CN105287363A - Micromolecular organic gel for orthotopic injection and preparation method and application thereof - Google Patents
Micromolecular organic gel for orthotopic injection and preparation method and application thereof Download PDFInfo
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- CN105287363A CN105287363A CN201510820509.5A CN201510820509A CN105287363A CN 105287363 A CN105287363 A CN 105287363A CN 201510820509 A CN201510820509 A CN 201510820509A CN 105287363 A CN105287363 A CN 105287363A
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Abstract
The present invention provides a micromolecular organic gel for orthotopic injection and a preparation method and application thereof. A technical scheme is as below: a micromolecular organic gel comprises a dicarboxylic acid derivative and polyethylene glycol. The preparation method of the micromolecular organic gel for orthotopic injection is as below: 1) preparing the dicarboxylic acid derivative; 2) taking the above dicarboxylic acid derivative, adding polyethylene glycol (PEG), properly heating under ultrasonic condition, dissolving and standing to obtain a stable clarified solution. The stable clarified solution can be used for orthotopic injection and form stable hydrogel with water. The temperature for heating under ultrasonic condition is 80-90 DEG C, and a water-bath is employed for heating. The prepared micromolecular organic gel for orthotopic injection can be used as a slow-release medicament. The invention has the advantages of small application amount of organic matter, and good stabilization, mechanical property and extremely low toxicity of the formed gel.
Description
Technical field
The invention belongs to materials chemistry, bioengineering field, relate to a kind of can the Low-molecular weight organogel and preparation method thereof of in-situ injection, application.
Background technology
Original position injection aquagel is the novel hydrogels system occurred in recent years, has purposes widely in organizational project and medicine controlled releasing etc.It has significant advantage: (1) change generation physics with contact environment or the change of chemistry, and therefore the physics and chemistry state of adjustable preparation and medicine state are in vivo adapting to the timely and effective treatment of the state of an illness; (2) can for a long time with agents area close contact, have good bioadhesive, thus improve bioavailability; (3) tridimensional network highly-hydrophilic, can be bound by contained medicine wherein or in gap, Drug controlled release; (4) histocompatibility is good, easy to use, decreases administration frequency, improves the compliance of patient; (5) have special physicochemical property, under in vitro conditions, have certain mobility, easy fill, is convenient to suitability for industrialized production.
Hydrogel can be water-swellable and water-fast polymer network.Implanted by the biomaterial with certain fluidity by the method for injection, be therefore easy to be full of and wholely have erose defect, operation wound is very little and simple to operate.This system its be at room temperature in a liquid state, can coating active cell and medicine, after being expelled to assigned address, in temperature, pH value, ion concentration or under ion, other conditioning, producing solution-gel phase in version at injection position place and form hydrogel.[Wei Hongliang, Wang Liancai, Zhang Aiying, Zhu Kaiqiang, Feng Zengguo. the preparation and application of injection aquagel. chemical progress, 2004,16 (6): 1008-1016].
Compare with preformed polymeric stent material, original position injection aquagel has obvious advantage: (1) aquogel system change environmentally can adjust system status; (2) under solution state, cell or medicine can be dispersed or be dissolved in macromolecular material; (3) injection material can form the hydrogel of required shape at damage location, better can fill like this to damage location that is complicated or multidimensional; (4) in gel formation process, crosslinked macromolecule mixture can be chimeric with between tissue tight, greatly strengthen the interface cohesion of hydrogel and tissue; (5) applied widely, preparation technology is simple, easy to operate.[Chen Tao, Yao Kangde. injection aquagel applies progress in organizational project. and chemical industry is in progress, and 2004,23 (8): 827-831].
Polyethylene Glycol (PEG) is a kind of water-soluble poly ether type macromolecular compound, is widely used in the fields such as medicine, health, food, chemical industry.PEG has the advantages such as hypotoxicity, not hemagglutinin and biocompatibility, and can be excreted rapidly by body and not produce toxic and side effects.When PEG and other molecule couplings, its many advantageous property also can be transferred in conjugate thereupon.Therefore, its application medically receives to be paid attention to widely, and obtains the accreditation of FDA (FDA).[seat is levied, and Artemisia silver is big, the preparation method of chemical crosslinking polyethylene glycol hydrogel. chemical propellant and macromolecular material, 2011,9 (3): 36-43].
About the report preparing injection aquagel is a lot, they can be divided into two large classes: one is prepare with the natural polymer of natural macromolecule or modification; Another kind of is prepare with synthesis macromolecule.Injectable poly-glucose aldehyde (PAG) hydrogel is used for bone tissue engineer by Lee etc.Antitumor drug daunomycin (daunomycin) is connected on this hydrogel by covalent bond, after the covalent bond hydrolysis between medicine and polymer, can medicine be discharged.[BouhadirKH,KrugerGM,LeeKY,etal.JournalofPharmaceuticalSciences,2000,89(7):910—919]。Westhaus etc. discharge from liposome by causing metal ion, develop the universal method forming hydrogel from the precursor solution containing polysaccharide and protein fast.They think that the method contributes to developing the injection aquagel of quick-gelatinizing, for the preparation of biomaterial, carry out the targeted release of tissue repair and reconstruction and medicine.[WesthausE,MessersmithPB.Biomaterials,2001,22:453—462]。
At present, the gel rubber material that the can be used for in-situ injection mainly macromolecular material reported.But the report that can be used for the original position micromolecule gel rubber material injected is little, only has PharmaceuticalResearch, 2004, Vol.21, No.3 in document, 454 reported that ALANINE, soybean oil and alcoholic solution are used for in-situ injection tested.
Summary of the invention
The invention provides a kind of can the Low-molecular weight organogel and preparation method thereof of in-situ injection and application.
Technical scheme: a kind of can the Low-molecular weight organogel of in-situ injection, be made up of following ingredients: dicarboxylic acid derivatives, Polyethylene Glycol.
Described dicarboxylic acid derivatives is octadecyl malonic acid or cetyl malonic acid.
Described Polyethylene Glycol be selected from PEG300, PEG400, PEG600 of medical grade any one.
The scope of described dicarboxylic acid derivatives in Polyethylene Glycol is 5.0-8.0g/L.
A kind of can the preparation method of Low-molecular weight organogel of in-situ injection, 1) synthesis of dicarboxylic acid derivatives, solid metal sodium is added in dehydrated alcohol, after treating that sodium dissolves completely, drip diethyl malonate, half an hour is reacted at 60-70 DEG C, slowly drip bromo-octadecane or bromohexadecane again, after after dripping, temperature is raised to 80 DEG C of backflow 3h, filtered while hot, filtrate decompression distillation obtains colourless oil liquid, dehydrated alcohol and sodium hydroxide solution is added to colourless oil liquid, 80 DEG C of backflow 8h, reactant liquor dilute hydrochloric acid regulates pH to be 4-5, then sucking filtration, vacuum drying, obtain white solid, with second alcohol and water repeatedly recrystallization, obtain final dicarboxylic acid derivatives, 2) get above-mentioned dicarboxylic acid derivatives, add Polyethylene Glycol, suitably heat under ultrasound condition, make it to dissolve, leave standstill, obtain stable settled solution, this clear stable solution may be used for in-situ injection and meets water forming stable hydrogel.Under ultrasound condition, the temperature of suitably heating is 80-90 DEG C, adopts heating in water bath.
Obtained can the Low-molecular weight organogel of in-situ injection to can be used to make slow releasing pharmaceutical.
Beneficial effect: Organic substance use amount is few, become gel stability, good mechanical property, toxicity is extremely low, the physics and chemistry state of adjustable preparation and medicine state in vivo with adapt to the state of an illness timely and effective treatment, can for a long time with agents area close contact, there are good bioadhesive, tridimensional network highly-hydrophilic, contained medicine can be bound by wherein or in gap, Drug controlled release, histocompatibility are good, easy to use, decrease administration frequency, improve the compliance of patient.
Accompanying drawing explanation
Fig. 1 be the present invention with octadecyl malonic acid, PEG (300,400,600) for raw material, add gel rubber material prepared by isopyknic distilled water;
Fig. 2 is that the present invention is with cetyl malonic acid, PEG(300,400,600) for raw material, add gel rubber material prepared by isopyknic distilled water;
Fig. 3 be the present invention with octadecyl malonic acid, PEG400 for raw material, be expelled in water the effect schematic diagram forming gel.
Fig. 4 is the medicament slow release curve that the present invention obtains with the gel rubber material that octadecyl malonic acid, PEG400, salicylic acid are prepared for raw material.
Detailed description of the invention
Undeclared part all represents with molar fraction below
Embodiment 1
(1) preparation of carboxylic acid derivates
In the round-bottomed flask of 50mL, add 10mL dehydrated alcohol, then add 0.23g(10mmol) solid sodium, after treating that sodium dissolves completely, drip 1.6g (10mmol) diethyl malonate.Half an hour is reacted at 60-70 DEG C.Slowly drip 3.33g (10mmol) bromo-octadecane again.Time for adding controlled in half an hour.After dripping, temperature is raised to about 80 DEG C backflow 3h.After having reacted, product filtered while hot.Filtrate is spin-dried for Rotary Evaporators.Obtain colourless oil liquid.Product normal hexane: ethyl acetate=20:1 column chromatography.End product is colourless oil liquid.
Take 1.648g(4mmol) octadecyl diethyl malonate, add 20mL ethanol.Add the sodium hydroxide solution that 5mL concentration is 2mol/L.About 80 DEG C backflow 8h.Reactant liquor dilute hydrochloric acid regulates pH to be 4-5.Then sucking filtration, vacuum drying, obtains white solid, with 50mL ethanol and 50mL water repeatedly recrystallization.Obtain final carboxylic acid derivates---octadecyl malonic acid (C18ma).
2) material preparation
Take a certain amount of above-mentioned carboxylic acid derivates, add Polyethylene Glycol (in PEG300, PEG400, PEG600 any one), suitably (heating in water bath is heated under ultrasound condition, temperature 80-100 DEG C), make it to dissolve, leave standstill, obtain stable settled solution, this clear stable solution may be used for in-situ injection and meets water forming stable hydrogel, the concentration 5.0 ~ 8.0g/L of carboxylic acid derivates in Polyethylene Glycol.
As shown in Figure 1, gelator dissolves in Polyethylene Glycol, adds water and can form stable gel rubber system, body is inverted, and gel can not flow, and illustrates that this gel has the good stability of the rate of exchange.And only need a small amount of gel, just can fix solvent, illustrate that gelling performance is relatively good.
As shown in Figure 3, gelator is dissolved in polyglycol solution, with injector to inject in water, we find that it can form gel in bottom very soon, and gel is more stable, illustrate that this system can realize in-situ injection in the system having water to exist, form gel rubber system fast and stable.
Embodiment 2
(1) preparation of carboxylic acid derivates
In the round-bottomed flask of 50mL, add 10mL dehydrated alcohol, then add 0.23g(10mmol) solid sodium, after treating that sodium dissolves completely, drip 1.6g (10mmol) diethyl malonate.Half an hour is reacted at 60-70 DEG C.Slowly drip 10mmol bromohexadecane again.Time for adding controlled in half an hour.After dripping, temperature is raised to about 80 DEG C backflow 3h.After having reacted, product filtered while hot.Filtrate is spin-dried for Rotary Evaporators.Obtain colourless oil liquid.Product normal hexane: ethyl acetate=20:1 column chromatography.End product is colourless oil liquid.
Take 4mmol cetyl diethyl malonate, add 20mL ethanol.Add the sodium hydroxide solution that 5mL concentration is 2mol/L.About 80 DEG C backflow 8h.Reactant liquor dilute hydrochloric acid regulates pH to be 4-5.Then sucking filtration, vacuum drying, obtains white solid, with 50mL ethanol and 50mL water repeatedly recrystallization.Obtain final carboxylic acid derivates---cetyl malonic acid (C16ma).
2) material preparation
Take a certain amount of above-mentioned carboxylic acid derivates, add Polyethylene Glycol (in PEG300, PEG400, PEG600 any one), suitably (heating in water bath is heated under ultrasound condition, temperature 80-100 DEG C), make it to dissolve, leave standstill, obtain stable settled solution, this clear stable solution may be used for in-situ injection and meets water forming stable hydrogel, the concentration 5.0 ~ 8.0g/L of carboxylic acid derivates in Polyethylene Glycol.
As shown in Figure 2, same, C16ma is the same with C18ma, gel is dissolved in Polyethylene Glycol, adds water and also can form stable gel rubber system.
Medicament slow release is tested
Take the above-mentioned carboxylic acid derivates of fixed amount, add Polyethylene Glycol (300,400 or 600), then add the salicylic acid solution of fixed amount, salicylic concentration is 100mg/L, 150mg/L, 200mg/L, 250mg/L.Suitable heating (heating in water bath, temperature 80-100 DEG C) is dissolved into solution, is cooled to gel, then adds PBS buffer and carry out medicament slow release experiment, surveys its ultraviolet absorption value, obtain standard curve at 300nm place.
As shown in Figure 4, the medicament slow release experiment of a kind of medicine that we choose finds, this gel rubber system has good sustained drug release effect, in the first five ten Hours drug release faster, until below along with the slow release of medicine, its slow release rate slowly tends towards stability.By this elution profiles, we can find, this gel rubber system has good slow release effect, and the network-like structure energy well packaging medicine of gel, realizes Co ntrolled release.
Claims (7)
1. can the Low-molecular weight organogel of in-situ injection, it is characterized in that: be made up of following ingredients: dicarboxylic acid derivatives, Polyethylene Glycol.
2. according to claim 1 can the Low-molecular weight organogel of in-situ injection, it is characterized in that: described dicarboxylic acid derivatives is octadecyl malonic acid or cetyl malonic acid.
3. according to claim 1 can the Low-molecular weight organogel of in-situ injection, it is characterized in that: described Polyethylene Glycol be selected from PEG300, PEG400, PEG600 of medical grade any one.
4. according to claim 1 can the Low-molecular weight organogel of in-situ injection, it is characterized in that: the scope of described dicarboxylic acid derivatives in Polyethylene Glycol is 5.0-8.0g/L.
5. one kind can the preparation method of Low-molecular weight organogel of in-situ injection, it is characterized in that: the 1) synthesis of dicarboxylic acid derivatives, solid metal sodium is added in dehydrated alcohol, after treating that sodium dissolves completely, drip diethyl malonate, half an hour is reacted at 60-70 DEG C, slowly drip bromo-octadecane or bromohexadecane again, after after dripping, temperature is raised to 80 DEG C of backflow 3h, filtered while hot, filtrate decompression distillation obtains colourless oil liquid, dehydrated alcohol and sodium hydroxide solution is added to colourless oil liquid, 80 DEG C of backflow 8h, reactant liquor dilute hydrochloric acid regulates pH to be 4-5, then sucking filtration, vacuum drying, obtain white solid, with second alcohol and water repeatedly recrystallization, obtain final dicarboxylic acid derivatives, 2) get above-mentioned dicarboxylic acid derivatives, add Polyethylene Glycol, suitably heat under ultrasound condition, make it to dissolve, leave standstill, obtain stable settled solution, this clear stable solution may be used for in-situ injection and meets water forming stable hydrogel.
6. according to claim 1 can the preparation method of Low-molecular weight organogel of in-situ injection, it is characterized in that: the temperature of suitably heating is 80-90 DEG C under ultrasound condition, adopt heating in water bath.
7. claim 1-4 arbitrary described can the Low-molecular weight organogel of in-situ injection as the application preparing slow releasing pharmaceutical.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110680829A (en) * | 2019-09-25 | 2020-01-14 | 赣南师范大学 | Injection type ester supramolecular gel material and application thereof |
| CN114983931A (en) * | 2022-05-30 | 2022-09-02 | 赣南师范大学 | Preparation method and application of injection type pyridine amide derivative micromolecule in-situ gel preparation |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104189951A (en) * | 2014-09-19 | 2014-12-10 | 赣南师范学院 | Liquid preparation for injection for quickly forming in-situ small molecule water gel and preparation method and application thereof |
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| CN104189951A (en) * | 2014-09-19 | 2014-12-10 | 赣南师范学院 | Liquid preparation for injection for quickly forming in-situ small molecule water gel and preparation method and application thereof |
Non-Patent Citations (3)
| Title |
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| CHRISTINE HIEMSTRA ET AL.: ""In-Situ Formation of Biodegradable Hydrogels by Stereocomplexation of PEG-(PLLA)8 and PEG-(PDLA) 8 Star Block Copolymers"", 《BIOMACROMOLECULES》 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110680829A (en) * | 2019-09-25 | 2020-01-14 | 赣南师范大学 | Injection type ester supramolecular gel material and application thereof |
| CN114983931A (en) * | 2022-05-30 | 2022-09-02 | 赣南师范大学 | Preparation method and application of injection type pyridine amide derivative micromolecule in-situ gel preparation |
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