A kind of biochargeable paperTechnical field
The present invention relates to a kind of biochargeable paper, particularly a kind of new medical absorbable biological paper, belongs to medical instruments field.
Background technology
In clinical operation to local hemostasis and the larger demand of post-operation adhesion preventing.The wound that the conventional hemostatic device such as oozing of blood cannot be processed, local hemostatic just becomes and is necessary very much.Post-operation adhesion preventing is significant: the post-operation adhesion of gynemetrics can cause infertility, abdominal tissue adhesion may cause the severe complications such as intestinal obstruction, the local adhesion of tendon-bone surgery can cause dyskinesia, and the adhesion of ambition portion can cause pectoralgia and the complication etc. such as pericardium is narrow.
At present, Biodegradable material is more and more in the clinical use of hemostasis, prevent adhesion.Common product has fibrin class, gelfoam class, collagen protein sponge class, hyalomitome acids, shitosan class, polylactic acid-based, absorbable cellulose class conventionally.By its material source, be divided into chemical synthesis and natural extraction class, removing polylactic acid-based is chemical synthesis, and all the other are bio-extract or its modification application.PLA degradation in vivo produces local sour environment, is unfavorable for organization healing.Natural extraction class can be divided into again plant-derived and animal derived, and wherein absorbable cellulose is plant-derived, and all the other are animal derived goods.Animal derived material need be considered animal sources application risk, and especially the potential problems such as immunogenicity, virus and/or infectious agent infection, exist clinical practice risk.Comprehensive, plant-derived material clinical safety is higher.
On market, the common formulation of existing product is sponge and sheet.It is representative that sponge be take gelatin (collagen) sponge, generally adopts after the chemical crosslinkings such as aldehydes vacuum freeze drying preparation.Prepared sponge exists that hardness is large, the slow shortcoming of degrading, and also has the residual potential danger of aldehydes.
Patent CN1217706C also provides take shitosan/chitin as raw material, adopts lyophilization to prepare the method for styptic sponge.But this method is used the toxic reagents such as ammoniacal liquor or ammoniacal liquor/ethanol, acetone, methyl alcohol in making, complex process, and shitosan/chitin belongs to animal derived material, and clinical risk is larger.In addition, because being cross-linked, sponge structure is loose, adds that thickness is large, has internal organs applicating property, the poor shortcoming of comfortableness during use.
It is main raw material that patent CN100348272C be take carboxymethyl cellulose and shitosan, and coordinating polyethylene glycol, sucrose, glycerine is auxiliary material, and vacuum freeze-drying method has been prepared styptic sponge.The raw materials used shitosan of this sponge is animal derived material, and need adopt while dissolving and have irritating acetic acid as solvent, and formula is also comparatively complicated.While also exists uncrosslinked, loosely organized, thickness ambassador used time internal organs applicating property, the poor shortcoming of comfortableness.
Sheet products be take biochargeable paper as representative.Patent CN1281816C relates to a kind of biodegradable biochargeable paper and preparation method.Adopt containing amino macromolecule and (comprise amino oligosaccharide, collagen, shitosan or derivatives thereof, or gelatin) and containing carboxyl macromolecule (comprise carboxymethyl cellulose, pectin and derivative thereof, alginic acid and derivative thereof, hyaluronic acid and derivative thereof), activated dose (comprises 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide hydrochloride (EDC), dimethyl aminopropyl ethyl carbodiimide (ETC), cyclohexyl methyl morpholine ethyl carbodiimide p-fourth dilute sulfuric acid compound (CMC), phenylene ethyl carbodiimide and 1, 6-hexamethylene two (carbodiimide)) crosslinked, rubber cement adds and is pressed into the scraps of paper after vacuum freezing drying dehydration.Biochargeable paper applicating property, comfortableness prepared by the method are better than sponge, but its complex manufacturing technology, and the poisonous activation crosslinking agent of excessive use, also relate to the use of animal derived material.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of good biocompatibility, prepares the new bio paper of simple bleeding stopping and adherence preventing purposes.
The technical scheme that the present invention solves the problems of the technologies described above is as follows: a kind of biochargeable paper, comprises the raw material of following percentage by weight: water-soluble cellulose 0.2～10%, ion crosslinking agent 0～5%, plasticizer 0～10%, solvent 75%～99.8%.
The invention has the beneficial effects as follows:
1. biological safety is good.Employing water-soluble cellulose is main raw material, divalence or trivalent ion crosslinking agent, and employing glycerine etc. is plasticizer, without any toxic chemical.Made biochargeable paper experiment showed, through the implantation of white rabbit muscle can be degradable in 14 days, nonirritant.
2. rule of surface, flexible, is not easy to scatter.Adopt progressively falling temperature method, avoided the too fast ice crystal, sleet of causing of pre-freeze excessive, finally affect the technical barrier of finished surface systematicness.
3. make simply, easily suitability for industrialized production.Conventional method exists complicated chemical crosslinking and crosslinking agent to remove process, or wash/removal of other toxic chemical substances process.There is not problems in this invention.
4. easy to use, applicating property, comfortableness are good.Sponge is because thickness is larger, and crosslinked rear intensity is large, and flexibility is poor, is unsuitable for sticking for internal organs in body.Biochargeable paper thickness 0.1～1mm that this method is made, pliability is good, and hygroscopicity is strong, and absorbing after body fluid can gelation, wound closure.Through pull test, detect, this biochargeable paper has comfortableness, can stretch with internal organs, joint.
On the basis of technique scheme, the present invention can also do following improvement.
Further, described water-soluble cellulose comprises carboxymethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose etc., should comprise low viscosity (being less than 50mPas), medium viscosity (100～500mPas), in high viscosity (1000～3000mPas) two kinds or three kinds.Wherein low viscosity component can not be used separately.
Further, described ion crosslinking agent is divalence or trivalent ion crosslinking agent.Comprise calcium, magnesium, zinc, iron, aluminium etc. one or more.If for hemostasis, preferably calcium is crosslinked, and more preferably calcium acetate is crosslinked.
Further, described plasticizer is medical glycerine.
Further, described solvent is purified water or water for injection.
Another technical scheme that the present invention solves the problems of the technologies described above is as follows: a kind of preparation method of biochargeable paper, comprise the following steps: in solvent, add water-soluble cellulose, ion crosslinking agent and plasticizer, heating while stirring, to becoming transparent uniform solution, filter again, then pack into and in mould, carry out pre-freeze, and then carry out successively vacuum freeze drying, compressing tablet, obtain described biochargeable paper;
Wherein, the mass percent of described water-soluble cellulose, ion crosslinking agent, plasticizer and solvent is 0.2～10%: 0～5%: 0～10%: 75%～99.8%.
On the basis of technique scheme, the present invention can also do following improvement.
Further, the temperature after described heating is 40～90 ℃; Described filtration is to filter with 0.2 micron of filter membrane.
Further, described pre-freeze specific practice is: pre-freeze initial temperature is 10～-5 ℃, and design temperature changing down is 0～5 ℃/h, and final temperature is-20～-30 ℃.
Further, the process conditions of described vacuum freeze drying are: in temperature, be-50～-90 ℃, and under the condition of pressure 1～40Pa, dry 5～30 hours.
Further, the thickness after described compressing tablet is 0.1～1mm.
The specific embodiment
Below principle of the present invention and feature are described, example, only for explaining the present invention, is not intended to limit scope of the present invention.
Embodiment 1
According to low viscosity carboxymethyl cellulose: high viscosity carboxymethyl cellulose: calcium acetate: glycerine: purified water (m: m: m: v: v)=0.5: 0.5: 0.5: 2: 100, be heated to 40 ℃, and constantly stirring and dissolving to forming transparent uniform solution.After 0.2 micron of filtering with microporous membrane, proceed to mould again, standing cool to room temperature.Carry out again pre-freeze, 10 ℃ of initial temperatures, final temperature is-20 ℃; In temperature, be-90 ℃ again, under the condition of pressure 1Pa, carry out vacuum freeze drying, drying time 30h.Sponge after dry, is pressed into paper, and paper thickness is 0.1mm.
Wherein the viscosity of low viscosity carboxymethyl cellulose is 50mPas, and the viscosity of described high viscosity carboxymethyl cellulose is 3000mPas.
Embodiment 2
According to low viscosity hydroxyethylcellulose: medium viscosity carboxymethyl cellulose: iron chloride: glycerine: purified water (m: m: m: v: v)=0.6: 0.5: 0.3: 3: 100, be heated to 60 ℃, and constantly stirring and dissolving to forming transparent uniform solution.After 0.2 micron of filtering with microporous membrane, proceed to mould again, standing cool to room temperature.Then carry out pre-freeze, initial temperature-5 ℃, design temperature changing down is 3 ℃/h, final temperature is-30 ℃.In temperature, be-80 ℃ again, carry out vacuum freeze drying under the condition that pressure is 40Pa, be 24h drying time.Sponge after dry, is pressed into paper, and paper thickness is 0.5mm.
Wherein the viscosity of low viscosity carboxymethyl cellulose is 30mPas, and the viscosity of described medium viscosity carboxymethyl cellulose is 500mPas.
Embodiment 3
According to low viscosity carboxymethyl cellulose: high viscosity carboxymethyl cellulose: calcium acetate: glycerine: purified water (m: m: m: v: v)=0.5: 0.5: 0.5: 2: 100, be heated to 90 ℃, and constantly stirring and dissolving to forming transparent uniform solution.Feed liquid, after 0.2 micron of filtering with microporous membrane, proceeds to mould, standing cool to room temperature.Carry out pre-freeze initial temperature-5 ℃, design temperature changing down is 5 ℃/h again, and final temperature is-30 ℃; In temperature, be-50 ℃ again, under the condition of pressure 40Pa, carry out vacuum freeze drying, drying time 5h.Sponge after dry, is pressed into paper, and paper thickness is 1mm.
Wherein the viscosity of low viscosity carboxymethyl cellulose is 0mPas, and the viscosity of described high viscosity carboxymethyl cellulose is 1000mPas.
Embodiment 4
According to medium viscosity hydroxyethylcellulose: medium viscosity hydroxypropyl cellulose: aluminium chloride: glycerine: purified water (m: m: m: v: v)=0.4: 0.4: 0.2: 4: 100, be heated to 80 ℃, and constantly stirring and dissolving to forming transparent uniform solution.Feed liquid, after 0.2 micron of filtering with microporous membrane, proceeds to mould, standing cool to room temperature.Carry out pre-freeze initial temperature-5 ℃, design temperature changing down is 2 ℃/h again, and final temperature is-30 ℃.In temperature, be-80 ℃ again, under the condition that pressure is 20Pa, carry out vacuum freeze drying, drying time 20h.Sponge after dry, is pressed into paper, and paper thickness is 0.8mm.
Wherein the viscosity of medium viscosity carboxyethyl cellulose is 100mPas, and the viscosity of described medium viscosity carboxymethyl cellulose is 200mPas.
Service check result:
1. implant Degrading experiment
Obtained biochargeable paper carries out albefaction rabbit backbone both sides muscle according to ISO 16886.6 and implants experiment, 10 days visible solid contents still, and 16 days are degradable; Carry out local excision of rat liver, implant experiment, have no tissue abnormalities reaction.7 days visible solid contents still, 14 days degradable, has no tissue abnormalities reaction.
2. intradermal reaction test
Prepared biochargeable paper carries out intradermal reaction test according to ISO 16886.10, take physiological saline and vegetable oil as lixiviate medium and contrast, and test group and the control group difference of average several minutes is 0.
3. cytotoxicity
Prepared biochargeable paper carries out cell toxicity test according to ISO 16886.5, and cytotoxicity rank is 0-1.
4. sensitization test (STT)
Prepared biochargeable paper carries out sensitization test (STT) according to ISO 16886.10, and result is without sensitization.
5. TENSILE STRENGTH
Biochargeable paper is carried out to quantitative measurement.Test specimen width 20mm, fixture 40mm, draw speed 30mm/min, measuring three sample breakage intensity is 6.79N, 11.46N and 10.41N, higher than the intensity (0.5N～0.20N) of the biochargeable paper of prior art.
6. comfortableness
According to YY0471.4 contact Wound dressing test method the 4th part comfortableness, the comfortableness of biochargeable paper is detected, record: extensibility IE=1.98N/cm, is not more than the requirement of 14N/cm far below medical adhesive tape extensibility.Permanent deformation 1%, should be not more than 5% requirement lower than medical adhesive tape permanent deformation.Result confirmation, prepared new bio paper has good comfortableness, even meets the requirement of external application medical adhesive tape.
More than comprehensive, the new bio paper that the present invention is prepared, has good biocompatibility, easily absorbs, and the feature that comfortableness is good, is worth in medical marketing, especially hemostasis, prevent adhesion clinical practice aspect.
The foregoing is only preferred embodiment of the present invention, in order to limit the present invention, within the spirit and principles in the present invention not all, any modification of doing, be equal to replacement, improvement etc., within all should being included in protection scope of the present invention.