CN115607746A - Self-expanding uterine cavity anti-adhesion repair device and application thereof - Google Patents
Self-expanding uterine cavity anti-adhesion repair device and application thereof Download PDFInfo
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- CN115607746A CN115607746A CN202211289212.7A CN202211289212A CN115607746A CN 115607746 A CN115607746 A CN 115607746A CN 202211289212 A CN202211289212 A CN 202211289212A CN 115607746 A CN115607746 A CN 115607746A
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Abstract
The invention discloses a self-expanding uterine cavity anti-adhesion restorer and application thereof, wherein the self-expanding uterine cavity anti-adhesion restorer consists of an outer layer coating made of a degradable micro-nano fiber membrane and an inner core membrane made of a high polymer material capable of swelling by absorbing water, the inner core membrane is gradually expanded in the process of absorbing seepage, the outer layer micro-nano fiber coating is propped open and pasted on the inner wall of a uterus to form a wound surface protection film, cells are induced to climb on a degradable micro-nano fiber membrane bracket to grow and quickly restore the wound surface, and meanwhile, pain caused by uterine contraction is relieved, and the self-expanding uterine cavity anti-adhesion restorer is used for postoperative anti-adhesion or perfusion administration.
Description
Technical Field
The invention belongs to the technical field of medical treatment, and particularly relates to a self-expanding type uterine cavity anti-adhesion restorer.
Background
The uterus cleaning is a common operation mode in clinical gynecology, and mainly aims to remove tissues remained in uterine cavities due to incomplete abortion. The uterus of women will contract after uterus cleaning to promote the discharge of blood stasis in the uterus, and the contraction of the uterus is mainly manifested as abdominal pain and vaginal bleeding. After uterus cleaning, the uterus contracts for 7 to 15 days, continuous pain caused by uterus contraction can occur, and meanwhile, blood which is accompanied with abdominal distension, abdominal pain and uterine cavity accumulation can be discharged through the vagina in the process of uterus contraction, and re-adhesion can occur. The uterine cavity adhesion is a common complication of diseases such as uterine cavity operation, inflammation and the like, and can cause gynecological diseases such as menstrual flow reduction, amenorrhea, abortion, infertility and the like, at present, anti-adhesion products such as uterine cavity anti-adhesion gel, uterine cavity anti-adhesion membrane and the like are clinically used, wherein the gel products are extruded and flow out in the uterine contraction process, the anti-adhesion membrane can curl in the uterine contraction process, the membrane falls off and shrinks to avoid complete coverage of a wound surface, particularly the positions of two uterine horns, and the problem of oviduct blockage of a plurality of women who have undergone the uterine cavity operation is caused, so that a product capable of completely covering the inner wall of the uterine cavity to prevent adhesion is clinically needed.
The intrauterine adhesion usually exists in the coexistence of endometrial regeneration disorder and local fibrosis, and an ideal treatment scheme for the intrauterine adhesion is to restore the normal shape of the uterine cavity and promote the growth of endometrium on the other hand, so that an ideal intrauterine adhesion prevention product can completely cover a wound surface 7-15 days after operation, a material covering the wound surface can promote healing, the inner wall of the uterine cavity is smooth after the wound surface is healed, particularly, the part of the uterine horn uterine tube orifice can be propped open, uterine contraction can be inhibited, and pain of a patient can be relieved.
Uterine cavity perfusion administration is a common clinical means for treating chronic inflammation and improving embryo implantation success rate, for example, HCG uterine cavity perfusion can enhance differentiation and proliferation capacity of endometrium, improve adhesion between endometrium and early embryo, and obviously improve embryo implantation success rate, in addition, HCG uterine cavity perfusion can reduce abortion rate of recurrent abortion female, GH uterine cavity perfusion can increase endometrium thickness, improve endometrial receptivity, and improve embryo freezing implantation rate and clinical pregnancy rate for thin type non-reactive endometrium. More commonly used drugs include granulocyte colony stimulating factor (G-CSF), human Chorionic Gonadotropin (HCG), growth Hormone (GH), and Platelet Rich Plasma (PRP); in the following, for example: the conventional medicines comprise anti-inflammatory medicines such as cephalosporins, clindamycin, penicillins or aminosugamines (gentamicin, streptomycin, tobramycin, ribostamycin, small glutinous rice star, amikacin and the like), for example, doxycycline is clinically used for treating infertility and chronic endometritis by combining with intrauterine metronidazole infusion, but the multiple infusion is very inconvenient for patients because the lasting medicine concentration cannot be maintained in the uterine cavity, so that a drug delivery apparatus which can firstly absorb the filled medicine and then slowly release the medicine to achieve an effective treatment effect is clinically very needed.
Disclosure of Invention
In order to solve the defects of the prior art and meet the requirement of completely covering the inner wall of the uterine cavity to achieve adhesion prevention and meanwhile, a drug delivery device which can firstly absorb filled drugs and then slowly release the drugs to achieve an effective treatment effect is successfully developed by the research team of the invention, the invention discloses a self-expanding uterine cavity anti-adhesion restorer which is similar to a uterine shape and can completely cover the wound surface of the inner wall of the uterus, after an inner core membrane of the restorer absorbs water and expands, the volume expansion is more than 10 times of the self weight, the uterus can be completely propped open and kept for 7-15 days, a micro-nano fiber membrane envelope made of degradable polyurethane materials is pasted on the wound surface of the inner wall of the uterus, the wound surface of the middle inner wall is completely covered, the wound surface healing can be promoted, the formation of endometrial scar tissues is reduced, and the pain of a patient caused by uterine contraction is relieved; for patients needing to be treated by infusing the medicine into the uterine cavity, the restorer can firstly absorb the filled medicine and then slowly release the medicine so as to achieve the effective treatment dose.
The invention provides a self-expanding uterine cavity anti-adhesion restorer which is composed of an outer-layer envelope made of degradable micro-nano fiber membranes and an inner core membrane made of a high polymer material capable of swelling by absorbing water, wherein the inner core membrane is sealed in the outer-layer envelope, and the self-expanding uterine cavity anti-adhesion restorer is in a uterus shape, is 30-70mm long, 30-65mm wide and 0.1-2mm thick.
The outer layer coating is a micro-nano fiber membrane, the fiber diameter range of the micro-nano fiber membrane is 10nm-5um, and the selected material is an absorbable polymer material; the size of the inner core membrane is smaller than that of the outer envelope, the shape is uterus shape, trapezoid shape, ellipse shape or other special shapes, the length is 10mm-60mm, the width is 10-55mm, the thickness is 0.1mm-2mm, and the inner core membrane can absorb liquid which is 10 times of the self weight and can prop open the outer envelope.
The self-expanding uterine cavity anti-adhesion restorer provided by the invention is characterized in that the degradable micro-nano fiber membrane material is one or two of degradable polyurethane, absorbable polyester, absorbable polyether and absorbable polyamino acid;
further, it is selected from absorbable polyesters such as polyglycolide, copolymers of polylactide and polyglycolide, polycaprolactone-glycolide, and degradable polyurethanes, specifically including PLGA (LA: GA = 1) and PLGA ring-opened by polyethylene glycol, polylactic acid (PLGA) polymers in which polyethylene glycol (PEG 200, 400, 600, 1000) ring-opened, PEG: LA: the GA comprises the following components in percentage by mass: 1, 10-5000;
wherein the degradable polyurethane comprises one or two of polylysine PU, PU material which takes polymer diol synthesized by taking CL, PDO, LA and GA as main raw materials as soft segment and takes lysine diisocyanate as hard segment, PU material which takes lysine diisocyanate to crosslink polylysine, PU material which takes natural polymer carboxymethyl cellulose or hyaluronic acid as soft segment and takes lysine diisocyanate as hard segment, or the combination of the two;
the degradable polyurethane is preferably polyester polyurethane, and specifically comprises polylysine PU, a PU material which takes polymer diol synthesized by taking CL, PDO, LA and GA as main raw materials as a soft segment and takes Lysine Diisocyanate (LDI) as a hard segment, and degradable polyurethane which takes caprolactone polymer diol ring-opened by polyethylene glycol (PEG 200, 400, 600 and 1000) and LDI as hard ends.
Further, the degradable polyurethane is preferably characterized by a polyurethane in which the polymer diol selected from the group consisting of polyethylene glycol (PEG 200, 400, 600, 1000), caprolactone (CL) ring-opened by small molecule diol, PDO, LA, GA is soft-ended, LDI and chain extender is hard-ended.
Further, the degradable polyurethane is preferably characterized by being a degradable polyurethane terminated with an amino acid or a derivative thereof or a polypeptide, wherein the polymer diol selected from the group consisting of polyethylene glycol (PEG 200, 400, 600, 1000), caprolactone (CL) opened by small molecule diol, PDO, LA, GA is soft-ended, LDI and chain extender are hard-ended.
The chain extender is selected from one or more of ethylene glycol, propylene glycol, butanediol, pentanediol, butanediamine, pentanediamine, hydroxyprogenic acid (methyl ester/ethyl ester), arginine (methyl ester/ethyl ester), cysteine (methyl ester/ethyl ester), cystine (methyl ester/ethyl ester), serine (methyl ester/ethyl ester), glutamic acid (methyl ester/ethyl ester), threonine (methyl ester/ethyl ester), aspartic acid (methyl ester/ethyl ester), tyrosine (methyl ester/ethyl ester), lysine (methyl ester/ethyl ester), arginine (methyl ester/ethyl ester) and diamine-like compounds, wherein the diamine-like compounds are synthesized by ester bonds after esterification reaction of two molecules of amino acid (one of 20 common amino acids) and one molecule of ethylene glycol or 1 and 3 propylene glycol, such as: the compound which is obtained by esterification reaction of two molecules of phenylalanine and one molecule of 1 and 3 propanediol and is connected by two ester bonds and has two active amino groups is as follows:
wherein the blocked amino acid or its derivative is selected from one or two of hydroxyprogenic acid (methyl ester/ethyl ester), arginine (methyl ester/ethyl ester), cysteine (methyl ester/ethyl ester), cystine (methyl ester/ethyl ester), serine (methyl ester/ethyl ester), glutamic acid (methyl ester/ethyl ester), threonine (methyl ester/ethyl ester), aspartic acid (methyl ester/ethyl ester), tyrosine (methyl ester/ethyl ester) and lysine (methyl ester/ethyl ester);
wherein the blocked polypeptide is selected from one or more of amino acids or derivatives thereof selected from lysine or lysine ethyl ester/methyl ester, arginine or arginine ethyl ester/methyl ester, histidine or histidine ethyl ester/methyl ester, collagen tripeptide or collagen tripeptide ethyl ester/methyl ester, fibronectin RGD, laminin or its ethyl ester/methyl ester, affinity TGF-beta 1 polypeptide, bone marrow homing polypeptide, osteogenic growth polypeptide, laminin sequence, nerve stem cell surface molecule capable of being combined, osteoblast adhesion molecule and VEGF.
In the degradable polyurethane, a small amount of catalyst (0.01 wt% -0.03wt% of the total amount) such as organotin and organobismuth is added in the material synthesis process, and the catalyst with low toxicity is preferably selected, such as: stannous octoate, dibutyltin diacetate, dibutyltin dilaurate, MB20 and DY-20 or a combination of two of the two.
The organic solvent for dissolving and degrading the polyurethane to prepare the micro-nano fiber membrane is selected from one or a combination of more than two of DMF, DMSO, tetrahydrofuran, ethanol, isopropanol, n-butanol, acetone, butanone, cyclohexanone, isoamyl acetate, ethyl acetate, dichloromethane, trichloromethane, 1, 4-dioxane or hexafluoroisopropanol.
The self-expanding uterine cavity anti-adhesion restorer provided by the invention is characterized in that the inner core membrane is made of a high-water-absorptivity degradable polymer material, specifically comprises alginate, modified alginate and alginate degraded into hexosamine and N-acetylglucosamine, a high-molecular antibacterial water-absorbing material, polyamino acid, chitosan, polylysine PU, polyvinyl alcohol, carbomer, polyvinyl pyrrolidone, sodium hyaluronate, zinc hyaluronate, collagen, organic silicon, polypeptides, amino acid and one or two of various anti-inflammatory drugs.
Further, the inner core membrane is selected from sodium hyaluronate, specifically one or a mixture of a certain proportion of cross-linked sodium hyaluronate and sodium hyaluronate is selected, wherein the cross-linked sodium hyaluronate can be cross-linked sodium hyaluronate gel obtained by a cross-linking mode disclosed in BDDE or DVS or documents, and the viscosity average molecular weight of non-cross-linked high-molecular sodium hyaluronate is more than 100 ten thousand.
More preferably, the weight ratio of the cross-linked sodium hyaluronate to the non-cross-linked high-molecular sodium hyaluronate is 1: 0.1-10;
more preferably, the weight ratio of the cross-linked sodium hyaluronate to the non-cross-linked high-molecular sodium hyaluronate is 1: 0.2-1.
The self-expanding uterine cavity anti-adhesion repairing device provided by the invention can be added with active compounds in the outer degradable micro-nano fiber membrane or the inner core membrane, and specifically comprises the following components: anti-infective drug, growth factor for promoting skin growth, vascular endothelial growth factor, collagen, polypeptide, amino acid, chondroitin sulfate, heparin, small molecule drug with biological anti-inflammatory activity, active component for promoting wound healing, drug for treating uterus diseases, and contraceptive drug.
The self-expanding uterine cavity anti-adhesion repair device is used for postoperative spun-bonded connection or perfusion administration, can be placed in a syringe and pushed into a uterine cavity, and can also be placed after being clamped by a special clamp for a doctor.
Further, the preparation material of the degradable micro-nano fiber membrane also comprises a high molecular material for promoting wound healing and a small molecular drug with biological anti-inflammatory activity, wherein the anti-inflammatory drug specifically comprises an antibacterial anti-inflammatory drug, and the current clinical common materials mainly comprise the following types: antibiotics, sulfonamides, metronidazole, antifungal and Chinese patent medicine. Such as beta-lactam antibiotics: 1. penicillin antibiotics such as penicillin G, penicillin V, procaine penicillin, amoxicillin, ampicillin, mezlocillin, carbenicillin, imipenem (tylon), meropenem, and panipenem; 2. cephalosporin antibiotics: such as cephalexin (pioneer 4), cefazolin sodium (pioneer 5), cephradine (pioneer 6), cefadroxil, ceftriaxone sodium (Junbizhi); 3. hydrocarbon and penems such as imipenem; 4. monocyclic antibiotics such as aztreonam; fluoroquinolone antibiotic drugs such as ciprofloxacin, ofloxacin, norfloxacin, levofloxacin hydrochloride, gatifloxacin; 5. macrolide antibiotics: such as roxithromycin, azithromycin, clarithromycin; 6. aminoglycoside antibiotics: gentamicin, amikacin, micronomicin; 7. other antibiotics, and the like, and also Chinese patent medicines such as: yunnan Baiyao, sanjin tablet active ingredients commonly used for anti-infection, shuanghuanglian oral liquid commonly used for upper respiratory infection and injection thereof, lianpu Shuangqing tablet active ingredients, bezoar antitoxic pill (tablet) active ingredients, andrographis paniculata tablet active ingredients, yinhuang capsule active ingredients, yankening capsule active ingredients and the like.
The polypeptide or protein active ingredients for promoting wound healing comprise Epidermal Growth Factor (EGF) transforming growth factor beta superfamily (TGF), fibroblast Growth Factor (FGF), insulin-like growth factor (IGF) and the like.
One of the purposes of the invention is to design a degradable self-expandable uterine cavity anti-adhesion repair device capable of rapidly repairing the wound surface of a uterine cavity.
The anti-adhesion restorer consists of an outer-layer coating film made of a degradable micro-nano fibrous membrane and an inner-core membrane made of a water-swellable absorbable high-molecular material, and is in a uterus-like shape, the inner-core membrane is sealed in the outer-layer coating film, the outer-layer coating film (marked 1 in figure 1) is in a uterus shape (shown in figure 1) made of the micro-nano fibrous membrane, the diameter range of fibers of the micro-nano fibrous membrane is 10nm-10um, the length is 30-70mm, the width is 30-65mm, the thickness range is 0.01mm-0.5mm, and the selected material is a degradable high-molecular material, preferably a degradable polyurethane material; the size of the inner core membrane (marked 2 in figure 1) is smaller than that of the outer layer envelope, the inner core membrane is sealed by two layers of micro-nano fiber membranes, the thickness of the inner core membrane is 0.1-2mm, the liquid absorption multiple is more than 10 times of the self weight, and the degradable polyurethane micro-nano fiber membranes have the effect of inducing the rapid repair of the intrauterine membrane.
The second purpose of the invention is to provide a preparation method of a degradable self-expanding uterine cavity anti-adhesion repairing device which can be industrialized
Usually, the advancing speed of electrostatic spinning of the nano-fiber is 0.2-4mm/h, the diameter of the obtained nano-fiber is about 200-500nm, the production efficiency of the spinning speed is too low to meet the requirement of the cost performance of an industrial product, therefore, the research and development team of the invention tests the micro-nano fiber membrane obtained at different advancing speeds, and finally screens the micro-nano fiber membrane with the fiber diameter range of 0.1-5 um (an electron microscope photo is shown in figure 4) as the outer layer envelope of the restorer of the invention, and the performance requirement of the outer layer membrane of the uterine cavity anti-adhesion restorer of the invention can be met through the test, because the advancing speed is improved to 10-30mm/h, the spinning efficiency is greatly improved, the requirement of the industrial product cost performance can be met, and the specific preparation method is exemplified as follows;
(1) Dissolving degradable polyurethane material or PLGA in a mixed solution of chloroform and DMF to prepare a solution with the concentration of 10-15%;
(2) Adopting an electrostatic spinning process, wherein the spinning speed is 10-30mm/h, the voltage is 15-30V, and the receiving distance is 15-20cm, so as to prepare a degradable micro-nano fiber membrane with the fiber diameter of 0.1-5 um and the thickness of 0.02-0.2 mm;
(3) Cutting the mixed membrane of the cross-linked sodium hyaluronate and the high-molecular non-cross-linked sodium hyaluronate into a size smaller than that of the outer coating;
(4) And (3) wrapping the sodium hyaluronate membrane in the step (2) in the micro-nano fibrous membrane, and cutting, heating and sealing the edges by using a die to obtain a product similar to the uterus.
The third purpose of the invention is to provide a slow-release administration device for the infusion administration in the uterine cavity
The intrauterine infusion administration is a common treatment method for improving the embryo implantation success rate and chronic intrauterine inflammation, but no administration device capable of absorbing the medicament to form a medicament storage and slowly releasing is available in the market, and the intrauterine infusion treatment can be only adopted for multiple times in clinic, so that the clinical cost and the pain of patients are greatly increased.
The restorer developed by the invention can absorb liquid more than 10 times of the self weight, can meet the absorption of most medicaments with 4 times of administration dosage, forms a medicament storage, and can achieve the clinical expectation of one-time perfusion and slow release about one month.
The using method comprises the following steps: for a patient needing treatment, medicines with treatment dosage of more than 4 times are filled into a uterine cavity, the repairing device is placed into the repairing device, the repairing device absorbs liquid medicine in the uterine cavity to expand, the medicines are sucked into the inner core membrane to form a medicine storage, gel of the inner core membrane slowly seeps out of gaps of the outer layer micro-nano fiber membrane, meanwhile, the gel slowly leaks out in the degradation process of the outer layer micro-nano fiber membrane, and the medicines are released along with the seepage of the gel, so that the effect of continuous administration of the uterine cavity is achieved, and the repairing device is a drug administration device with great clinical potential.
The beneficial effects of the prosthetic device of the invention are summarized as follows:
1. the restorer comprises an outer layer envelope made of degradable micro-nano fiber membrane and an inner core membrane made of water-swellable high polymer material, wherein the inner core membrane is sealed in the outer layer envelope, and the restorer is in the shape of uterus (shown in figure 1), and has a length of 30-70mm, a width of 30-65mm and a thickness of 0.1-2mm.
2. According to the uterine cavity anti-adhesion restorer, the inner core membrane can absorb liquid more than 10 times of the self weight, the restorer expands to the size of a uterus after absorbing the liquid, the micro-nano fibrous membrane which props the outer layer is closely attached to the surface of a uterine cavity wound, micro-adhesion formed in the contraction process of the surface of the uterine cavity wound is effectively prevented, and therefore the formation of endometrial scar tissues is inhibited, uterine contraction can be effectively inhibited, and pain of a patient is relieved.
3. After the inner core membrane absorbs water and expands, the micro-nano fiber outer layer coating completely covers the inner wall of the uterus to form a wound surface protection film, so that a healing environment of the wet dressing is formed, and the repair of the wound surface is promoted.
4. For the patient needing to be infused for treatment, the treatment medicine can be infused into the uterine cavity, and then the restorer of the invention is put into the uterine cavity, the restorer can absorb the medicine in the uterine cavity and expand to the size of the uterus to form a slow-release medicine storage bank, the medicine is slowly released in the process of gel exudation, and the effective medicine concentration is maintained, thereby the effective local treatment is carried out on the uterine cavity diseases.
Drawings
FIG. 1 is a schematic structural diagram of a self-expandable uterine cavity anti-adhesion prosthesis;
FIG. 2 is a photograph of a self-expanding uterine cavity anti-adhesion prosthesis product;
FIG. 3 is a photograph of the product after the self-expandable uterine cavity anti-adhesion prosthesis absorbs water and expands;
FIG. 4 is a scanning electron microscope photograph of the micro-nano fiber film;
fig. 5 is a drug release curve of the uterine cavity anti-adhesion restorer A, B, C and D after absorbing drugs, the abscissa is different sampling time points, and the ordinate is drug content.
Description of the reference numerals:
1. coating the outer layer; 2. an inner core membrane.
Detailed Description
In order to make the technical problems, technical solutions and advantages of the present invention more apparent, the following detailed description is given with reference to the accompanying drawings and specific embodiments.
As shown in fig. 1-3, the invention provides an anti-adhesion restorer which is composed of an outer layer envelope 1 made of degradable micro-nano fibrous membranes and an inner core membrane 2 made of absorbable polymer materials capable of swelling by absorbing water, the inner core membrane is sealed in the outer layer envelope, wherein the outer layer envelope 1 is in the shape of a uterus made of the micro-nano fibrous membranes, the diameter range of the micro-nano fibrous membranes is 10nm-10um, the length is 30-70mm, the width is 30-65mm, the thickness range is 0.01mm-0.5mm, and the selected materials are degradable polymer materials, preferably degradable polyurethane materials; the size of the inner core membrane 2 is smaller than that of the outer layer envelope, the inner core membrane is sealed by the two layers of micro-nano fiber membranes, the thickness of the inner core membrane is 0.1-2mm, the multiple of absorbed liquid is more than 10 times of the self weight, and the degradable polyurethane micro-nano fiber membranes have the effect of inducing the rapid repair of the intrauterine membrane.
Example one, selecting different biodegradable materials to screen micro-nano fiber membrane degraded in 7-15 days
The degradable biological material is provided by Zhuhairui spreading biological material company Limited, the soft end and the molecular weight are shown as the following chart, LDI and 1, 3 propylene glycol are adopted in the hard end, the number average molecular weight (Mn) is between 7-8 ten thousand, a mixed solvent of chloroform and DMSO is used for preparing a 12.5% solution, an electrostatic spinning process is adopted, a micro-nano fiber film with the thickness of 0.05mm is obtained under the process conditions of voltage 25V, spinning speed of 10mm/h and receiving distance of 20cm, the degradable polyurethane main structure and the micro-nano fiber film for preparing the micro-nano fiber film are soaked in physiological saline at 37 ℃ for 5-20 days, and the test phenomenon is observed and shown as the following table:
weaving machine Number (C) | Material | Soft segment | Soft end point Quantum of | Mn | Soaking 5 Sky | Soaking for 10 days | Soaking for 15 days | Soaking for 20 days |
1 | Hydroxyl-terminated polyurethanes Esters | PEG400 initiated CL | 1500 | 7.2 | Complete (complete) | Without obvious change Transforming | Complete soft and soak solution Become turbid | Complete softness, thinness and flocculent Article (A) |
2 | Capping with arginine ethyl ester Of (2) a polyurethane | PEG400 initiated CL | 1500 | 7.4 | Complete (complete) | Without obvious change Transforming | Complete soft and soak solution Become turbid | Wholly soft, thin and flocculent Article (A) |
3 | Collagen tripeptide termination Of (2) a polyurethane | PEG400 initiated CL | 1500 | 7.7 | Complete (complete) | Without obvious change Transforming | Complete softening and soaking liquid Become turbid | Wholly soft, thin, flocculent Article (A) |
4 | Hydroxyl-terminated polyurethanes Esters | PEG400 initiated PDO | 1500 | 7.5 | Is complete, Become turbid Turbidity to the body | Has a flocculent shape Material and film soft Soft | Broken into slag | Into turbid liquid |
5 | Hydroxyl-terminated polyurethanes Esters | PEG400 initiated GA | 1500 | 8.0 | Complete (complete) | With flocculent shape Object and film change Hard | Broken into slag | Into turbid liquid |
6 | PLGA(LA:GA=7: 3) | - | - | 7 | Complete (complete) | Has a flocculent shape Object and film change Hard | Become hard and split into a plurality of pieces | Into turbid liquid |
7 | PPDO | - | - | 7.5 | Complete (complete) | Has a flocculent shape Object, film crack Become several pieces | Cracked into slag | Into turbid liquid |
In conclusion, the degradable polyurethane micro-nano fiber films with the numbers 1, 2 and 3 are obviously degraded within about 15 days, the micro-nano fiber film with the number 4 is degraded within 5 days, and PLGA and PPDO show fragmentation type disintegration. The treatment of the uterine cavity chronic disease usually needs to maintain a medicament reaching a therapeutic dose in the uterine cavity for 7-15 days, the micro-nano fiber membrane should be kept complete within 7 days, the medicament is slowly released along with the slow seepage of non-crosslinked gel, the micro-nano fiber membrane starts to degrade after 7 days, the medicament is slowly released from the membrane along with the seepage of the crosslinked gel, the micro-nano fiber membrane is broken after 15 days, the medicament and the gel are discharged from the uterine cavity, and an ideal medicament releasing device should be the mutual synergy of the degradation of the micro-nano fiber membrane and the seepage of the medicament storage gel, so that the micro-nano fiber membrane is prepared by selecting the mixed materials with the numbers 1, 2, 3 and 4, and simultaneously, the influence of the proportion of the crosslinked sodium hyaluronate and the non-crosslinked sodium hyaluronate on the medicament releasing speed is very important.
EXAMPLE II preparation method of self-expanding uterine cavity anti-adhesion prosthesis
(1) Dissolving degradable polyurethane (numbers 2 and 4 in different weight ratios in example I, weight ratio shown in example three lists) in a chloroform DMSO mixed solvent to prepare a 12% solution, and obtaining a micro-nano fiber membrane with the thickness of 0.06mm by adopting an electrostatic spinning technology under the process conditions of voltage 25V, spinning speed 15mm/h and receiving distance of 20 cm;
(2) A mixed gel sheet of cross-linked sodium hyaluronate (swelling degree greater than 40) and sodium hyaluronate (viscosity average molecular weight 200 ten thousand) (weight ratio =1 and 1 2 );
(3) And (3) wrapping the micro-nano fiber film prepared in the step (1) with the cross-linked sodium hyaluronate film prepared in the step (2), cutting and thermally sealing by using a die, wherein the cross-linked sodium hyaluronate film is in the shape shown in the figure (1), and the product numbers are A, B, C and D, and the size is 5.5 multiplied by 6.5cm.
Example three: the samples A, B, C and D prepared in the second example are placed in clindamycin hydrochloride injection, and then the release behaviors of the samples are researched
Mixing 4 pieces of clindamycin hydrochloride injection (5ml,the absorbed injection is about 15mL, the prosthesis is expanded as shown in a figure (3), 4 mL of each solution is precisely measured at preset time intervals (1 day, 5 days, 10 days and 15 days), meanwhile, equal volume of water for injection is supplemented, the solution is taken out and centrifuged for 10 min at the rotating speed of 10000 r/min, after centrifugation is finished, supernate is taken as a test solution and is measured by HPLC, the drug release amount (unit: g) is calculated, a release curve is drawn and shown in a figure 5, and the sample number, the proportion and the drug release condition are shown in the following table:
repairing device | Example I weight ratio of No. 2 to No. 4PU | Weight ratio of crosslinked sodium hyaluronate to | 1 day | 5 days | 10 | 15 days |
A | 2:1 | 1:1 | 0.60 | 0.41 | 0.65 | 0.45 |
B | 2:1 | 1:2 | 0.80 | 0.85 | 0.51 | 0.1 |
C | 1:1 | 1:1 | 0.65 | 0.50 | 0.63 | 0.56 |
D | 1:2 | 1:1 | 0.57 | 0.71 | 0.86 | 0.20 |
The result shows that the gel in the restorers A, B, C and D is basically and completely leaked from the micro-nano fiber envelope within 15 days, the medicine is nearly completely released, the medicine release curve is shown in figure 5, the restorer A and C are relatively stable in medicine release speed, the restorer B is suddenly released, the analysis reason may be that the medicine is released too fast due to the overhigh proportion of non-crosslinked sodium hyaluronate, the restorer D is basically and completely released at the 10 th day, and the analysis reason may be that the degradation speed of polyurethane with the structure of No. 4 is overhigh, the gel is leaked, therefore, the crosslinked sodium hyaluronate is selected: the weight ratio of the non-crosslinked sodium hyaluronate is more than or equal to 1, and the polyurethane with the structure of the number 2: the weight ratio of the polyurethane with the structure of No. 4 is more than or equal to 1, and the medicine release within 15 days is ideal.
While the foregoing is directed to the preferred embodiment of the present invention, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (9)
1. The self-expanding uterine cavity anti-adhesion restorer is characterized by comprising an outer-layer envelope (1) made of a degradable micro-nano fiber membrane and an inner core membrane (2) made of a water-swellable high polymer material, wherein the inner core membrane is sealed in the outer-layer envelope, and the self-expanding uterine cavity anti-adhesion restorer is in a uterine shape, is 30-70mm long, 30-65mm wide and 0.1-2mm thick.
2. The self-expanding uterine cavity anti-adhesion repair device according to claim 1, wherein the outer layer envelope made of the degradable micro-nanofiber membrane is a micro-nanofiber membrane, wherein the fiber diameter of the micro-nanofiber membrane is 0.01um to 5um, and the thickness of the micro-nanofiber membrane is 0.01mm to 0.5mm; the thickness of the inner core membrane is 0.1mm-2mm, the length is 10mm-60mm, the width is 10mm-55mm, and the multiple of absorbing liquid is more than 10 times of the self weight.
3. The self-expanding uterine cavity anti-adhesion prosthesis according to claim 1 or 2, wherein the degradable micro-nanofiber membrane is made of one or two of degradable polyurethane, absorbable polyester, absorbable polyether and absorbable polyamino acid.
4. The self-expandable uterine cavity adhesion-preventing prosthesis according to claim 3, wherein the degradable micro-nanofiber membrane is made of a material selected from absorbable polyesters including polyglycolide, copolymers of polylactide and polyglycolide, and polycaprolactone-glycolide copolymers, such as: PLGA and PLGA ring-opened by polyethylene glycol; a polyethylene glycol ring-opened polylactic-co-glycolic acid (PLGA) polymer, wherein the PLGA polymer structure comprises PEG: LA: the GA comprises the following components in percentage by mass: 1; the degradable polyurethane PU is selected from polyester PU, specifically one or two combinations of polylysine PU, PU taking polymer diol synthesized by taking PEG, CL, PDO, LA and GA as main raw materials as a soft segment and taking lysine diisocyanate LDI as a hard segment, PU material taking lysine diisocyanate to crosslink polylysine, and PU material taking natural high molecular weight carboxymethyl cellulose or hyaluronic acid as a soft segment and taking lysine diisocyanate LDI as a hard segment.
5. The self-expanding uterine cavity adhesion-preventing prosthesis according to claim 3, wherein the degradable polyurethane is selected from polyethylene glycol, caprolactone CL, PDO, LA, GA with ring-opened small molecule diol, and LDI and the chain extender are polyurethane with soft end.
6. The self-expanding uterine cavity adhesion-preventing prosthesis according to claim 1 or 2, wherein the inner core membrane is made of a material selected from water-absorbent degradable polymer materials, comprising: alginate, modified alginate, alginate degraded into hexosamine and N-acetylglucosamine, high-molecular antibacterial water-absorbing material, polyamino acid, chitosan, polylysine, polyvinyl alcohol, carbomer, polyvinyl pyrrolidone, hyaluronic acid, cross-linked sodium hyaluronate, zinc hyaluronate, collagen, organic silicon, polypeptide and amino acid.
7. The self-expanding uterine cavity anti-adhesion prosthesis according to claim 1 or 2, wherein the inner core membrane is in the shape of uterus, trapezoid, ellipse or other irregular shapes, has a size smaller than that of the outer layer envelope, and is prepared from sodium hyaluronate, including: one or a mixture of a certain proportion of cross-linked sodium hyaluronate and sodium hyaluronate.
8. The application of the self-expanding uterine cavity anti-adhesion repair device is characterized in that the self-expanding uterine cavity anti-adhesion repair device is used for postoperative anti-adhesion or perfusion administration.
9. The utility model provides an use of anti-adhesion restorer of formula palace chamber of self-expanding, its characterized in that for absorb slowly release behind the treatment medicine of perfusing the palace chamber, be used for palace chamber local treatment, wherein, the treatment medicine of absorption perfusing the palace chamber is selected from anti-infectious medicine, the growth factor that promotes skin growth, vascular endothelial growth factor, collagen, polypeptide, amino acid, chondroitin sulfate, heparin, the micromolecular medicine that has biological anti-inflammatory activity, the active ingredient that promotes wound healing, one or more than two combination of the medicine of treating uterus disease, contraceptive.
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