Multi-arm polyethylene glycol derivatives, conjugates and gels of pharmaceuticals and the same

a polyethylene glycol and derivative technology, applied in the field of multi-arm polyethylene glycol derivatives, can solve the problems of reducing the stability of the derivative, limited straight-chain polyethylene glycol derivatives with metachronous double functional groups, etc., and achieves the effect of simple structure and increased active group types

Active Publication Date: 2016-02-09
JENKEM TECH CO LTD TIANJIN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Straight-chain polyethylene glycol derivatives with metachronous double functional groups are limited to some extent in applications.
If one molecule is needed more than another one, for example, if one molecule has with low in vivo activity, more connections will be required for the low activity molecules than the high-activity molecules, which is a challenge to the straight-chain polyethylene glycol derivatives with metachronous double functional groups.
This connection is different in the way, and can reduce the stability of the derivatives.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of 4-Arm Poly (Ethylene Glycol) Hydroxy—Single-Acetic Acid (III-1) and 4-Arm Poly(Ethylene Glycol) Hydroxy—Double-Acetic Acid (IIIA-1)

[0082]

[0083]Procedure:

[0084]4-ARM-PEG (10 kDa, 100 g) in 800 ml of TI-W was azeotropically dried by distilling off THF (20%) under nitrogen and the solution was cooled to room temperature. To the solution was added potassium tert-butoxide (4.48 g) and stirred 2 hours at room temperature. Tert-butyl bromoacetate (5.17 ml) was added dropwise and the mixture was stirred at room temperature overnight. The mixture was filtered and evaporated under vacuum to remove solvents. The residue was dissolved in a aqueous solution (H2O 500 mL+sodium hydroxide 8.16 g+sodium phosphate) and stirred 2 hours at 80° C. The PH of the aqueous solution was adjusted to about 2-3. Sodium chloride (15%) was added and the product was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, filtered, concentrated under vacuum at 50° C., and t...

example 2

Synthesis of Four-Arm Polyethylene Glycol Hydroxy—Single-N-hydroxysuccinimidyl Ester (IV-1)

[0086]

[0087]Procedure:

[0088]4-arm poly (ethylene glycol) hydroxy—single-acetic acid (III-1) (10 kDa, 0.5 g) and N-hydroxysiccinimide (0.01439 g) were dissolved in dichloromethane. DCC (0.01290 g) was added and the solution was stirred overnight at room temperature, filtered, concentrated under vacuum at 40° C. The residue was dissolved in hot iso-propanol and then crystallized by cooling the solution to 0° C. The resulting precipitate was collected, washed with iso-propanol and dried to afford the 4-arm poly(ethylene glycol) hydroxy—single-N-hydroxysuccinimidyl ester (IV-1).

[0089]NMR (DMSO) δ: 2.89 (s,

[0090]

4.55 (t, CH2CH2OH).

example 3

4-Arm Poly(Ethylene Glycol) Hydroxy—Single-Methyl Acetate (IVA-1)

[0091]

[0092]Procedure:

[0093]4-arm poly (ethylene glycol) hydroxyl—single-acetic acid (III-1) (10 kDa, 3.2 g) was dissolved in methanol (16 ml). The solution was cooled to 0° C. and the concentrated sulfuric acid was added drop wise. The solution was stirred 3 hours at room temperature. The solution was adjusted PH to about 7.0 with 8% NaHCO3 anqueous solution. The product was extracted with dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in 40° C., and then precipitated into diethyl ether. The filtrate was dried over vacuum to afford the four-arm poly(ethylene glycol) hydroxy—single methyl acetate (IVA-1).

[0094]NMR (DMSO) δ: 3.32 (s, CH2COOCH3), 4.13 (s, CH2COOCH3), 4.57 (t, CH2OH).

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Abstract

A multi-arm polyethylene glycol (I) having different kinds of reactive groups and the uses thereof are disclosed, which is formed by polymerizing ethylene oxide with oligo-pentaerythritol as an initiator, wherein, PEG is same or different and is —(CH2CH2O)m-, the average value of m is an integer of 2-250; l is an integer of 1 or more. The method for producing the multi-arm polyethylene glycol having different kinds of reactive groups, the multi-arm polyethylene glycol active derivatives comprising linking groups X attached to PEG and terminal reactive groups F attached to X, the gels formed by the multi-arm polyethylene glycol active derivatives, the drug conjugates formed by the multi-arm polyethylene glycol active derivatives and drug molecules, and the uses thereof in preparing drugs are also disclosed.

Description

TECHNICAL FIELD[0001]The present invention relates to the multi-arm polyethylene glycol derivatives with different kinds of active groups and their preparation methods, drug molecules conjugates and the gel materials. The invention also relates to the role of the described above new multi-arm polyethylene glycol derivatives with different types of active groups and its gels in the preparation of pharmaceutical preparations and medical device materials.BACKGROUND ART[0002]At present, the polyethylene glycol derivatives are widely used in combination with proteins, peptides, and other therapeutic agents to extend the physiological half-life of drugs referred to, reduce immunogenicity and toxicity. In clinical use, PEG and its derivatives which act as the carrier in the production of pharmaceutical preparations have been widely used in lots of medicines. The attempts to bond PEG to the drug molecules have also seen significantly development in the past decade, and widely used in many a...

Claims

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Application Information

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Patent Type & AuthorityPatents(United States)
IPC IPC(8): C08G65/34C08G65/48A61K47/48C08G65/26C08G65/329C08G65/332A61K31/727C08G65/333
CPCA61K47/48215A61K31/727A61K47/48784C08G65/2609C08G65/329C08G65/3322C08G65/33337C08G2650/24C08L2203/02
InventorZHAO, XUANLIN, MEINA
OwnerJENKEM TECH CO LTD TIANJIN