CN1966547B - Double-chain structured polyethylene glycol derivative preparation and its combination with pharmaceutical molecule - Google Patents
Double-chain structured polyethylene glycol derivative preparation and its combination with pharmaceutical molecule Download PDFInfo
- Publication number
- CN1966547B CN1966547B CN2006100973957A CN200610097395A CN1966547B CN 1966547 B CN1966547 B CN 1966547B CN 2006100973957 A CN2006100973957 A CN 2006100973957A CN 200610097395 A CN200610097395 A CN 200610097395A CN 1966547 B CN1966547 B CN 1966547B
- Authority
- CN
- China
- Prior art keywords
- group
- methylene dichloride
- polyethylene glycol
- dissolved
- drug molecules
- 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.)
- Expired - Fee Related
Links
- 0 CNNC(**)=C Chemical compound CNNC(**)=C 0.000 description 3
Abstract
Many drug molecules with biological activities, especially proteins and peptides biological macromolecules, have been successfully used in a broad treatment. However, these biological macromolecules in clinical application also have many disadvantages, such as easy immune rejection, poor stability and less solubility, and faster clearance rate. Polyehylene glycol (PEG) technology developing in recent years is a very effective improvement of biological macromolecules pharmacokinetics. This invention relates to a new type of polyethylene glycol derivatives with lipoic acid as a connector and double-chain structure, their preparation methods and combination with drug molecules. The referred derivatives can be used for connecting drug molecules, especially amino groups and sulfhydryl groups of proteins and peptides biological macromolecules, so as to improve the pharmacokinetics nature of drug molecules. The invention also relates to drug compositions including the combinations.
Description
Technical field
The present invention relates to have duplex structure polyethylene active derivatives, its preparation method and with the binding substances of drug molecule, described drug molecule is macromole such as protein and polypeptide particularly, the invention still further relates to the pharmaceutical composition that comprises described binding substances.
Background technology
Biomacromolecules such as the drug molecule of numerous biologically actives, especially protein and peptide class, widespread use in treatment, and succeed.But these biomacromolecules also have many disadvantages in clinical application, for example produce easily that immunological rejection, stability and solubility are relatively poor, clearance rate is very fast.Therefore, people have adopted the whole bag of tricks to eliminate above-mentioned unfavorable factor, and wherein the Pegylation technology is a kind of very effective method of improving the biomacromolecule pharmacokinetic property that development in recent years is got up.
Pegylation technology (PEGylation PEGization) is called chemically modified again, be present molecule allosteric chemistry (moleculealtering structure chemistry, MASC) in one of most important technology.The PEGization Study on Technology starts from the eighties in 20th century; be covalently bound to polyoxyethylene glycol on the protein first time such as Abuchowski; exempt from destruction with protected protein matter; found that polyethyleneglycol modified not only can increase proteinic water-soluble; the removing of kidney be can also reduce, proteinic pharmacokinetics and pharmacodynamic properties changed.Through the development of nearly decades, the PEGization technology not only obtains general application in the exploitation of protein drug, and has expanded to every field such as new drug carrier, controlled release preparation.
In the Pegylation technology, need the end group of polyoxyethylene glycol be activated, introduce suitable active group, this active group has activity to wanting at least one functional group in the bonded drug molecule, can form stable chemical bond with it.
Many methods that prepare polyethylene active derivatives are in the news, and people such as Davis are at United States Patent (USP) 4,179, and 337 kinds disclose polyoxyethylene glycol is attached on the protein, thereby it is lower to obtain a kind of immunogenicity, and can keep the binding substances of most of physiologically active.People such as Nakagawa disclose PEG have been attached on the island activation of protein to reduce its side effect and immunogenicity.People such as Veronese disclose on the 11:141-152 (1985) with phenyl chloroformate class activated polyethylene glycol to modify rnase and superoxide-dismutase at Applied Biochem.And Biotech.People such as Katre are at United States Patent (USP) 4,766, also disclose on 106 and 4,917,888 by polymkeric substance in conjunction with making the protein solubilising, with polyoxyethylene glycol with recombinant protein in conjunction with to weaken proteinic immunogenicity and to improve their transformation period.
At present, polyethyleneglycol derivative is widely used in and the combining to prolong the transformation period of described medicine of protein, polypeptide 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 pharmaceutical preparation, and the technology that PEG is attached on the drug molecule is also used in many approval medicines widely.As PEG-intron, the binding substances of a kind of Interferon, rabbit and polyoxyethylene glycol has just shown longer transformation period and better result of treatment.The binding substances of taxol and polyoxyethylene glycol has also reduced toxicity accordingly and has prolonged biological activity.
The method of above-mentioned formation PEG-protein conjugate and have several problems by the binding substances that described method obtains, the method that the first forms these binding substancess can make protein inactivation.In addition, used easily hydrolysis in vivo of some linking group when forming these PEG-protein conjugates, fracture, when administration later on such fracture took place, these binding substancess had just lost the advantageous property that is brought by PEG.
Summary of the invention
The invention provides a kind of novelly, as linker, have the polyethylene active derivatives of duplex structure, have following general structure with Thioctic Acid:
R1 wherein, R2 is hydroxyl or functional group of PEG itself, is selected from the group of being made up of C1 ~ C12 alkoxyl group, cycloalkyloxy and aralkyl.F is an activity functional groups, is selected from the group of being made up of succinimido, dimaleoyl imino or aldehyde radical, can be connected with amino or the sulfydryl formation covalent linkage on medicine or the matrix.
According to the present invention, the preferred molecule of this reactive derivative has following structure, but is not limited only to following structure:
Structure 1
Structure 2
Structure 3
Structure 4
Structure 5
Structure 6
The present invention also provides the method for preparing above-mentioned reactive derivative, may further comprise the steps:
Getting mono methoxy polyethylene glycol acid is dissolved in the methylene dichloride, add an amount of sulfur oxychloride, after stirring at room 5-7 hour, rotary evaporation removes and desolvates and remaining sulfur oxychloride, the gained solids is dissolved in the methylene dichloride, add Thioctic Acid (reduced form) and pyridine again, under the room temperature stirring and refluxing 16-24 hour.Filter and with gained filtrate decompression evaporate to dryness, solids is dissolved in the methylene dichloride, adds N-hydroxy-succinamide (N-hydroxyl maleimide) again, in the presence of Dimethylamino pyridine (DMAP) and dicyclohexylcarbodiimide (DCCI), temperature-20 ~ 10 ℃ was reacted 4 hours.With the water separator branch branch that anhydrates, continue to reflux and spend the night, vacuum is taken out methylene dichloride then, mixture is through ether sedimentation, ethyl alcohol recrystallization, be further purified through Sephadex G-25 post again, can get and to get pure product double focusing ethylene glycol sulfo-S-acid esters Thioctic Acid succinimide ester (or maleimide ester) (structure 1 and 2), put-20 ℃ of preservations.
Getting mono methoxy polyethylene glycol is dissolved in the methylene dichloride, add an amount of sulfur oxychloride, after stirring at room 5-7 hour, rotary evaporation removes and desolvates and remaining sulfur oxychloride, the gained solid matter is dissolved in the ethanol, add Thioctic Acid (reduced form) and NaOH again, use salt acid for adjusting pH value to 5.0 under the room temperature after stirring and refluxing 18-24 hour.With the admixture solvent evaporated under reduced pressure, solids is dissolved in the methylene dichloride, adds N-hydroxy-succinamide (N-hydroxyl maleimide) again, in the presence of Dimethylamino pyridine (DMAP) and dicyclohexylcarbodiimide (DCCI), temperature-20 ~ 10 ℃ was reacted 4 hours or is spent the night.With the water separator branch branch that anhydrates, continue to reflux and spend the night, vacuum is taken out methylene dichloride then, mixture is through ether sedimentation, ethyl alcohol recrystallization, be further purified through the SephadexG-25 post again, can get pure product double focusing ethylene glycol thioether Thioctic Acid succinimide ester (maleimide ester) (structure 3 and 4), put-20 ℃ of preservations.
Get Thioctic Acid (reduced form) and N, the N-carbonyl dimidazoles is suspended in the methylene dichloride, and stirring at room was reacted 12 hours or spent the night, and filtrate is rotated evaporate to dryness, and the gained solid is dissolved in the tetrahydrofuran (THF) and in the presence of Lithium Aluminium Hydride, room temperature reaction spends the night.The gained mixture is filtered back rotation evaporate to dryness.The gained solid is dissolved in the methylene dichloride, add the mono methoxy polyethylene glycol chlorine (mPEG-Cl) or mono methoxy polyethylene glycol acyl chlorides (mPEG-COCl) and an amount of sulfur oxychloride that have prepared, after stirring at room 5-7 hour, rotary evaporation removes and desolvates and remaining sulfur oxychloride, the gained solid matter is dissolved in the methylene dichloride, dried over sodium sulfate, mixture is through ether sedimentation, ethyl alcohol recrystallization, be further purified through Sephadex G-25 post again, can get and to get pure product double focusing ethylene glycol sulfo-S-acid esters Thioctic Acid aldehyde (or double focusing ethylene glycol thioether Thioctic Acid aldehyde) (structure 5 and 6), put-20 ℃ of preservations.
According to another aspect of the present invention, provide above-mentioned reactive derivative by F group and the binding substances of drug molecule formation and the pharmaceutical composition that comprises this binding substances.Above-mentioned polyethylene active derivatives can be under the physiological condition of gentleness (pH value in reaction between 4 ~ 9,0 ~ 20 ℃ of temperature of reaction) combines with the drug molecule with free amino group or sulfydryl, forms the macromole binding substances.This binding substances has following general structure:
The above drug molecule can be protein or polypeptide, preferred but be not limited to Interferon, rabbit, erythropoietin, G-CSF, Zadaxin, thymopeptide-5 (TP-5), Thymosin alpha 1, carnosine, Leuprolide, gonadorelin, my Rayleigh, Sermorelin, Sostatin, Somatostatin, Angiotensin, A Ji Rayleigh etc.
Except protein or polypeptide, drug molecule can also be to be selected from the molecule that has free amino group or sulfydryl in the drug molecules such as amino acid, carbohydrate, organic acid, alkaloid, flavonoid, glucoside, quinones, terpene.
Specific embodiments
Embodiment 1
The preparation of double focusing ethylene glycol sulfo-S-acid esters Thioctic Acid succinimide ester
Reaction formula:
Getting 10g mono methoxy polyethylene glycol acid 5000 (0.002mol) is dissolved in the 50ml methylene dichloride, add an amount of sulfur oxychloride, after stirring at room 5-7 hour, rotary evaporation removes and desolvates and remaining sulfur oxychloride, the gained solids is dissolved in the 75ml methylene dichloride, add 0.21g Thioctic Acid (reduced form) again (0.001mol) and 0.40g pyridine (0.005mol), stirring and refluxing 16-24 hour.Filter and with gained filtrate decompression evaporate to dryness, solids is dissolved in the 50ml methylene dichloride, adds 0.58g N-hydroxy-succinamide (0.005mol) again, in the presence of Dimethylamino pyridine (DMAP) and dicyclohexylcarbodiimide (DCCI), temperature-20 ~ 10 ℃ was reacted 4 hours or is spent the night.With the water separator branch branch that anhydrates, continue to reflux and spend the night, vacuum is taken out methylene dichloride then, mixture is through ether sedimentation, and ethyl alcohol recrystallization is further purified through Sephadex G-25 post again, can get and to get pure product double focusing ethylene glycol sulfo-S-acid esters Thioctic Acid succinimide ester 8.2g, put-20 ℃ of preservations.
Embodiment 2
The preparation of double focusing ethylene glycol sulfo-S-acid esters Thioctic Acid maleimide ester
Reaction formula:
Getting 16g mono methoxy polyethylene glycol acid 8000 (0.002mol) is dissolved in the 50ml methylene dichloride, add an amount of sulfur oxychloride, after stirring at room 5-7 hour, rotary evaporation removes and desolvates and remaining sulfur oxychloride, the gained solid matter is dissolved in the 75ml methylene dichloride, add 0.21g Thioctic Acid (reduced form) again (0.001mol) and 0.40g pyridine (0.005mol), stirring and refluxing 16 hours.Filter and with gained filtrate decompression evaporate to dryness, solids is dissolved in the 50ml methylene dichloride, adds 0.57g N-hydroxyl maleimide (0.005mol) again, in the presence of Dimethylamino pyridine (DMAP) and dicyclohexylcarbodiimide (DCCI), temperature-20 ~ 10 ℃ was reacted 4 hours or is spent the night.With the water separator branch branch that anhydrates, continue to reflux and spend the night, vacuum is taken out methylene dichloride then, mixture is through ether sedimentation, ethyl alcohol recrystallization, be further purified through Sephadex G-25 post again, can get and to get pure product double focusing ethylene glycol sulfo-S-acid esters Thioctic Acid maleimide ester 14.1g, put-20 ℃ of preservations.
Embodiment 3
The preparation of double focusing ethylene glycol thioether Thioctic Acid succinimide ester
Reaction formula:
Getting 20g mono methoxy polyethylene glycol 10000 (0.002mol) is dissolved in the 50ml methylene dichloride, add an amount of sulfur oxychloride, after stirring at room 5-7 hour, rotary evaporation removes and desolvates and remaining sulfur oxychloride, the gained solid matter is dissolved in the 75ml methylene dichloride, add 0.21g Thioctic Acid (reduced form) again (0.001mol) and the ethanolic soln 20ml of 0.20g NaOH (0.005mol), after stirring and refluxing 18-24 hour with salt acid for adjusting pH value to 5.0.With the admixture solvent evaporated under reduced pressure, solids is dissolved in the 50ml methylene dichloride, adds 0.58g N-hydroxy-succinamide (0.005mol) again, in the presence of Dimethylamino pyridine (DMAP) and dicyclohexylcarbodiimide (DCCI), temperature-20 ~ 10 ℃ was reacted 4 hours or is spent the night.With the water separator branch branch that anhydrates, continue to reflux and spend the night, vacuum is taken out methylene dichloride then, mixture is through ether sedimentation, and ethyl alcohol recrystallization is further purified through the SephadexG-25 post again, can get pure product double focusing ethylene glycol thioether Thioctic Acid succinimide ester 18.3g, put-20 ℃ of preservations.
Embodiment 4
The preparation of double focusing ethylene glycol thioether Thioctic Acid maleimide ester
Reaction formula:
Getting 40g mono methoxy polyethylene glycol 20000 (0.002mol) is dissolved in the 100ml methylene dichloride, add an amount of sulfur oxychloride, after stirring at room 5-7 hour, rotary evaporation removes and desolvates and remaining sulfur oxychloride, the gained solids is dissolved in the 150ml methylene dichloride, add 0.21g Thioctic Acid (reduced form) again (0.001mol) and the ethanolic soln 30ml of 0.2g NaOH (0.005mol), under the room temperature after stirring and refluxing 18-24 hour with salt acid for adjusting pH value to 5.0.With the admixture solvent evaporated under reduced pressure, solids is dissolved in the 100ml methylene dichloride, adds 0.57g N-hydroxyl maleimide (0.005mol) again, in the presence of Dimethylamino pyridine (DMAP) and dicyclohexylcarbodiimide (DCCI), temperature-20 ~ 10 ℃ was reacted 4 hours or is spent the night.With the water separator branch branch that anhydrates, continue to reflux and spend the night, vacuum is taken out methylene dichloride then, mixture is through ether sedimentation, and ethyl alcohol recrystallization is further purified through Sephadex G-25 post again, can get pure product double focusing ethylene glycol thioether Thioctic Acid maleimide ester 35.4g, put-20 ℃ of preservations.
Embodiment 5
The preparation of double focusing ethylene glycol sulfo-S-acid esters Thioctic Acid aldehyde
Reaction formula:
Get 0.21g Thioctic Acid (reduced form) (0.001mol) and 0.24g N, N-carbonyl dimidazoles (0.0015mol) is suspended in the 25ml methylene dichloride, stirring at room was reacted 12 hours or was spent the night, filtrate is rotated evaporate to dryness, the gained solid is dissolved in the 20ml tetrahydrofuran (THF) and in the presence of Lithium Aluminium Hydride, and room temperature reaction spends the night.The gained mixture is filtered back rotation evaporate to dryness.The gained solid is dissolved in the 50ml methylene dichloride, add mono methoxy polyethylene glycol chlorine 8000 (mPEG-Cl) that 16g prepared (0.002mol) and an amount of sulfur oxychloride, after stirring at room 5-7 hour, rotary evaporation removes and desolvates and remaining sulfur oxychloride, the gained solid matter is dissolved in the 50ml methylene dichloride, dried over sodium sulfate, mixture is through ether sedimentation, ethyl alcohol recrystallization, be further purified through Sephadex G-25 post again, can get and to get pure product double focusing ethylene glycol sulfo-S-acid esters Thioctic Acid aldehyde 15.0g, put-20 ℃ of preservations.
Embodiment 6
The preparation of double focusing ethylene glycol thioether Thioctic Acid aldehyde
Reaction formula:
Get 0.21g Thioctic Acid (reduced form) (0.001mol) and 0.24g N, N-carbonyl dimidazoles (0.0015mol) is suspended in the 25ml methylene dichloride, stirring at room was reacted 12 hours or was spent the night, filtrate is rotated evaporate to dryness, the gained solid is dissolved in the 20ml tetrahydrofuran (THF) and in the presence of Lithium Aluminium Hydride, and room temperature reaction spends the night.The gained mixture is filtered back rotation evaporate to dryness.The gained solid is dissolved in the 100ml methylene dichloride, add mono methoxy polyethylene glycol acyl chlorides 20000 (mPEG-COCl) that 40g prepared (0.002mol) and an amount of sulfur oxychloride, after stirring at room 5-7 hour, rotary evaporation removes and desolvates and remaining sulfur oxychloride, the gained solid matter is dissolved in the 75ml methylene dichloride, dried over sodium sulfate, mixture is through ether sedimentation, ethyl alcohol recrystallization, be further purified through Sephadex G-25 post again, can get and to get pure product double focusing ethylene glycol thioether Thioctic Acid aldehyde 35.1g, put-20 ℃ of preservations.
Embodiment 7
The preparation of double-chain polyethylene glycol-Interferon, rabbit
Get the Interferon, rabbit borate buffer of 10mg/ml, pH=9.0 adds double focusing ethylene glycol sulfo-S-acid esters Thioctic Acid succinimide ester 5000 dry powder 500mg, and reaction is 8 hours under 4 ℃ of conditions, through the anionresin column purification, can get the PEG-IFN sample.
Claims (3)
1. the polyethylene active derivatives that has following general structure
R wherein
1And R
2Be selected from methoxyl group, oxyethyl group or benzyl group.
2. polyethylene active derivatives as claimed in claim 1 is characterized in that: the molecular weight of polyoxyethylene glycol is 1000～40,000.
3. a polyethylene active derivatives as claimed in claim 1 is by its active end group and the formed mixture of drug molecule, and this mixture has following general structure:
Y is a linking group, is selected from the group of being made up of alkyl, amide group; Described drug molecule is selected from protein, polypeptide or contains free amino group or the organic acid of sulfydryl, carbohydrate, alkaloid, flavonoid, glucoside, quinones, terpene.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2006100973957A CN1966547B (en) | 2006-11-06 | 2006-11-06 | Double-chain structured polyethylene glycol derivative preparation and its combination with pharmaceutical molecule |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2006100973957A CN1966547B (en) | 2006-11-06 | 2006-11-06 | Double-chain structured polyethylene glycol derivative preparation and its combination with pharmaceutical molecule |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1966547A CN1966547A (en) | 2007-05-23 |
| CN1966547B true CN1966547B (en) | 2011-11-09 |
Family
ID=38075546
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2006100973957A Expired - Fee Related CN1966547B (en) | 2006-11-06 | 2006-11-06 | Double-chain structured polyethylene glycol derivative preparation and its combination with pharmaceutical molecule |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1966547B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CL2008002399A1 (en) | 2007-08-16 | 2009-01-02 | Pharmaessentia Corp | Substantially pure conjugate having a polymeric portion, a protein portion (interferon alpha 2b) and an aliphatic binder of 1 to 10 carbon atoms, useful in the treatment of hepatitis b or c. |
| RU2625771C2 (en) * | 2012-05-23 | 2017-07-18 | Дженентек, Инк. | Therapeutics selection method |
| KR20230079520A (en) | 2014-11-06 | 2023-06-07 | 파마에센시아 코퍼레이션 | Dosage Regimen for PEGylated Interferon |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4917888A (en) * | 1985-06-26 | 1990-04-17 | Cetus Corporation | Solubilization of immunotoxins for pharmaceutical compositions using polymer conjugation |
| CN1088721C (en) * | 1996-05-31 | 2002-08-07 | 弗·哈夫曼-拉罗切有限公司 | Interferon conjugates |
| CN1511848A (en) * | 2002-12-30 | 2004-07-14 | 北京三元基因工程有限公司 | Branched chain polyethylene glycol-integrated int3erferon composition and preparation |
| CN1187392C (en) * | 2001-12-14 | 2005-02-02 | 田浤 | Composition of protein and double chain polyethylene glycol |
-
2006
- 2006-11-06 CN CN2006100973957A patent/CN1966547B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4917888A (en) * | 1985-06-26 | 1990-04-17 | Cetus Corporation | Solubilization of immunotoxins for pharmaceutical compositions using polymer conjugation |
| CN1088721C (en) * | 1996-05-31 | 2002-08-07 | 弗·哈夫曼-拉罗切有限公司 | Interferon conjugates |
| CN1187392C (en) * | 2001-12-14 | 2005-02-02 | 田浤 | Composition of protein and double chain polyethylene glycol |
| CN1511848A (en) * | 2002-12-30 | 2004-07-14 | 北京三元基因工程有限公司 | Branched chain polyethylene glycol-integrated int3erferon composition and preparation |
Non-Patent Citations (3)
| Title |
|---|
| Olaf Kinstler,et al..Mono-N-terminal poly(ethylene glycol)–protein conjugates.《Advanced Drug Delivery Reviews》.2002,第54卷第477-485页. * |
| 姜忠义等.蛋白质和肽类分子的聚乙二醇化化学.《有机化学》.2003,第23卷(第12期),第1340-1347页. * |
| 马金波等.多肽蛋白质类药物聚乙二醇化修饰研究进展.《中国药物化学杂志》.2005,第15卷(第2期),第116-121页. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1966547A (en) | 2007-05-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2824093C (en) | Polymeric prodrug with a self-immolative linker | |
| JP5934743B2 (en) | Cyclodextrin-based polymer for therapeutic agent delivery | |
| KR100396983B1 (en) | Highly reactive branched polymer and proteins or peptides conjugated with the polymer | |
| EP1909845B1 (en) | N,n-bis-(2-hydroxyethyl) glycine amide as linker in polymer conjugated prodrugs | |
| EP2459227B1 (en) | Prodrugs containing an aromatic amine connected by an amide bond to a carrier | |
| CA2387611C (en) | Manufacture of polyglutamate-therapeutic agent conjugates | |
| DE10112825A1 (en) | HESylation of active ingredients in aqueous solution | |
| Molteni | [22] Dextran and inulin conjugates as drug carriers | |
| KR0184858B1 (en) | Polymyxin conjugates | |
| CA2818071C (en) | Modified cyclodextrin ring compounds having exactly two hydroxyl moieties substituted with an amino acid for therapeutics delivery | |
| CN1966547B (en) | Double-chain structured polyethylene glycol derivative preparation and its combination with pharmaceutical molecule | |
| JP2005514505A (en) | Preparation and use of multi-arm dendritic and functional PEG | |
| CN101045164A (en) | Double-chain structured polyethylene active derivatives, and ligature with other molecules | |
| EP1625855A1 (en) | Polymeric prodrug with a self-immolative linker | |
| AU2012247051A1 (en) | Cyclodextrin-based polymers for therapeutics delivery | |
| KR100888371B1 (en) | Antivirus agent comprising bridged co-polymer derivatives and interferon complexes |
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 | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20111109 Termination date: 20211106 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |