=1.1 (KCl-glycine/HCl), the pH=7.4 (Na of 40mL respectively
2HPO
4/ KH
2PO
4), pH=8.0(tris/ CaCl
2), pH=10.0(Na
2CO
3/ NaHCO
3) buffer solution in, constant temperature to 37 ℃ carries out release experiment.The 5.0mL that takes a sample at a certain time interval carries out the ultraviolet test, quantitatively determines the amount of medicine that this interval discharges, and replenishes the 5.0mL fresh buffer to delivery systme simultaneously, is 40 mL with the solution of keeping delivery systme.The accumulative total burst size of medicine is calculated as follows.
Cumulative release amount (%)=100 * (40.0C
n+ 5.0 ∑ C (n-1))/W
0
In the formula: W
0The quality (mg) of Met in the-macromolecular prodrug to be measured;
C
n-t discharges the concentration (mg/mL) of Met in the liquid when measuring for the n time in the time, the formula that its value press the working curve match by ultraviolet spectra is definite;
C
N-1Discharge the concentration (mg/mL) of Met in the liquid when measuring for-the n-1 time;
The Met concentration sum that ∑ C (n-1)-preceding measures for n-1 time.
Fig. 4 has shown that the PEG-PVA-Met macromolecular prodrug is respectively the releasing effect in the 31.5h in three kinds of buffer solution of 1.1,7.4,10.0 at pH.PEG-PVA-Met pro-5.5h rate of release is very fast, and burst size reaches 25.7%, 33.5%, 45.1% of total amount in three kinds of buffer solution; When burst size reaches 50%, the about institute 6.5h that is required to be, 19h and respectively greater than 31.5h; 31.5 total burst size reaches 46.4%, 58.1%, 76 % in the h, the grand mean burst size is: 1.5%/h, 1.8%/h, 2.4%/h.
Embodiment 5: the enzymolysis release experiment of polyethylene glycol-vinyl alcohol polymer-metaxalone prodrug
PEG-PVA-Met is respectively charged into long bag filter (molecular cut off 3500) of 4cm and sealing, put into pH=8.0(2-amino-2-methylol-1 respectively, 3-propylene glycol/calcium chloride) contain among the buffer solution 40mL of Chymetin (concentration is the 0.001M HCl solution of 20 μ L * 10-5M), and constant temperature to 37 ℃ carries out releasing research, the 5.0mL that takes a sample at a certain time interval carries out the ultraviolet test, quantitatively determine the amount of medicine that this interval discharges, replenishing the 5.0mL fresh buffer to delivery system simultaneously, is 40mL with the solution of keeping delivery systme.
As shown in Figure 5, polyethylene glycol-vinyl alcohol polymer-metaxalone macromolecular prodrug is in the presence of Chymetin, and in the identical interval, the Met that the Met that discharges all discharges when not existing is many, but the amount that increases and little.
Claims (5)
1. the polyethylene glycol-ethenol copolymer-metaxalone prodrug shown in the general structure (I),
Wherein, R is
N is 10-100, and X is the integer of 3-10.
2. the synthetic method of the described polyethylene glycol-ethenol copolymer of claim 1-metaxalone prodrug comprises the steps:
(1) reaction of 5-aryloxy methyl-2-oxazolidone and chloracetyl chloride obtains N-chloracetyl-5-[(3,5-dimethyl benzene oxygen) methyl]-the 2-oxazolidone;
(2) methyl polyethylene glycol-ethenol copolymer and N-chloracetyl-5-[(3,5-dimethyl benzene oxygen)]-reaction of 2-oxazolidone obtains polyethylene glycol-ethenol copolymer-metaxalone prodrug.
3. the synthetic method of polyethylene glycol-ethenol copolymer according to claim 2-metaxalone prodrug is characterized in that: in the step (2), be reflected at 40～70 ℃ and carry out.
4. the synthetic method of polyethylene glycol-ethenol copolymer according to claim 3-metaxalone prodrug is characterized in that: be reflected at 55～65 ℃ and carry out.
5. the synthetic method of polyethylene glycol-ethenol copolymer according to claim 2-metaxalone prodrug is characterized in that: in the step (2), reaction dissolvent is DMF.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110162519 CN102228696B (en) | 2011-06-17 | 2011-06-17 | Polyethylene glycol-polyvinyl alcohol copolymer-metaxalone prodrug and synthesis method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110162519 CN102228696B (en) | 2011-06-17 | 2011-06-17 | Polyethylene glycol-polyvinyl alcohol copolymer-metaxalone prodrug and synthesis method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102228696A true CN102228696A (en) | 2011-11-02 |
| CN102228696B CN102228696B (en) | 2013-01-30 |
Family
ID=44841327
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201110162519 Expired - Fee Related CN102228696B (en) | 2011-06-17 | 2011-06-17 | Polyethylene glycol-polyvinyl alcohol copolymer-metaxalone prodrug and synthesis method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102228696B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108569831A (en) * | 2018-04-25 | 2018-09-25 | 中原工学院 | A kind of extraction separation method of effective activated sludge exoprotein and application |
-
2011
- 2011-06-17 CN CN 201110162519 patent/CN102228696B/en not_active Expired - Fee Related
Non-Patent Citations (1)
| Title |
|---|
| 《中国优秀硕士学位论文全文数据库》 20060915 薄澜 "连接基在大分子前药合成中的应用及药物缓释研究" 摘要部分，第17－19页 1－5 , * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108569831A (en) * | 2018-04-25 | 2018-09-25 | 中原工学院 | A kind of extraction separation method of effective activated sludge exoprotein and application |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102228696B (en) | 2013-01-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2018287018A1 (en) | Cannabidiolic acid esters compositions and uses thereof | |
| CN104684901A (en) | Cystathionine-y-gamma-lyase (cse) inhibitors | |
| CN101878042A (en) | Oligomer-tricyclic conjugates | |
| CN109563087A (en) | The solid form of sGC stimulant | |
| WO2014190763A1 (en) | Low molecular weight polyethylene glycol drug conjugates having improved drug biological activity | |
| CN101716161A (en) | New thymosin chitosan microsphere type oral medicinal preparation and preparation method thereof | |
| CN104870428A (en) | Conjugates and small molecules which interact with the CD16A receptor | |
| CA2924353A1 (en) | Compositions for the treatment of hypertension and/or fibrosis | |
| CN101773475B (en) | Preparation method of capsicine micro spheres | |
| CN102525876A (en) | Aspirin solid dispersion, as well as preparation method, pharmaceutical composition and use thereof | |
| CN108715579B (en) | Organic amine ester derivative medicine of 2- (α hydroxypentyl) benzoic acid | |
| CN102228696B (en) | Polyethylene glycol-polyvinyl alcohol copolymer-metaxalone prodrug and synthesis method thereof | |
| KR20230128471A (en) | Heteroaryl-acetylenes, pharmaceutical compositions thereof, and therapeutic applications thereof | |
| CN107714641A (en) | A kind of preparation method of the double medicine supramolecular hydrogels of camptothecine prodrug load for drug combination | |
| CN106631957A (en) | Antitumor compound targeting FAP-alpha enzyme and preparation method and application thereof | |
| CN1944378A (en) | Biphenyl ammonia acetate butantriol salt and its preparing method | |
| CN103193792A (en) | New compound for treating ischemic cardiovascular and cerebrovascular diseases | |
| EP3680233A1 (en) | NOVEL AMIDE COMPOUND, AND Pin1 INHIBITOR, THERAPEUTIC AGENT FOR INFLAMMATORY DISEASES AND THERAPEUTIC AGENT FOR CANCER THAT USE THE SAME | |
| CN104497167B (en) | Hyaluronic acid derivative and therapeutic thereof | |
| CN101998866A (en) | Oligomer-aryloxy-substituted propanamine conjugates | |
| WO2019096095A1 (en) | Integrin receptor-targeted anti-cancer conjugate | |
| CN102989017A (en) | Usage of berberine or derivatives thereof in preparation of tumor diagnosis imaging agent | |
| CN103562183A (en) | Benzoic acid salt of otamixaban | |
| WO2021018172A1 (en) | Adenosine receptor antagonist | |
| US20160237177A1 (en) | Single-step functionalization and cross-linking of hyaluronic acid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20130130 Termination date: 20130617 |