CN107213524A - Preparation method of inflammation response type guided tissue regeneration membrane - Google Patents

Abstract

A method for preparing an inflammation-responsive guided tissue regeneration membrane belongs to the field of material surface modification. An anti-inflammatory drug with a carboxyl group is bonded to the membrane surface by an ester bond, and the cholesterol esterase released by macrophage aggregation during inflammation selectively enzymatically hydrolyzes the ester bond to achieve a responsive release effect. Specific method: ITXSP (isopropyl thioxanthone semipinacol) is introduced into the membrane surface by ultraviolet light initiation; an initiator, a cross-linking agent and an enol monomer are simultaneously added to the activated ITXSP surface to form a hydrogel layer; the drug is reacted with the enol monomer to form a drug molecule containing an ester group and a carbon-carbon double bond; finally, the drug molecule, the enol monomer and the cross-linking agent are thermally initiated and then loaded with a drug-containing gel layer, wherein the drug is fixed in the gel layer on the membrane surface by an ester bond. The inflammation-responsive membrane of the present invention has the characteristics of excellent biocompatibility and inflammation-responsive drug release.

Description

A preparation method of an inflammation-responsive guided tissue regeneration membrane

technical field

The invention belongs to the field of material surface modification, and in particular relates to a preparation method of an inflammation-responsive release anti-inflammatory drug film.

Background technique

Heterotopic ossification (HO) refers to the appearance of mature lamellar bone in the soft tissue around the joint. Complications such as complex regional pain syndrome, joint stiffness, and nerve entrapment can occur. So far, the pathogenesis of HO is still unclear. However, existing studies suggest that the formation of heterotopic bone is related to the improper differentiation of mesenchymal stem cells into osteoblasts in soft tissues. For postoperative heterotopic bone formation, changes in the local environment triggered by local inflammatory responses are crucial factors that promote this improper differentiation ^[1] .

HO is one of the most common complications after total disc replacement (TDR). A meta-analysis of the incidence of HO after cervical disc replacement showed that the combined incidence rates at 12 months and 24 months after surgery were 44.6% and 58.2%, and the incidence rates of severe HO were 11.1% and 16.7%, respectively ^[2 ] ^】 . Compared with traditional intervertebral fusion, the core significance of carrying out artificial disc replacement is to maintain the mobility of the spine, and the occurrence of heterotopic ossification around the intervertebral disc prosthesis undoubtedly hinders the promotion of this technology. How to effectively reduce the incidence of heterotopic ossification after artificial cervical disc replacement is a clinical problem to be solved urgently.

After artificial disc replacement, there must be local inflammation. The necrotic cells in the tissue damage site release danger signals, and the cell recognition signals of the innate immune system lead to the release of some cytokines, inflammatory factors and inflammatory mediators. These factors act synergistically to induce inappropriate differentiation of mesenchymal stem cells into osteoblasts, resulting in ectopic bone formation. Among them, transforming growth factor TGF-βs, bone morphogenetic proteins BMPs and prostaglandin 2 (PGE2) are considered to play a key role in inducing the differentiation of mesenchymal stem cells into osteoblasts.

At present, there is no effective means to prevent and inhibit HO after artificial cervical disc replacement, and local radiation therapy and oral non-steroidal anti-inflammatory drugs (non-steroid anti-inflammatory drugs, NSAIDs) are commonly used. The mechanism of radiotherapy is to prevent the differentiation of pluripotent mesenchymal stem cells into osteoblasts by changing the DNA structure of rapidly differentiating cells, thereby inhibiting the occurrence of HO. However, radiotherapy to prevent HO has great limitations, and it is easy to cause cancer, nonunion, and affect reproductive ability. Oral NSAIDs are currently the most common and effective method for preventing postoperative heterotopic ossification. Studies have shown that preoperative use of NSAIDs can reduce the incidence of postoperative HO by about 57%-59%. The method of oral NSAIDs to prevent postoperative HO is simple and the treatment cost is relatively low, so it has been widely used, but its side effects are also very obvious, mainly manifested as peptic ulcer, and about 20-37% of patients are due to gastrointestinal reactions And can not complete treatment, secondly, also can cause the adverse reaction of liver, urinary system and blood system. In addition, the clinical manifestations of heterotopic ossification after cervical disc replacement first appeared 3 weeks after surgery, and there are also reports of 6 months or even 1 year after surgery, which has large clinical individual differences. However, the radiotherapy or oral NSAIDs currently used are generally intervened in the perioperative period, which cannot prevent and inhibit individual differences.

When inflammation occurs, a large number of macrophages will gather, and the aggregated macrophages will secrete a large amount of cholesterol esterase (cholesterol esterase, CE). And ester bonds have selective enzymolysis. Drugs grafted onto the membrane surface via ester linkages are responsive to enzymes produced during inflammation. When inflammation occurs, the ester bond is broken by enzymes, and the drug is released; the higher the degree of inflammation, the more macrophages gather around, the more enzymes are released, and the more the drug is released. Using CE to selectively enzymatically hydrolyze ester bonds, drug molecules are immobilized on the membrane surface through ester bonds, and the content of ester bonds connecting drugs reaches a certain amount, and it is possible to construct a membrane that releases drugs in response to inflammation. In order to achieve the purpose of effectively preventing and inhibiting inflammation according to the differences in the onset time and severity of different patients.

references:

[1] Balboni TA, Gobezie R, Mamon HJ, Heterotopic Ossification: Pathophysiology, Clinical Features, And The Role Of Radiotherapy For Prophylaxis. Int. J. Radiation Oncology Biol. Phys., 2006, 65: 1289–1299.

[2] Chen J, Wang XW, Bai WS, Shen XL, Yuan W. Prevalence of heterotopicossification after cervical total disc arthritis: a meta-analysis: Eur SpineJ, 2012, 21: 674-680.

Contents of the invention

In view of the limitations of the existing methods for preventing and inhibiting the occurrence of postoperative heterotopic ossification, this application proposes to immobilize non-steroidal anti-inflammatory drugs commonly used in clinical practice on the surface of implanted membrane materials with ester bonds, and use CE released by inflammatory macrophages to The selective enzymatic hydrolysis of ester bonds achieves the purpose of controlling and regulating the release of NSAIDs through the degree of inflammatory response, thereby achieving the purpose of overcoming the serious side effects caused by oral NSAIDs commonly used in clinical practice, and locally effectively preventing and inhibiting the occurrence of postoperative heterotopic ossification.

1. A preparation method for an inflammation-responsive film, characterized in that: the polymer film is a base material, and the ITXSP dormant species is introduced into the polymer film surface by ultraviolet light; the ITXSP dormant species is activated by ultraviolet light, and the ITXSP dormant species is activated in the Activate the surface and add initiators, cross-linking agents and enol monomers to graft a layer of hydrogel on the surface of the membrane to change the water solubility of the membrane surface; combine anti-inflammatory drugs with carboxyl groups with enol monomers body reaction to form monomers containing ester groups and carbon-carbon double bonds; finally, the monomers containing ester groups and carbon-carbon double bonds, enol monomers, and cross-linking agents are triggered by thermal initiators. A gel layer containing drugs is loaded on the surface of the membrane, wherein the drugs are fixed in the gel layer by ester bonds.

2. The method according to claim 1, characterized in that, its specific operation steps are:

(1) ITX acetone saturated solution is coated on polymer film surface, cover quartz plate, by ultraviolet initiation, ITXSP functional group is introduced into polymer film surface, obtains the polymer film that is loaded with ITXSP functional group;

(2) Enol monomers and anti-inflammatory drugs with carboxyl groups undergo esterification reaction under the catalysis of DCC/DMAP (N,N'-dicyclohexylcarboimide/4-dimethylaminopyridine), so as to obtain drug-containing , ester bond and double bond monomer, the obtained monomer is recorded as Drug; DCC/DMAP is N,N'-dicyclohexylcarboimide/4-dimethylaminopyridine, wherein the reaction monomer and the initiator The feeding molar ratio of agent is IDCM:HEMAA:DCC:DMAP=1:3:3:0.5,

(3) Initiator, crosslinking agent and monomer containing ester group and carbon-carbon double bond are prepared into solution according to molar ratio=1:1:5, concentration 10-30wt%; The surface is coated with the solution, covered with a quartz plate, and induced by ultraviolet light, thereby introducing a hydroxyl-containing gel layer on the surface of the polymer film;

(4) Drug, initiator, crosslinking agent and emulsifier obtained in step (2) are prepared into an emulsion system whose mass concentration is 10-30wt% according to the molar ratio of 6:1:1:0.5; in the hydroxyl-containing gel On the layer, apply a layer of the emulsion and react in an oven at 30°C-70°C for 0.5h-2h to obtain a drug-loaded gel layer.

3. Further, the polymer film has a thickness of 100 μm-1 mm, a non-porous or porous structure, and a pore size of 1-10 μm, and its preparation methods include: electrospinning, melt casting or vacuum molding.

4. The method according to claim 1, wherein the polymer film is polyurethane and/or silicone rubber.

5. Further, the carboxylated anti-inflammatory drug is a non-steroidal anti-inflammatory drug.

6. Further, enol monomer N-hydroxyethylacrylamide, N-methylolacrylamide.

7. Further, the initiator is potassium persulfate or ammonium persulfate.

8. Further, the crosslinking agent is N,N'-methylenebisacrylamide.

9. Further, the emulsifier is a compound system of sodium dodecylsulfonate and sodium dodecylsulfonate-gelatin.

10. Further, the wavelength of ultraviolet light induced in step (1) or step (3) is 200-400nm, the irradiation time is 10-60min, and the irradiation distance is 50mm.

Description of drawings

Figure 1 Schematic diagram of the process method for loading drugs on polyurethane surface

in:

MBA: N,N'-methylenebisacrylamide crosslinker

HEAA:N-Hydroxyethylacrylamide

K ₂ S ₂ O ₈ : ammonium persulfate initiator

SDS: Sodium Dodecyl Sulfate Surfactant

Figure 2 is the esterification of N-hydroxyethylacrylamide (HEMAA) and indomethacin (IDCM) under the catalysis of DCC/DMAP (N,N'-dicyclohexylcarboimide/4-dimethylaminopyridine) The equation for the chemical reaction:

Figure 3 The high performance liquid chromatography curve of drug release after immersion in PBS buffer solution without CE and 50U/ml CE enzyme solution for inflammation responsive drug release membrane material for 3 hours

Fig. 4 HPLC spectrogram after soaking in CE enzyme for 12h-72h, it can be found that the concentration of drug molecules connected with C=C decreases gradually, while the content of indomethacin increases. It can be seen that the ester bond has a certain effect on cholesterol esterase Very high sensitivity.

Figure 5 Comparison of the effects of no lipopolysaccharide (LPS) stimulation (Con) and different drug loading samples (Y10, Y20) under LPS stimulation and direct drug addition (DM1) on the secretion of inflammatory factor IL-6

Con: blank control (no stimulation, no drug added); LPS: lipopolysaccharide; Y10, Y20: material group (Y10: drug loading is 10wt%; Y20: drug loading is 20wt%); DM: add indole directly Mexin drug control group

detailed description

The present invention is further described below through specific examples, but is not limited to the following examples. After reading the content taught by the present invention, those skilled in the art can make various changes or modifications to the present invention, but within the spirit and principle of the present invention, changes and modifications of these equivalent forms should be included in the present invention within the scope of protection.

Example 1

(1) On the surface of electrospun porous polyurethane (PU), apply a saturated solution of ITX acetone on the surface of polyurethane, cover the surface of polyurethane, cover with a quartz plate, and irradiate with ultraviolet light for 10 minutes (wavelength 200nm, irradiation distance 50mm ), the ITXSP functional group was introduced into the surface of polyurethane (PU) membrane (thickness 100 μm, average pore size 1 μm).

(2) Carried out by N-hydroxyethylacrylamide (HEMAA) and indomethacin (IDCM) under the catalysis of DCC/DMAP (N, N'-dicyclohexylcarboimide/4-dimethylaminopyridine) Esterification reaction to obtain monomers containing drugs, ester bonds and double bonds. The molar ratio of the reaction monomer and the initiator is IDCM:HEMAA:DCC:DMAP=1:3:3:0.5, the solvent is anhydrous DMF, the reaction temperature is 40°C, and the reaction time is 24h. First add other raw materials except DCC at one time, then add DCC under ice bath conditions, and continue to ice bath for about 20 minutes; after the reaction is completed, cool the reaction solution in an ice bath to precipitate N, N'dicyclohexylurea (DCU), and filter with suction , the filtrate was precipitated with an aqueous solution, and stood/centrifuged until the supernatant was clarified; the supernatant was poured out, and the lower precipitate was ultrasonically shed with ether, filtered to obtain a precipitate, and washed 3 times with petroleum ether; with a mixed solution of ethyl acetate and petroleum ether ( The mobile phase with a volume ratio of 6:1) was purified through a column, and the product was obtained by rotating at 45°C. Collect the product and store it in the refrigerator. Drug molecules containing C=C are obtained by this method.

(3) Ammonium persulfate initiator (K2S2O8), N, N'-methylenebisacrylamide crosslinking agent (MBA) and N-hydroxyethylacrylamide (HEAA) are prepared according to the molar ratio of 1:1:5 into a solution, the three mass accounts for 10wt% of the total mass of the solution. On the polyurethane surface loaded with ITXSP functional groups, the prepared solution was coated, covered with a quartz plate, and induced by ultraviolet light (wavelength 200nm, duration 60min, irradiation distance 50mm), thereby introducing a hydroxyl-containing gel layer on the surface of the film. Two ultraviolet light triggers one with light intensity and one with distance. It is recommended to modify it to be consistent

(4) The product obtained in step (2), K ₂ 5 ₂ O ₈ , MBA and SDS are formulated into an emulsion system with a mass ratio of 10wt% according to a molar ratio of 6:1:1:0.5, and the emulsion system is coated in the step (3) The surface of the obtained hydroxyl group-containing gel layer. After reacting in an oven at 70° C. for 0.5 h, a drug-containing gel layer is obtained on the surface of the film, wherein the drug is fixed in the gel layer by ester bonds. And the drug content is 1.5 μg/cm2. The drug release reaches 95% of the total amount in 1 hour.

Example 2

(1) On the surface of electrospun porous polyurethane (PU), apply a saturated solution of ITX acetone on the surface of polyurethane, cover the surface of polyurethane, cover with a quartz plate, and irradiate with ultraviolet light for 10 minutes (wavelength 400nm, irradiation distance 50mm ), introducing ITXSP functional groups to the surface of polyurethane (PU) membrane (thickness 1mm, average pore size 10 μm);

(2) Carried out by N-hydroxyethylacrylamide (HEMAA) and indomethacin (IDCM) under the catalysis of DCC/DMAP (N, N'-dicyclohexylcarboimide/4-dimethylaminopyridine) Esterification reaction to obtain monomers containing drugs, ester bonds and double bonds. The molar ratio of the reaction monomer to the initiator is IDCM:HEMAA:DCC:DMAP=1:3:3:0.5, the solvent is anhydrous DMF, the reaction temperature is 40°C, and the reaction time is 24h. First add other raw materials except DCC at one time, then add DCC under ice bath conditions, and continue the ice bath for about 20 minutes; after the reaction is completed, cool the reaction solution in an ice bath to precipitate DCU, filter with suction, and the filtrate is precipitated with an aqueous solution, and stand/centrifuge To the clarification of the upper layer liquid; pour out the supernatant liquid, and the lower layer precipitate is ultrasonically shed with ether, and the precipitate is filtered and washed 3 times with sherwood oil; The column was purified, and the product was obtained by rotation under the condition of 45°C. Collect the product and store it in the refrigerator. The thickness of the gel layer is 0.1 mm.

(3) Mix persulfate amine initiator (K ₂ S ₂ O ₈ ), N,N'-methylenebisacrylamide crosslinking agent (MBA) and N-hydroxyethylacrylamide (HEAA) in a molar ratio of 1 : 1:5 to be prepared into a solution, the mass of the three accounts for 30wt% of the total mass of the solution. On the surface of polyurethane loaded with ITXSP functional groups, the prepared solution was coated, covered with a quartz plate, and induced by ultraviolet light (wavelength 400nm, duration 30min, irradiation distance 50mm), thereby introducing a hydroxyl-containing gel layer on the surface of the membrane.

(4) The product obtained in step (2), K ₂ S ₂ O ₈ , MBA and SDS are formulated into an emulsion system with a mass ratio of 30wt% according to a molar ratio of 6:1:1:0.5, and the emulsion system is coated in the step (3) The surface of the obtained hydroxyl group-containing gel layer. React in an oven at 30°C for 2 hours to obtain a drug-containing gel layer on the surface of the film, in which the drug is fixed in the gel layer by ester bonds, and the drug content is 1 μg/cm ² , and the drug release reaches 96% of the total amount in 1 hour .

Example 3

(1) On the surface of electrospun porous polyurethane (PU), apply a saturated solution of ITX acetone on the surface of polyurethane, cover the surface of polyurethane, cover with a quartz plate, and irradiate with ultraviolet light for 10 minutes (wavelength 350nm, irradiation distance 50mm ), introducing ITXSP functional groups to the surface of polyurethane (PU) membrane (thickness 0.5mm, average pore size 6μm);

(2) Carried out by N-hydroxyethylacrylamide (HEMAA) and indomethacin (IDCM) under the catalysis of DCC/DMAP (N, N'-dicyclohexylcarboimide/4-dimethylaminopyridine) Esterification reaction to obtain monomers containing drugs, ester bonds and double bonds. The molar ratio of the reaction monomer to the initiator is IDCM:HEMAA:DCC:DMAP=1:3:3:0.5, the solvent is anhydrous DMF, the reaction temperature is 40°C, and the reaction time is 24h. First add other raw materials except DCC at one time, then add DCC under ice bath conditions, and continue the ice bath for about 20 minutes; after the reaction is completed, cool the reaction solution in an ice bath to precipitate DCU, filter with suction, and the filtrate is precipitated with an aqueous solution, and stand/centrifuge To the clarification of the upper layer liquid; pour out the supernatant liquid, and the lower layer precipitate is ultrasonically shed with ether, and the precipitate is filtered and washed 3 times with sherwood oil; The column was purified, and the product was obtained by rotation under the condition of 45°C. Collect the product and store it in the refrigerator. The thickness of the gel layer is 0.1 mm.

(3) Mix persulfate amine initiator (K ₂ S ₂ O ₈ ), N,N'-methylenebisacrylamide crosslinking agent (MBA) and N-hydroxyethylacrylamide (HEAA) in a molar ratio of 1 : 1:5 is prepared into a solution, and the mass of the three accounts for 20wt% of the total mass of the solution. On the surface of polyurethane loaded with ITXSP functional groups, the prepared solution was coated, covered with a quartz plate, and induced by ultraviolet light (wavelength 350nm, duration 45min, irradiation distance 50mm), thereby introducing a hydroxyl-containing gel layer on the surface of the film.

(4) The product obtained in step (2), K ₂ 5 ₂ O ₈ , MBA and SDS are formulated into an emulsion system with a mass ratio of 20wt% according to a molar ratio of 6:1:1:0.5, and the emulsion system is coated in the step (3) The obtained hydroxyl-containing gel layer surface. React in an oven at 40° C. for 1.5 h to immobilize the drug on the surface of the electrospun polyurethane membrane with ester bonds. A drug-containing gel layer was obtained on the surface of the membrane, wherein the drug was fixed in the gel layer by ester bonds, and the drug content was 0.8 μ g/cm ² . The drug release reached 98% of the total amount in 1 hour.

Example 4

The electrospun polyurethane PU membrane in Example 3 was replaced by a non-porous PU membrane prepared by melt casting, and other experimental conditions were the same as in Example 3. The drug was immobilized in the drug-loaded gel layer on the surface of the electrospun polyurethane membrane with an ester bond, and the drug content was 0.3 μg/cm ² . Drug release reached 97% of the total amount in 1 hour.

Example 5

The electrospun polyurethane PU membrane in Example 1 was replaced by a non-porous PU membrane prepared by vacuum molding, and other experimental conditions were the same as in Example 1. The drug was immobilized in the gel layer loaded with the drug on the surface of the electrospun polyurethane membrane by ester bonds, and the drug content was 0.6 μg/cm ² . The drug release reached 98% of the total amount in 1 hour.

Example 6

The electrospun polyurethane PU film in Example 3 was replaced by a 0.5 mm thick non-porous silicone rubber film prepared by melt casting, and other experimental conditions were the same as in Example 3. The drug was immobilized in the drug-loaded gel layer on the surface of the non-porous silicone rubber membrane prepared by the melt-casting method with an ester bond, and the drug content was 0.3 μg/cm ² . Drug release reached 97% of the total amount in 1 hour.

Example 7

The N-hydroxyethylacrylamide (HEMAA) in Example 1 was replaced with N-methylolacrylamide (HAM), and other experimental conditions were the same as in Example 1. The product synthesized by N-methylolacrylamide (HAM) and indomethacin (IDCM) was tested by mass spectrometry and NMR. It was found that a substance with a molecular weight of 440.9 appeared in the mass spectrogram, and the chemical shift of the corresponding H in the NMR map was compared. , it can be confirmed that the desired product is obtained. The drug was immobilized by ester bonds in the thick drug-loaded gel layer on the surface of the electrospun polyurethane membrane, and the drug content was 1.3 μg/cm ² . Drug release reached 97% of the total amount in 1 hour.

Example 8

The anti-inflammatory drug indomethacin in Example 1 was replaced by aspirin, and other experimental conditions were the same as in Example 1. Measure the mass spectrum and nuclear magnetic spectrum of the reaction product of aspirin and N-hydroxyethylacrylamide (HEMAA), and find that a substance with a molecular weight of 277.29 appears in the mass spectrum, and compare the chemical shift of the corresponding H in the nuclear magnetic spectrum. Need product. The drug was immobilized in the gel layer loaded with the drug on the surface of the electrospun polyurethane membrane by ester bond, and the drug content was 1.2 μg/cm ² . Drug release reached 96% of the total amount in 1 hour.

Example 9

The thermal initiator potassium persulfate in embodiment 1 is replaced by ammonium persulfate, and other experimental conditions are identical with embodiment 1. The drug was immobilized in the gel layer loaded with the drug on the surface of the electrospun polyurethane membrane by ester bond, and the drug content was 1.3 μg/cm ² . Drug release reached 98% of the total amount in 1 hour.

Example 10

The emulsifier sodium lauryl sulfonate in embodiment 1 is changed into the composite system of sodium lauryl sulfonate-gelatin, and other experimental conditions are identical with embodiment 1. The drug was immobilized by ester bonds in the thick drug-loaded gel layer on the surface of the electrospun polyurethane membrane, and the drug content was 1.5 μg/cm ² . Drug release reached 94% of the total amount in 1 hour.

Claims (10)

1. a kind of preparation method of inflammatory response type film, it is characterized in that：Polymeric membrane is matrix material, by ultraviolet light-initiated, ITXSP dormancy kinds are incorporated into polymeric membrane surface；By ultraviolet light-initiated, ITXSP dormancy kinds are activated, in activated surface simultaneously Initiator, crosslinking agent and enol class monomer are added, so as in film surface grafting last layer hydrogel layer, change the water-soluble of film surface Property；By the anti-inflammatory drug with carboxyl and enol class monomer reaction, the monomer containing ester group and carbon-carbon double bond is formed；This is finally contained into ester Monomer, enol class monomer, the crosslinking agent of base and carbon-carbon double bond, under the initiation of thermal initiator, reload one on the surface of the film Gel layer of the layer containing medicine, wherein medicine is fixed in gel layer with ester bond.

2. according to the method described in claim 1, it is characterised in that its concrete operation step is：

(1) ITX acetone saturated solutions are coated in polymeric membrane surface, cover quartz plate, triggered by ultraviolet, by ITXSP official It can roll into a ball and introduce polymeric membrane surface, obtain being loaded with the polymer film of ITXSP functional groups；

(2) enol class monomer with carboxyl anti-inflammatory drug in DCC/DMAP (N, N'- Dicyclohexylcarbodiimides/4- dimethylaminos Pyridine) the lower progress esterification of catalysis, so as to obtain the monomer of drug containing, ester bond and double bond, obtained monomer is designated as Drug； DCC/DMAP is N, and N'- Dicyclohexylcarbodiimides/DMAP, wherein feeding intake for reaction monomers and initiator rub You are than being IDCM:HEMAA:DCC:DMAP=1:3:3:0.5,

(3) by initiator, crosslinking agent and monomer containing ester group and carbon-carbon double bond are according to mol ratio=1:1:5, concentration 10-30wt% It is configured to solution；The polymer film surface of ITXSP functional groups is being loaded with, the solution is being coated, covers quartz plate, drawn by ultraviolet light Hair, so as to introduce the gel layer of hydroxyl on the polymeric membrane surface；

(4) by Drug, initiator obtained by step (2), crosslinking agent and emulsifying agent are according to mol ratio 6：1：1：0.5 to be configured to quality dense Spend the emulsion system for 10-30wt%；On the gel layer of hydroxyl, one layer of emulsion of coating is anti-in 30 DEG C of -70 DEG C of baking ovens 0.5h-2h is answered, the gel layer of loading medicine is obtained.

3. according to the method described in claim 1, it is characterised in that：Polymeric membrane, its thickness is 100 μm of -1mm, with non-porous Or porose structure, 1-10 μm of aperture, its preparation method includes：Electrostatic spinning, melt casting or vacuum mold platen press.

4. according to the method described in claim 1, it is characterised in that polymeric membrane is polyurethane and or silicon rubber.

5. according to the method described in claim 1, it is characterised in that：Band carboxyl anti-inflammatory agent is non-steroidal anti-inflammatory drug.

6. according to the method described in claim 1, it is characterised in that：Enol class monomer N- hydroxyethyl acrylamides, N- methylols Acrylamide.

7. method according to claim 1, it is characterised in that：Described initiator is potassium peroxydisulfate or ammonium persulfate.

8. according to the method described in claim 1, it is characterised in that：Crosslinking agent is N, N '-methylene-bisacrylamide.

9. according to the method described in claim 1, it is characterised in that：Emulsifying agent is dodecyl sodium sulfate, dodecyl sodium sulfonate The compound system of sodium-gelatin.

10. according to the method described in claim 1, it is characterised in that：By step (1) or the ultraviolet light-initiated wavelength of step (3) For 200-400nm, duration 10-60min, irradiation distance 50mm are irradiated.