CN103432632A - Temperature-sensitive gel composition and preparation method thereof - Google Patents
Temperature-sensitive gel composition and preparation method thereof Download PDFInfo
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- CN103432632A CN103432632A CN2013104197847A CN201310419784A CN103432632A CN 103432632 A CN103432632 A CN 103432632A CN 2013104197847 A CN2013104197847 A CN 2013104197847A CN 201310419784 A CN201310419784 A CN 201310419784A CN 103432632 A CN103432632 A CN 103432632A
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- Medicinal Preparation (AREA)
- Materials For Medical Uses (AREA)
Abstract
The invention relates to a temperature-sensitive gel composition containing poloxamer 407, acidic amino acid, polyethylene glycol and water and a preparation method thereof. In a surgical operation, the temperature-sensitive gel composition is injected into a blood vessel to form a gel suppository so as to realize a hemostatic effect.
Description
Technical field
The invention belongs to field of medical technology, relate to a kind of intravenous thermosensitive in situ gel, there is not damaged, advantage simply and fast.
Background technology
Nearly all surgical operation all can't be avoided intraoperative hemorrhage, and along with the appearance of scientific and technological development and some novel hemostatic materials and equipment, in surgical operation, hemostatic technique has also produced revolutionary development.Hemostasis is one of core of essential surgical skills technology, the surgical procedures at any position of human body almost relates to hemorrhage and hemostasis bar none, hemostatic technique has been developed into the technical system of the numerous and complicated under the modern surgery condition by simple apparatus hemostasis measure of past, mainly comprise that Interventional hemostasis measure, physics and chemistry hemostasis measure and hemostatic for external use fibres albumen viscose glue are several.
The Interventional hemostatic treatment refers in conduit, entry needle, air bag or other related equipments importing internal organs that will treat use under endoscope, ultrasonic, CT or x-ray monitor, and give localized pulverization or inject the plug treatments such as haemostatic medicament, biogum, chemical glue, or import the chemical factors such as high frequency electric, laser, microwave, reach the purpose for the treatment of hemorrhagic focus.
Physics and chemistry hemostasis physics and chemistry Hemostasis is long-standing, and along with the progress of modern science and technology, more more superior hemostatic techniques arise at the historic moment, as methods such as high-frequency electrocoagulation hemostasis, laser hemostasis, microwave bleeding and thermal hemostasis.
Hemostatic for external use fibres albumen viscose glue technical system comprises the application of some microfilament fiber collagen hemorrhages, oxidized cellulose and oxidized regenerated cellulose.
For the process of surgical hemostasis, a kind of not damaged, simply and fast Hemostasis is maximum advantage.F127 with temperature-sensing property has these potential qualities.Raymond etc. utilize the Thermo-sensitive of F127 to be applied to temporary tremulous pulse plug plug in bypass operation of coronary artery first.The up-to-date a kind of product gone out of match Norfin, Inc
it is a kind of good solution, it is that poloxamer188 thermosensitive hydrogel hemostatic technique is applied to commercially produced product, utilized poloxamer188, at room temperature and low temperature state, be liquid, being injected into after human vas temperature goes up and rises to 37 ℃ of left and right, will form a gel plug, thereby stop blood flow.That this method has is painless, control fast, at any time and the advantage such as nontoxic, and the market application is very wide.
clinical verification is under the prerequisite of injured blood vessel not, makes the blood flow volume that flows to operative region be down to minimum effect.Some hemostasis instruments commonly used (as mosquito forceps or elastic tape) can not guarantee the operative region depletion of blood and may destroy blood vessel.
to the temperature altitude sensitivity, when room temperature, be liquid, and it is solid-state to become gel when high temperature.After being injected into blood vessel,
form and take the gel embolism that shape of blood vessel is mould, can stop blooding and reach 15 minutes.After vascular suture, blood vessel embolism can be in 15 minutes automatic dissolving.If need make thromboembolism dissolve fast, only need be on blood vessel cold compress or inject cold normal saline, thromboembolism will soon disappear, the blood flow immediate recovery of operative site is normal.
The patent 00107386.9 of China provides a kind of vascular occlusive agent and process of preparing thereof.It is to adopt poloxamer188 and a certain amount of medicine, normal saline.The suppository of preparation.Have stability better, can high-temperature sterilization, plug plug effect is better, can carry cancer therapy drug and other medicines, can be widely used in the plug plug chemotherapy of tumor; Alimentary canal inflammation, ulcer etc. are hemorrhage.
Summary of the invention
The invention provides compositions and the preparation method of the thermosensitive in situ gel that a kind of clotting time is more durable, particularly, to adopt Polyethylene Glycol, poloxamer188 and a kind of acidic amino acid to form, the phase transition temperature that this gel adopts Polyethylene Glycol to regulate thermosensitive hydrogel, after this liquid gel intravasation, promptly form a thromboembolism, stop flowing of blood; Added acidic amino acid to change the electric charge of poloxamer188, made the gel plug holdup time in vivo of formation longer, more than having reached 30min, after operation finishes, only needed the suitable cooling blood vessel embolism of the mode district of employing, it is normal that blood flow will recover very soon.
Thermosensitive hydrogel of the present invention is to adopt Polyethylene Glycol, poloxamer188, water and acidic amino acid to form, specifically this gel adopts the phase transition temperature that Polyethylene Glycol has been regulated thermosensitive hydrogel, by amino acid change the electric charge of gel, make it to be easier to form gel plug holdup time in vivo longer, thereby extended the time of the blood flow retardance of blood vessel, for the better time of being provided smoothly of operation ensures, after operation is accepted, overlay on area vasculosa with ice or cold object, blood flow will recover at once.
Thisly to heat sensitive and there is the liquid gel that biocompatibility is nontoxic, when it is injected in blood vessel, a gel plug can be formed, blood flow can be temporarily stoped.This gel plug is by cooling or or can dissolve rapidly after dozens of minutes under autonomous state.Once, after dissolving, because the concentration of poloxamer is too low, gel plug just can not be recovered.
Poloxamer is that a kind of nontoxic, non-irritating adjuvant is widely used, because the commercial adjuvant of the difference of molecular weight has Pluronic/Lutrol F 44, PLURONICS F87, poloxamer 237, poloxamer 388 and poloxamer188.Poloxamer188 (Poloxamer407, P407) be the block copolymer of polyoxyethylene and polyoxypropylene, by approximately 70% ethylene oxide and 30% propylene oxide form, molecular weight is 9840～14600, and poloxamer188 has the solidifying character of special reverse hot glue, is liquid during low temperature, become gel under body temperature, advantages such as its toxicity is low, and zest is little, good biocompatibility and receiving much concern.
In the present invention, poloxamer is as the material of thermosensitive hydrogel, and its consumption is 10～35%, and the consumption of further optimizing is between 15～35%.
The adjusting of the phase transition temperature of thermosensitive hydrogel is to control key of the present invention, in the present invention, except the concentration of controlling poloxamer188, adopted in addition the combination of Polyethylene Glycol and acidic amino acid regulate gel electrically and phase transition temperature.
Polyethylene Glycol is macromolecular material, by intermolecular hydrogen bond and poloxamer188 combination, can obviously improve phase transition temperature, makes poloxamer can compare independent use when relative low concentration, has improved phase transition temperature.
The Polyethylene Glycol of selecting in the present invention is lower molecular weight, and the Polyethylene Glycol adopted through screening is Macrogol 600, and it is the most suitable that Polyethylene Glycol 800 and cetomacrogol 1000 are regulated the poloxamer188 Phase-change Problems.
Adding of Polyethylene Glycol successively do not require.For better and poloxamer188 mix, mode is first to add aminoacid or Polyethylene Glycol in water preferably, stirring and dissolving, and then add the poloxamer188 stirring and dissolving.
The control of temperature has crucial effect for preparation process, because temperature raises, the meeting that poloxamer188 dissolves in water is slack-off, and viscosity increases simultaneously, in solution, can produce a large amount of foams, is unfavorable for the preparation of gel.Of the present invention be that process for preparation is controlled at the temperature of solution below 10 ℃, whole like this process is solution state, can make so the abundant mix homogeneously of aminoacid, Polyethylene Glycol and poloxamer188, is conducive to the performance of gelation.The present invention is controlled at the temperature of equipment below 10 ℃ at preparation, stirring, filtration and pouring process, and ambient temperature is controlled at 20 ℃ of left and right.
Macrogol 600, Polyethylene Glycol 800 and cetomacrogol 1000 can be a kind of Polyethylene Glycol, it can be also its combination of any two or three, according to the molecular weight difference, consumption can play the phase transition temperature of better adjusting thermosensitive hydrogel in 2～20% (weight ratios), by test, according to the difference of molecular weight polyethylene glycol and the temperature of required adjusting, the amount that Polyethylene Glycol is further optimized is 3～8% (weight ratios).
Acidic amino acid is containing usually containing 1 amino and 2 carboxyls, isoelectric point, IP is between 2.8～3.2, especially aspartic acid (Asp) and glutamic acid (Glu), this two seed amino acid joins in aqueous solution, with positive charge, utilize in the present invention it to change the electrical of thermosensitive hydrogel, make gel systems after forming gel plug, can in the blood vessel standard, maintain the longer time.Certainly, after blood vessel local cooling, the gel plug of formation becomes fast the liquid gel plug and disappears, and also immediate recovery is mobile normally for blood simultaneously.The aminoacid that the present invention adds can be the combination of any proportioning of any one or two kinds of aspartic acid and glutamic acid.
The consumption of aspartic acid has the longer persistent period at 1～20% (weight ratio) thermosensitive hydrogel in the formation gel plug later, and preferably the amount of aspartic acid is between 2～7%.
The amount of glutamic acid is in the persistent period preferably that has of 1～15% (weight ratio), and thermosensitive hydrogel has the longer persistent period in the formation gel plug later, and preferably the amount of glutamic acid is 1～5%.
Two kinds of two kinds of acidic amino acid glutamic acid and aspartic acids also arbitrarily proportioning be used in combination.Preferred consumption is 1-12% (weight ratio).
The optimum pH of thermosensitive hydrogel of the present invention is 3～5, can adopt the aqueous solution of two kinds of acidic amino acids that the present invention relates to or sodium hydroxide solution adjustment to reach the acidity needed, and further preferred pH is 3.5～4.5.
Thermosensitive hydrogel of the present invention is liquid when low temperature, during use, need quiet notes to bring into play the block blood flow effect in blood vessel, so need to carry out aseptic and apyrogeneity processing to it, the method of sterilizing has adopted conventional autoclaving, adopt temperature and condition to be: 121 ℃ keep 15min or 115 ℃ to keep 30 minutes, such condition can be removed the antibacterial in thermosensitive hydrogel, makes it to be suitable for intravenous injection.Also can adopt the method for ray sterilizing to remove the antibacterial in thermosensitive hydrogel.
For the pyrogen of introducing in aminoacid, Polyethylene Glycol, poloxamer188, water and environment in thermosensitive hydrogel, the present invention adopts the method for activated carbon adsorption to remove, specifically a certain amount of active carbon is joined in the thermosensitive hydrogel prepared, mechanical agitation 15-30min, after filtration, thermosensitive hydrogel is packed into after ampulla sealing or injector package and carried out sterilizing.
In thermosensitive hydrogel, the removal of pyrogen also can adopt the methods such as high-temperature heating, ultrafiltration, and these methods are the pharmacy worker and know.
Must hide in chamber and be cooled in advance below 10 ℃ in refrigerator and cooled when thermosensitive hydrogel prepared by the present invention is used, such temperature can guarantee that the state of thermosensitive hydrogel is liquid, thereby be injected into formation gel plug in body, reaches anastalsis.
The present invention can make restoration of blood flow with the position of ice-cold deposited injection thermosensitive hydrogel after preparing the thermosensitive hydrogel application after operation completes, and also can inject cold normal saline at injection thermosensitive hydrogel position simultaneously and make the fast quick-recovery of blood flow.
The specific embodiment
Embodiment 1
Preparation method,
1. the poloxamer188 of recipe quantity is dissolved in water, adds recipe quantity glutamic acid and Macrogol 600, stirring and dissolving, make thermosensitive hydrogel liquid. control 5 ℃ of temperature.
2. employing glutamic acid aqueous solution or sodium hydroxide solution add the pH regulator of thermosensitive hydrogel liquid 0.1% active carbon to 4.0., stir 15min, control 8 ℃ of temperature.
3. filter, active carbon is removed, control 5 ℃ of temperature.
4. will be filled in ampulla or the pre-syringe of loading, content 2-10ml, the temperature of controlling filling machine fluid reservoir, system and environment is 10 ℃.
5. ampulla is sealed.
6.121 ℃ sterilizing 15 minutes.
Embodiment 2
Preparation method,
1. the poloxamer188 of recipe quantity is dissolved in water, adds recipe quantity aspartic acid and Macrogol 600, stirring and dissolving, make thermosensitive hydrogel liquid. control 5 ℃ of temperature.
2. employing aspartic acid aqueous solution or sodium hydroxide solution add the pH regulator of thermosensitive hydrogel liquid 0.1% active carbon to 4.0., stir 15min, control 8 ℃ of temperature.
3. filter, active carbon is removed, control 5 ℃ of temperature.
4. will be filled in the syringe of pre-filling, content 2-10ml, the temperature of controlling filling machine fluid reservoir, system and environment is 10 ℃.
5.121 ℃ sterilizing 15 minutes.
Embodiment 3
1. the poloxamer188 of recipe quantity is dissolved in water, adds recipe quantity glutamic acid, aspartic acid and Polyethylene Glycol 800, stirring and dissolving, make thermosensitive hydrogel liquid. control 5 ℃ of temperature.
2. employing aspartic acid aqueous solution or sodium hydroxide solution add the pH regulator of thermosensitive hydrogel liquid 0.1% active carbon to 4.0., stir 15min, control 8 ℃ of temperature.
3. filter, active carbon is removed, control 5 ℃ of temperature.
4. will be filled in ampulla, content 5-20ml, the temperature of controlling filling machine fluid reservoir, system and environment is 10 ℃.
5. ampulla is sealed.
6.121 ℃ sterilizing 15 minutes.
Embodiment 5
Preparation method,
1. the poloxamer of recipe quantity is dissolved in water, adds recipe quantity aspartic acid and cetomacrogol 1000, stirring and dissolving, make thermosensitive hydrogel liquid. control 5 ℃ of temperature.
2. employing aspartic acid aqueous solution or sodium hydroxide solution add the pH regulator of thermosensitive hydrogel liquid 0.1% active carbon to 4.0., stir 15min, control 8 ℃ of temperature.
3. filter, active carbon is removed, control 5 ℃ of temperature.
4. in fill ampulla, content 2-10ml, the temperature of controlling filling machine fluid reservoir, system and environment is 10 ℃.
5. ampulla is sealed.
6.121 ℃ sterilizing 15 minutes.
Embodiment 6
Preparation method:
1. the poloxamer188 of recipe quantity is dissolved in water, adds recipe quantity glutamic acid and Macrogol 600, stirring and dissolving, make thermosensitive hydrogel liquid. control 5 ℃ of temperature.
2. employing glutamic acid aqueous solution or sodium hydroxide solution add the pH regulator of thermosensitive hydrogel liquid 0.1% active carbon to 4.0., stir 15min, control 8 ℃ of temperature.
4. will be filled in ampulla or the pre-syringe of loading, content 2-10ml, the temperature of controlling filling machine fluid reservoir, system and environment is 8 ℃.
5. ampulla is sealed.
6.300 ℃ heating 120 minutes.
Test implementation example 1
The mensuration of the phase transition temperature of gel
Viscosimetry is measured, and sample is placed in to water-bath, and the rotating cylinder of viscosity apparatus is placed in to sample, temperature is made as to 10,15,20,25,30,35,40,45 ℃ respectively, every temperature keeps starting to measure viscosity after 5min, matched curve, the phase transition temperature of investigation different formulations.
Table 1. is commercially available to be contrasted with the embodiment phase transition temperature
| ? | The listing formula | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 |
| Phase transition temperature (℃) | 31.5 | 29.3 | 28.9 | 27.8 | 26.8 | 25.9 |
Adopt embodiment 1, embodiment 2, embodiment 3, embodiment 4, embodiment 5, contrast is according to external listing product.Measure the phase transition temperature of thermosensitive hydrogel.Result can find out that the phase transition temperature of the embodiment of the present invention is all lower than Comparative Examples, illustrates that being easier to the present invention respectively forms gel plug in vivo and be beneficial to hemostasis.
Adopt the gel of preparation in embodiment 4, prepare 6 batches, by upper method, investigate phase transition temperature, the visible phase transition temperature difference of result is very little, within the acceptable range.
The differences between batches of table 2. embodiment 4 phase transition temperatures
| Test number (TN) | 1 | 2 | 3 | 4 | 5 | 6 |
| Phase transition temperature (℃) | 28.1 | 27.4 | 28.9 | 27.8 | 27.3 | 26.8 |
Test implementation example 2
To the femoral artery of new zealand white rabbit, first with the vascular clamp folder, close about 1cm long femoral artery or ventral aorta, then with microsyringe, a certain amount of gel is injected in this section arterial lumen; The other end loses blood flow immediately, writing time, the time of observing restoration of blood flow.
The contrast of table 3. thermosensitive hydrogel bleeding stopping period
| ? | The listing formula | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 |
| Clotting time (min) | 19.5 | 39 | 45.5 | 40.5 | 48.0 | 47.5 |
With external listing kind, compare, the clotting time of the embodiment of the present invention 1, embodiment 2, embodiment 3, embodiment 4 and embodiment 5 is all apparently higher than commercially available prod.Bleeding stopping period of the present invention is more than 2 times of commercially available prod, can be so more enforcement time of winning of smooth operation.
Claims (8)
1. a thermosensitive in situ gel compositions, contain poloxamer188, acidic amino acid and low-molecular-weight Polyethylene Glycol and water.
2. thermosensitive in situ gel claimed in claim 1, wherein adopt poloxamer188 as temperature-sensitive material, and preferred consumption is 15%～35% (weight ratio).
3. the described thermosensitive in situ gel of claim 2, contain glutamic acid, and its preferred consumption is 2～7% (weight ratios).
4. the described thermosensitive in situ gel of claim 2, contain aspartic acid, and its preferred consumption is 1～5% (weight ratio).
5. the described thermosensitive in situ gel of claim 2, the combination that contains two kinds of acidic amino acid glutamic acid and aspartic acids.Preferred consumption is 1～12% (weight ratio).
6. claim 3,4,5 described thermosensitive in situ gel, also contain Macrogol 600, the combination of Polyethylene Glycol 800 and cetomacrogol 1000 or its arbitrary proportion, and consumption is 3%～8% (weight ratio).
7. thermosensitive in situ gel claimed in claim 6, its pH is 3～4.5, advancing the preferred pH of (weight ratio) step is 3.5～4.5.
8. thermosensitive in situ gel claimed in claim 7, reach for the vein blood vessel injection purpose that occluding vascular stops blooding, and surgical operation is carried out smoothly.
Priority Applications (1)
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| CN104353108A (en) * | 2014-09-29 | 2015-02-18 | 南京康玻斯医药科技有限公司 | Injection applied to blood vessel anastomosis and endovascular occlusion |
| CN106581737A (en) * | 2017-01-06 | 2017-04-26 | 哈尔滨鼓润生物技术有限公司 | Hemostasis composition and preparing method thereof |
| CN107496442A (en) * | 2017-08-25 | 2017-12-22 | 南京斯泰尔医药科技有限公司 | A kind of chlorine dioxide responsive to temperature type spray gel and preparation method thereof |
| CN109432511A (en) * | 2018-12-29 | 2019-03-08 | 常州乐奥医疗科技股份有限公司 | A kind of temperature-sensitive hydrogel and its preparation method and application |
| CN109953940A (en) * | 2017-12-25 | 2019-07-02 | 成都昕才医药科技有限公司 | A kind of temperature-sensitive hydrogel precursor |
| CN110420175A (en) * | 2019-08-21 | 2019-11-08 | 赣南师范大学 | A kind of injection-type amino acid derivativges small molecule gel rubber material and its application |
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| CN109953940A (en) * | 2017-12-25 | 2019-07-02 | 成都昕才医药科技有限公司 | A kind of temperature-sensitive hydrogel precursor |
| CN109432511A (en) * | 2018-12-29 | 2019-03-08 | 常州乐奥医疗科技股份有限公司 | A kind of temperature-sensitive hydrogel and its preparation method and application |
| CN110420175A (en) * | 2019-08-21 | 2019-11-08 | 赣南师范大学 | A kind of injection-type amino acid derivativges small molecule gel rubber material and its application |
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