CN102321248B - Injectable temperature sensitive gel used for filling and repairing damaged tissues - Google Patents
Injectable temperature sensitive gel used for filling and repairing damaged tissues Download PDFInfo
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Abstract
The invention relates to an injectable temperature sensitive gel used for filling and repairing damaged tissues. The gel is characterized in that: medical-grade hyaluronic acid and chitosan are used as gel raw materials; the gel swelling ratio is 2-500; and a temperature sensitive temperature is 32-37 DEG C. The gel provided by the invention has the advantages that the injection temperature sensitive gel has physical and chemical properties of a general gel, also has injectable and temperature sensitive properties and a good fluidity at a room temperature and is easy for injection; the formability in organisms is good and the degradation is slow so that the general gel can not be compared; a cross-linking agent is not used for the gel so that harms of the cross-linking agent to a human body are avoided; a gel system can prolong a persistence time of the gel in a body, and also can continuously stimulate the body to produce reactions so that the tissue in-situ regeneration and repair is promoted and the filling quality is increased; and the gel simultaneously has the advantages of reducing bacterial invansion, anticoagulation and low allergic reaction and the like.
Description
Technical field
The present invention relates to a kind of preparation method for filling and repair the capable of injecting temperature sensitive gel of damaged tissue, belong to medical material manufacture method technical field.
Background technology
Injectable filling and repair materials are a kind of intelligent macromolecule materials, are newer research fields that grows up over past ten years, are very popular research topics of intelligent macromolecule material.The injectable material of Thermo-sensitive is compared with the injectable material of routine, to utilize bionic principle, take the organism of occurring in nature as source, develop the temperature sensitive macromolecular material that approaches even surpass bio-tissue in function, thereby the biomaterial of realization lifeless matter activity is to the transition that bioactive biomaterial is arranged; Increase its response susceptibility, improve its logical-disconnected characteristic.The thermodynamics reversibility of material makes at normal temperatures mobile enhancing of material, be beneficial to injection, and material temperature solidifies in the body, and its constancy and plasticity-strengthen.In addition injectable gel in vivo and between the repair tissue mosaic good, realize that in-situ injection reaches Wicresoft's purpose, become the focus of soft tissue repair, reconstruction, filling.Therefore, the application of the injectable gelatinous material of Thermo-sensitive has significant advantage.
In recent years, the development of skin of face filling agent is very fast, and the annual growth of its produce market is then to be expected in 16.9%, 2012 year to surpass 1,600,000,000 U.S. dollars, and wherein hyaluronic acid product accounts for the largest percentage.In the technology of existing injectable weighting material and preparation method thereof, the normal injection fillers thing that adopts is that crosslinked hyaluronic acid and collagen protein is main its salts solution of gel.For example: by the auspicious indigo plant of hyaluronic acid dermal filler (restvlane) of the exploitation of Sweden Q-Med company and production.
Hyaluronic Acid (hyaluronic acid) is a kind of saccharan that extensively is present in biological and types of organization.The Karl Meyer of Columbia University had at first found hyaluronic acid in 1934, was one of main component of extracellular matrix, indifference between each species on the chemical structure.Hyaluronic acid is absorption and the primary structure of keeping moisture in skin, aspect storing moisture and locking water function, can effectively absorb nearly 3000 times of water volume of storage, and non-general Moisture factor can provide.Hyaluronic acid is except making skin keep moisture, can also making eyes keep lubricated, joint maintenance elasticity.Therefore, hyaluronic acid has very good use record in fields such as ophthalmologic operation, arthritis treatment and Cosmetics Surgerys.Physics and the biological natures such as but pure HA is soluble in water, absorb rapidly and the residence time is short in tissue limit it as the use of functional component carrier, need to use chemically crosslinked to modify, and to increase its molecular weight, to prolong degradation time, improve stability.
But hyaluronicly simple crosslinkedly can not alleviate it and degrade fast.Still need repeatedly filling to reach repairing effect, therefore the patient is caused certain economical load.With regard to the material that makes up dermal filler and tissue repair, the thermodynamic (al) reversibility of material is most important.Though hyaluronic acid is to promote the biomaterial of tissue growth still not possess thermodynamic (al) reversibility.A kind of capable of injecting temperature sensitive gel of the present invention's preparation, this gelling system has the synergy of Hyaluronic Acid and chitosan, has not only prolonged the time that the injection site is repaired, and has been easier to injection, and had antibiotic, anticoagulation, the character such as the interior good moldability of organism.
Summary of the invention
The invention provides a kind of preparation method of thermo-sensitive gel.Notable feature of the present invention is: chitosan is introduced temperature sensitive functional group through processing and chemical reaction, the preparation thermo-sensitive gel.Hyaluronic acid is directly processed with sodium periodate without crosslinked, obtains active aldehyde radical, reacts by the amino group on chemical reaction and the chitosan, obtains having the plural gel of temperature sensitive performance.In this manufacture method, plural gel does not need crosslinking polymerization, has simplified production stage, has saved production cost.Temperature-sensitive makes its at normal temperatures good fluidity simultaneously, is easy to injection; Good moldability in the organism, degraded are slowly.
For achieving the above object, technical scheme of the present invention is as follows:
The purpose of this invention is to provide a kind of preparation method who prepares temperature sensitive plural gel by chemical reaction.
The contriver prepares temperature sensitive chitosan and the hyaluronic preparation of active aldehyde radical by sec.-propyl propionic acid amide in the grafting, has the gel of temperature-sensitive by chemical reaction preparation, thereby has easy injection and lasting character.
Easily the preparation method of injection thermo-sensitive gel may further comprise the steps:
(1) active aldehyde radical hyaluronic acid preparation
With raw material hyaluronic acid (HA) and deionized water wiring solution-forming.Add the sodium periodate aqueous solution, stirring reaction under lucifuge, room temperature condition.Add ethylene glycol solution and stop unreacted sodium periodate.
Above-mentioned raw materials hyaluronic acid (HA) and deionized water are made into concentration for being 0.01～20g/100ml;
Above-mentioned sodium periodate concentration of aqueous solution is 0.1～10M, and volume is 1～100ml
(2) gel that step (1) made is removed unreacted monomer and other impurity with soaked in absolute ethyl alcohol, washing, extracting, solution dialysis purifying then, and lyophilize obtains pure jel product.
(3) temperature sensitive chitosan preparation
An amount of chitosan is dissolved in 1～98% the acetic acid solution, slowly adds a certain amount of N-sec.-propyl propionic acid amide (NIPAAm) and initiator, after the stirring at room dissolving, pass at a certain temperature stirring reaction of nitrogen.With above-mentioned reactant acetone precipitation, filter.Vacuum-drying makes the jel product with temperature-sensitive;
Above-mentioned additive N-sec.-propyl propionic acid amide (NIPAAm) is 1: 90～90: 1 with chitosan in mass ratio.
Above-mentioned initiator: comprise a kind of of Potassium Persulphate (KPS), Diisopropyl azodicarboxylate, peroxidation two acyls, benzoyl peroxide or di-t-butyl peroxide.
The mass ratio of above-mentioned initiator and chitosan is 0.02%～10%.
(4) preparation of plural gel
Under the room temperature, two kinds of gels in step (2) and (3) are made into the homogeneous aqueous solution by the certain mass ratio, stirring reaction prepares plural gel under the room temperature.Then this gelating soln dialysis purifying, lyophilize obtains pure jel product.Above-mentioned two kinds of gels are used the abundant swelling of damping fluid PBS under room temperature, be made into injection liquid, and by needle tubing, promote homogenize with constant speed, obtain injectable hydrogel.
The proportioning of hyaluronic acid and chitosan is 1: 9～9: 1 in the above-mentioned plural gel
The concentration of above-mentioned plural gel and damping fluid PBS is 0.01～30mg/ml
(5) each factor in the above-mentioned copolymerization process (such as different monomers, initiator, temperature, reaction times etc.) is affected rule research to product property, adopt orthogonal experiment, each factor is estimated, understanding in depth on the basis that affects rule, building-up process is carried out computer simulation.
Beneficial effect:
1. to prepare easy injection thermo-sensitive gel be preparation and the hyaluronic preparation of active aldehyde radical by temperature sensitive chitosan in the present invention, by under the chemical reaction effect chitosan and hyaluronic acid being combined, make the gel with temperature-sensitive, the gel that makes is the liquid of normal temperature current downflow, is gel state in vivo under the temperature.Having swelling property, Thermo-sensitive, easy characteristics such as promotion, antibiotic, persistence, good biocompatibility, is a kind of desirable filling and the material of reparation.The thermo-responsive hydro gel of the present invention's preparation has reduced the infringement of linking agent to human body and injection site.This gelling system can not only prolong its retention time in vivo, and can constantly stimulate the body generation to reply, and namely promotes the in-situ regeneration reparation of tissue, to improve filling quality.Simultaneously because the adding of chitosan has reduced the advantages such as the intrusion of bacterium and anaphylaxis be low.Restoration, healing equipment, prosthese, implants in vivo, drug delivery system and the aspects such as medical treatment and beauty treatment that can be widely used in various damaged organs.
Plural gel have high purity, toxicological harmless, nonirritant, chemical stability good, degrade, do not cause inflammation, without anaphylaxis, good biocompatibility, not carcinogenic, heavy metal content is low, pH value is little, does not cause the performances such as haemolysis and blood coagulation.Plural gel also should have required Physical and mechanical properties and processing characteristics, also can stand high-temperature disinfection treatment.
3. the synergy of plural gel has some strength and flexural stiffness, can resist tissue repairing's ability that the damaged body of human body is pressed.In addition, the gel that simple cross-linked-hyaluronic acid obtains, because its transformation period is short, fast degradation.Therefore need multiple injection, need larger Financial cost.But plural gel is because the germ resistance of chitosan, the healing at the position that is conducive to be wound and be difficult for causing the infection at position of being wound.Owing to having temperature-sensitive, it has preferably syringeability and biocompatibility simultaneously.And its long transformation period makes it have permanence, does not need multiple injection, and the economic pressures and the multiple injection that reduce the patient are painful.Because plural gel is degradable, and when the injection site deformed or be undesirable, available lytic enzyme dissolved, do not need underwent operative to remove in addition, reduce patient's misery.
Description of drawings
Fig. 1 is the injectable thermo-sensitive gel reaction synoptic diagram that the embodiment of the invention 2 is prepared.
Fig. 2 is the infrared spectrogram of the injectable thermo-sensitive gel prepared of the embodiment of the invention 2.
Fig. 3 is the Phase Transition Analysis figure of the injectable thermo-sensitive gel prepared of the embodiment of the invention 2.
Fig. 4 is the Swelling Dynamics curve of the injectable thermo-sensitive gel prepared of the embodiment of the invention 2.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used for explanation the present invention and be not used in and limit the scope of the invention.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after the content of having read the present invention's instruction, these equivalent form of values fall within the application's appended claims limited range equally.
(1) the hyaluronic preparation of active aldehyde radical:
Raw material hyaluronic acid and deionized water are mixed by proportioning 0.01g/100ml, add 0.1M, the sodium periodate aqueous solution of 100mL at room temperature adds ethylene glycol solution behind the lucifuge stirring reaction, and stirring reaction makes the aldehyde radical hyaluronic acid at normal temperatures;
(2) with the gel that makes with soaked in absolute ethyl alcohol, washing, extracting, remove unreacted monomer and other impurity, solution dialysis purifying then, lyophilize obtains pure jel product;
(3) temperature sensitive chitosan preparation:
The CS of 0.2g is dissolved in 1% the acetic acid solution, slowly adds 0.2g N-sec.-propyl propionic acid amide (NIPAAm) and 4mg Potassium Persulphate (KPS), after the stirring at room dissolving, pass into the nitrogen gas stirring reaction.With above-mentioned reactant acetone precipitation, filter.Vacuum-drying makes the jel product with temperature-sensitive;
(4) preparation of plural gel:
(4.1) under the room temperature, the temperature sensitive chitosan gel rubber that the hyaluronic acid derivatives that step (2) is obtained and step (3) obtain, with above-mentioned two kinds of gel hyaluronic acids and chitosan 1/9 aqueous solution that is made into 20mg/mL in mass ratio, stirring reaction under the room temperature, preparation plural gel;
(4.2) with the gelating soln dialysis purifying of above-mentioned steps (4.1), lyophilize obtains pure jel product.Above-mentioned two kinds of gels are mixed with the abundant swelling of solution that concentration is 1mg/ml with damping fluid PBS under room temperature, and the needle tubing by 2.5ml, homogenize 3 times promoted with constant speed.Obtain injectable hydrogel.
Embodiment 2
(1) the hyaluronic preparation of active aldehyde radical:
Raw material hyaluronic acid and deionized water are mixed by proportioning 1g/100ml, add 0.5M, the sodium periodate aqueous solution of 5mL, at room temperature the lucifuge stirring reaction adds ethylene glycol solution, at normal temperatures stirring reaction after reaction finishes.Make hyaluronic acid derivatives;
(2) with the gel that makes with soaked in absolute ethyl alcohol, washing, extracting, remove unreacted monomer and other impurity, solution dialysis purifying then, lyophilize obtains pure jel product;
(3) temperature sensitive chitosan preparation:
The chitosan of 0.2g is dissolved in 5% the acetic acid solution, slowly adds 2g N-sec.-propyl propionic acid amide (NIPAAm) and 4mg Diisopropyl azodicarboxylate, after the stirring at room dissolving, pass into the nitrogen gas stirring reaction.With above-mentioned reactant acetone precipitation, filter.Vacuum-drying makes the jel product with temperature-sensitive;
(4) preparation of plural gel:
(4.1) under the room temperature, the temperature sensitive chitosan gel rubber that the hyaluronic acid that step (2) is obtained and step (3) obtain, with above-mentioned two kinds of gel hyaluronic acids and chitosan 1/9 aqueous solution that is made into 20mg/ml in mass ratio, reaction preparation plural gel under the room temperature;
(4.2) with the gelating soln dialysis purifying of above-mentioned steps (4.1), lyophilize obtains pure jel product.Above-mentioned two kinds of gels are mixed with the abundant swelling of solution that concentration is 20mg/ml with damping fluid PBS under room temperature, and the needle tubing by 2.5ml, homogenize 3 times promoted with constant speed.Obtain injectable hydrogel.
Embodiment 3
(1) the hyaluronic preparation of active aldehyde radical:
Raw material hyaluronic acid and deionized water are mixed by proportioning 20g/100ml, add 10M, the sodium periodate aqueous solution of 100ml, at room temperature the lucifuge stirring reaction adds ethylene glycol solution, at normal temperatures stirring reaction after reaction finishes.Make hyaluronic acid derivatives;
(2) with the gel that makes with soaked in absolute ethyl alcohol, washing, extracting, remove unreacted monomer and other impurity, solution dialysis purifying then, lyophilize obtains pure jel product;
(3) temperature sensitive chitosan preparation:
The CS of 0.2g is dissolved in 98% acetic acid solution, slowly adds 18g N-sec.-propyl propionic acid amide (NIPAAm) and 1mg Potassium Persulphate (KPS), after the stirring at room dissolving, pass into the nitrogen gas stirring reaction.With above-mentioned reactant acetone precipitation, filter.Vacuum-drying makes the jel product with temperature-sensitive;
(4) preparation of plural gel:
(4.1) under the room temperature, the temperature sensitive chitosan gel rubber that the hyaluronic acid that step (2) is obtained and step (3) obtain, with above-mentioned two kinds of gel hyaluronic acids and chitosan 5/5 aqueous solution that is made into 20mg/ml in mass ratio, stirring reaction under the room temperature, preparation plural gel;
(4.2) with the gelating soln dialysis purifying of above-mentioned steps (4.1), lyophilize obtains pure jel product.Above-mentioned two kinds of gels are mixed with the abundant swelling of solution that concentration is 50mg/ml with damping fluid PBS under room temperature, and the needle tubing by 2.5ml, homogenize 3 times promoted with constant speed.Obtain injectable hydrogel.
Embodiment 4
(1) the hyaluronic preparation of active aldehyde radical:
Raw material hyaluronic acid and deionized water are mixed by proportioning at 10: 100, add 0.5M, the sodium periodate aqueous solution of 50ml, at room temperature the lucifuge stirring reaction adds ethylene glycol solution, at normal temperatures stirring reaction after reaction finishes.Make hyaluronic acid derivatives;
(2) with the gel that makes with soaked in absolute ethyl alcohol, washing, extracting, remove unreacted monomer and other impurity, solution dialysis purifying then, lyophilize obtains pure jel product;
(3) temperature sensitive chitosan preparation:
The CS of 0.2g is dissolved in 20% the acetic acid solution, slowly adds 2g N-sec.-propyl propionic acid amide (NIPAAm) and 2g benzoyl peroxide, after the stirring at room dissolving, pass into the nitrogen gas stirring reaction.With above-mentioned reactant acetone precipitation, filter.Vacuum-drying makes the jel product with temperature-sensitive;
(4) preparation of plural gel:
(4.1) under the room temperature, the temperature sensitive chitosan gel rubber that the hyaluronic acid that step (2) is obtained and step (3) obtain, with above-mentioned two kinds of gel hyaluronic acids and chitosan 5/5 aqueous solution that is made into 1mg/ml in mass ratio, stirring reaction under the room temperature, preparation plural gel;
(4.2) with the gelating soln dialysis purifying of above-mentioned steps (4.1), lyophilize obtains pure jel product.Above-mentioned two kinds of gels are mixed with the abundant swelling of solution that concentration is 0.01mg/ml with damping fluid PBS under room temperature, and the needle tubing by 2.5ml, homogenize 3 times promoted with constant speed.Obtain injectable hydrogel.
Embodiment 5
(1) the hyaluronic preparation of active aldehyde radical:
Raw material hyaluronic acid and deionized water are mixed by proportioning 1: 100mg/ml, add 0.5M, the sodium periodate aqueous solution of 5mL, at room temperature the lucifuge stirring reaction adds ethylene glycol solution, at normal temperatures stirring reaction after reaction finishes.Make hyaluronic acid derivatives;
(2) with the gel that makes with soaked in absolute ethyl alcohol, washing, extracting, remove unreacted monomer and other impurity, solution dialysis purifying then, lyophilize obtains pure jel product;
(3) temperature sensitive chitosan preparation:
The CS of 0.2g is dissolved in 50% the acetic acid solution, slowly adds 2g N-sec.-propyl propionic acid amide (NIPAAm) and 4mg Potassium Persulphate (KPS), after the stirring at room dissolving, pass into the nitrogen gas stirring reaction.With above-mentioned reactant acetone precipitation, filter.Vacuum-drying makes the jel product with temperature-sensitive;
(4) preparation of plural gel:
(4.1) under the room temperature, the temperature sensitive chitosan gel rubber that the hyaluronic acid that step (2) is obtained and step (3) obtain, with above-mentioned two kinds of gel hyaluronic acids and chitosan 5/5 aqueous solution that is made into 20mg/ml in mass ratio, stirring reaction under the room temperature, preparation plural gel;
(4.2) with the gelating soln dialysis purifying of above-mentioned steps (4.1), lyophilize obtains pure jel product.Above-mentioned two kinds of gels are mixed with the abundant swelling of solution that concentration is 50mg/ml with damping fluid PBS under room temperature, and the needle tubing by 2.5ml, homogenize 3 times promoted with constant speed.Obtain injectable hydrogel.
Claims (6)
1. preparation method who be used for to fill with the injectable thermo-sensitive gel of repairing damaged tissue is characterized in that the method may further comprise the steps:
(1) active aldehyde radical hyaluronic acid preparation: raw material hyaluronic acid (HA) and deionized water are made into 0.01～50 by quality and volume ratio: the solution of 100mg/ml, add the sodium periodate aqueous solution, stirring reaction under lucifuge, room temperature condition adds ethylene glycol solution and stops unreacted sodium periodate;
(2) gel that step (1) made is removed unreacted monomer and other impurity with soaked in absolute ethyl alcohol, washing, extracting, solution dialysis purifying then, and lyophilize obtains pure jel product;
(3) temperature sensitive chitosan preparation: an amount of chitosan is dissolved in 1～98% the acetic acid solution, by with the chitosan mass ratio be 1: 90～90: 1 slowly interpolation NIPAs (NIPAAm); And be 0.02%～10% to add initiator by the mass ratio with chitosan, after the stirring at room dissolving, pass into nitrogen stirring reaction under 20～60 ℃ of temperature, with above-mentioned reactant acetone precipitation, filter, vacuum-drying makes the jel product with temperature-sensitive;
(4) preparation of plural gel: under the room temperature, stirring reaction under 1: 9 in mass ratio～9: 1 room temperatures of hyaluronic acid derivatives in step (2) and (3) and temperature sensitive chitosan gel rubber is prepared plural gel, then this gelating soln dialysis purifying, lyophilize obtains pure jel product, plural gel is used the abundant swelling of damping fluid PBS under room temperature, be made into injection liquid, and pass through needle tubing, promote homogenize with constant speed, obtain injectable hydrogel.
2. method according to claim 1 is characterized in that, the hyaluronic acid raw material of employing is for extracting from microbe or obtaining by fermentation.
3. method according to claim 1 is characterized in that, the sodium periodate concentration of aqueous solution is 0.1～10M, and volume is 1～100ml.
4. method according to claim 1 is characterized in that, chitosan comes from de-acetyl chitin, and deacetylation is 15～95%.
5. method according to claim 1 is characterized in that, initiator is a kind of of Potassium Persulphate (KPS), Diisopropyl azodicarboxylate, peroxidation two acyls, benzoyl peroxide or di-t-butyl peroxide.
6. method according to claim 1 is characterized in that, the concentration of plural gel and damping fluid is 0.01～30mg/ml.
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