CN104479129A

CN104479129A - Polymer and preparation method and application thereof

Info

Publication number: CN104479129A
Application number: CN201410330259.2A
Authority: CN
Inventors: 张雅珍; 李铁力
Original assignee: Individual
Current assignee: Individual
Priority date: 2013-07-19
Filing date: 2014-07-13
Publication date: 2015-04-01

Abstract

The invention discloses a new non-linear multiblock copolymer and a preparation method and an application of the polymer. In comparison with other polymers or medicines or agentia of polymers, the non-linear multiblock copolymer shows high efficiency and smoothness when passing through a thin syringe needle. The non-linear multiblock copolymer is dramatically different from other polymers.

Description

A kind of polymkeric substance and its preparation method and application

Technical field

The invention discloses the non-linear segmented copolymer that a class is new, and the preparation method of this polymkeric substance and purposes.

Background technology

Current a variety of injection is due to the diversification of administering mode, and the feature of medicine itself, proposes a lot of requirements to excipient substance and medicine packaging material.The present inventor has invented the special medicine sustained and controlled release putting material of a kind of character, the feature of this material can continue and is not 30 or less thinner syringe needle by syringe needle number with at all not blocking, and in the test of medicine prepared at slow controlled-release material of these two kinds of syringe needles at present and the process of Clinical practice, often easily cause the blocking of syringe needle, thus a large amount of losses causing medicine to cause in administration process, thus affect medicine release conditions in vivo, the Plasma Concentration of remote effect medicine and medicine peak time.

Sustained and controlled release medicine material of the present invention can as highly stable and efficient carrier, the nanometer formulation that medicine is formed or microball preparation easily pass through No. 30 or less thinner syringe needle very much, freely pass through No. 30 or less thinner syringe needle at the initial stage that injection uses and later stage equal indistinction ground.

Summary of the invention

Content of the present invention is as follows:

The invention discloses the non-linear segmented copolymer shown in following formula I, its structure is as follows:

The non-linear segmented copolymer be shown below, its structure is as follows:

Integer wherein between n=1-200; Integer wherein between W=1-500.Integer wherein between n=1-200; Preferred n=1-100, the integer wherein between W=1-500, preferred 1-300.Preparation method characteristic is:

1) compd A is obtained by reacting with compound first and compound second;

2) compd A and acetylating 1,6-two (to carboxyphenoxy) hexane are obtained by reacting polymer B, the wherein integer of n=1-200, preferred 1-100;

Compound first

Compound second

Wherein compound first also can be selected from:

Wherein compound second also can be selected from:

compd A;

Polymer B.

Wherein optionally use solvent in chemical reaction step, described in step 1, solvent is selected from: one or more in methyl alcohol, ethanol, benzene, toluene, pyridine, tetrahydrofuran (THF), chloroform, tetracol phenixin, methylene dichloride, dimethyl sulfoxide (DMSO), DMF, dicyclohexylcarbodiimide; Step 2 optionally uses solvent, one or more in described solvent selected from methanol, ethanol, methylene dichloride, chloroform, tetracol phenixin, dimethyl sulfoxide (DMSO), DMF, toluene, pyridine, tetrahydrofuran (THF), chloroform, tetracol phenixin, methylene dichloride, dicyclohexylcarbodiimide.

Preparation method of the present invention is specific as follows:

1) two for 1,6-(to carboxyphenoxy) hexane is refluxed in diacetyl oxide, form acetylizad 1,6-two (to carboxyphenoxy) hexane (also can be purchased);

2) compound first is dissolved with compound second and is mixed in a solvent, and at room temperature reaction is spent the night, and drying obtains compd A;

3) acetylizad 1,6-two (to carboxyphenoxy) hexane is mixed with compd A, react at 100-200 DEG C, reaction times 20min to 2h; After the cooling of question response mixture, washing, drying obtains polymer B;

Its reaction equation is as follows:

+

↓

+

↓

；

The purposes of polymkeric substance is drug-carrying is No. 30 or thinner syringe needle by coding smoothly.Wherein coding No. 30 syringe needles refer to that internal diameter is less than 0.15 millimeter.Wherein carry medicine to refer to be combined with medicine generation valence link, also can refer to by physically encapsulation, then form simple mixture, also can form suitable nanometer formulation or microball preparation.Wherein smoothly by pointed injection process from start to end, be maintained by when injection volume is large always and smooth and easyly do not block.

accompanying drawing illustrates:

fig. 1the nuclear magnetic resonance map of embodiment 1.

Embodiment

Specific embodiment is described in further detail the present invention below, but the present invention not only limits to following examples.

Preparation embodiment is as follows:

embodiment 1

1) the mixture backflow of 1,6-two (to carboxyphenoxy) hexane 25g in 500ml diacetyl oxide, to form acetylizad 1,6-two (to carboxyphenoxy) hexane;

2) compound first 3g, compound second 51mg, dicyclohexylcarbodiimide 165mg and pyridine 8mg mix, and at room temperature stir and spend the night; Then washed with diethylether is used, and dry under vacuo, obtain polymkeric substance;

3) by the 1st) step and the 2nd) step Product mix puts into flask, decompression melting polyreaction 1 hour at 180 DEG C; Thing to be polymerized is cooled to room temperature chloroform and dissolves, and also dry by petroleum ether;

embodiment 2

1) the mixture backflow of 1,6-two (to carboxyphenoxy) hexane 30g in 300ml diacetyl oxide, to form acetylizad 1,6-two (to carboxyphenoxy) hexane;

2) compound first 2.7g, compound second 29mg, dicyclohexylcarbodiimide 130mg and pyridine 5mg mix, and at room temperature stir and spend the night; Then washed with diethylether is used, and dry under vacuo, obtain polymkeric substance;

3) by the 1st) step and the 2nd) step Product mix puts into flask, decompression melting polyreaction 1 hour at 150 DEG C; Thing to be polymerized is cooled to room temperature chloroform and dissolves, and also dry by petroleum ether;

effect experimental is as follows:

The PLGA(polylactic-co-glycolic acid 50:50 of sample prepared by embodiment 1-2 and purchase) (buying in Sigma-Aldrich of the U.S.), polyoxyethylene glycol (molecular weight is 20000), poly-(two (p-carboxyphenoxy) hexane of 1,6-) (buying in Sigma-Aldrich of the U.S.) is carried out effect and is implemented experiment.

For Dx, implement to carry the effect of medicine by No. 30 syringe needles.By the Dx of equivalent and the polymkeric substance of equivalent by identical preparation method with react the nanometer formulation being prepared into and carrying Dx, method is as follows: the Dx of 30mg and various polymkeric substance 200mg are put into 20ml dimethyl sulphoxide solution 48 hours; Then to insert in baking oven 3 hours; In subzero 10-20 degree, ultrasonic 15 minutes; Homogenizer high-speed stirring 1 minute, the cholic acid solution 400 turns then putting into 5% stirs 2 hours; Freeze-drying after collected by centrifugation, obtains nanometer formulation end product.

Get No. 30 syringes some, carry Dx by syringe with polymkeric substance, fixing syringe, carry out pressure injection emitter with the identical pressure (1.5 normal atmosphere) that identical counterweight pressure produces, compare the time.The through performance of comparative polymers is carried out by the speed of writing time.Each polymkeric substance record tests 10 times, averages.

The each group of nanometer formulation that table 1 takes 0.08mg compares the time of passing through

Group	Time (second)
		Embodiment 1	3.2±0.3
Embodiment 2	3.1±0.2
		PLGA	23.1±3.2
Polyoxyethylene glycol	21.8±2.2
		Poly-(two (p-carboxyphenoxy) hexane of 1,6-)	23.1±6.7

The each group of nanometer formulation that table 2 takes 1mg compares the time of passing through

Group	Time (second)
		Embodiment 1	3.7±0.3
Embodiment 2	3.5±0.4
		PLGA	Cannot pass through
Polyoxyethylene glycol	Cannot pass through
		Poly-(two (p-carboxyphenoxy) hexane of 1,6-)	Cannot pass through

Mathematical statistics shows, and embodiment group and other each group have difference.

Claims

1. the non-linear segmented copolymer be shown below, its structure is as follows:

Integer wherein between n=1-200; Integer wherein between W=1-500.

2. the multipolymer of claim 1, the integer wherein between n=1-200; Preferred n=1-100, the integer wherein between W=1-500, preferred 1-300.

3. the multipolymer of claim 1, the preparation method of multipolymer any one of claim 1-2, is characterized in that:

1) compd A is obtained by reacting with compound first and compound second;

Compound first

Compound second

Wherein compound first also can be selected from:

，

Wherein compound second also can be selected from:

，

Compd A;

Polymer B.

4. preparation method according to claim 3, wherein optionally use solvent in chemical reaction step, described in step 1, solvent is selected from: one or more in methyl alcohol, ethanol, benzene, toluene, pyridine, tetrahydrofuran (THF), chloroform, tetracol phenixin, methylene dichloride, dimethyl sulfoxide (DMSO), DMF, dicyclohexylcarbodiimide; Step 2 optionally uses solvent, one or more in described solvent selected from methanol, ethanol, methylene dichloride, chloroform, tetracol phenixin, dimethyl sulfoxide (DMSO), DMF, toluene, pyridine, tetrahydrofuran (THF), chloroform, tetracol phenixin, methylene dichloride, dicyclohexylcarbodiimide.

5. the purposes of any one of claim 1-4 polymkeric substance, purposes is drug-carrying is No. 30 or thinner syringe needle by coding smoothly.

6. the purposes of claim 5, wherein coding No. 30 syringe needles refer to that internal diameter is less than 0.15 millimeter.

7. the purposes of claim 5, wherein carries medicine and refers to be combined with medicine generation valence link, also can refer to by physically encapsulation, then form simple mixture, also can form suitable nanometer formulation or microball preparation.

8. the purposes of claim 5, wherein smoothly by pointed injection process from start to end, be maintained by when injection volume is large always and smooth and easyly do not block.