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WO2003013552A1 - Matières d'embolisation contenant de la chitine et du chitosane et méthode de préparation associée - Google Patents

Matières d'embolisation contenant de la chitine et du chitosane et méthode de préparation associée Download PDF

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Publication number
WO2003013552A1
WO2003013552A1 PCT/KR2002/001443 KR0201443W WO03013552A1 WO 2003013552 A1 WO2003013552 A1 WO 2003013552A1 KR 0201443 W KR0201443 W KR 0201443W WO 03013552 A1 WO03013552 A1 WO 03013552A1
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Prior art keywords
embolic materials
chitosan
embolic
beads
chitin
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PCT/KR2002/001443
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English (en)
Inventor
Sang-Mun Han
Byung-Kook Kwak
Hyung-Jin Shim
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Sang-Mun Han
Byung-Kook Kwak
Hyung-Jin Shim
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Application filed by Sang-Mun Han, Byung-Kook Kwak, Hyung-Jin Shim filed Critical Sang-Mun Han
Publication of WO2003013552A1 publication Critical patent/WO2003013552A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/722—Chitin, chitosan

Definitions

  • the present invention relates to embolic materials comprising of chitin and/or chitosan, and method for preparing thereof, and more particularly, to functional embolic materials comprising of chitin and/or chitosan, which are harmless to humans, activation of immunity, gradually degradable in a blood vessel and which may be solidified a contrast media or an anticancer drug, and method for preparing thereof.
  • Embolization generally is, when obstruction or devascularization of blood vessels in organs or tissues are needed clinically, to occlude blood vessel by inserting a catheter into blood vessels and injecting embolic materials therefrom.
  • the embolic materials should effectively be occluded in the blood vessels at the treatment site, injected easily through the catheter and not pass through capillary vessels.
  • PVA particle is a permanent embolic material, which is nonabsorbable to the human body, however, it has demerits such as blood vessel revascularization, difficulty in being obtained of a uniform size due to its irregularity of particle size and shape, clogging in the catheter, and its high costs.
  • Such blood vessel revascularization may cause a relapse of lesions, and such irregular in shape of embolic materials like PVA particles causes difficulty in embolization of the blood vessels at the treatment site and such embolic materials pass though the blood vessels of lesions and may cause a patient to die by embolizing of a distant organ's blood vessels (mainly, pulmonary artery).
  • embolizing of a distant organ's blood vessels mainly, pulmonary artery.
  • the shells of crustaceans such as crabs or lobsters discharged from food processing, contain a large quantity of natural polysaccharide. It is known that such polysaccharide is a natural polymer which is produced at the rate of one hundred billion ton in one year and is degraded by life on this planet. Chitin or chitosan, derived from the shells of crustaceans having high biocompatibility and little of antigen, is easily decomposed by an internal enzyme in the body, easily obtained as a natural material causing inexpensive production cost and has no tumor induction or toxicity, which are necessary conditions for embolic materials; thus attention has been paid to its use as a medical material recently.
  • Chitin is mucopolysaccharide as nitrogen-inclusive polysaccharide, which exists in the shells of crustaceans and as a constituent material of a cell membrane of fungi. It exists as a form of glycoprotein in the human body and is obtained from removal of protein by an alkali treatment, and is not dissolved in water, organic solvent, or alkali solution. If it is hydrolyzed with acid, monosaccharide or oligosaccharide is obtained. Chitin is poly-N-acetyl-D-glucosamine which is
  • chitosan is a ⁇ -poly-D-glucosamine which is obtained by
  • alkali solution or melting alkali
  • Korea is a country rich in high-quality chitin or chitosan resources.
  • Recycling of waste into resources is of help to the protection of the environment, and furthermore, has an important meaning in a side view of the development of a new use of a new high-functional and high value added material.
  • chitosan has medical benefits in antibacterial, inhibition of tumor metastasis, anti-AIDS activity, anti-blood coagulation activity, reduction of blood cholesterol, and the cure of a burn, and the like.
  • Even chitinous substance in a cuttlebone is so highly biocompatible that its powder has been used as a hemostatic, or a treatment, for injury in the past. At present, it is being used clinically for an antipyrotic or bioabsorbable suture in Japan and Russia, and it is expected that the scope of its application will be expanded in the future.
  • embolic materials examples include gelfoam, PVA particle, coil, split balloon, anhydrous ethanol, N-butyl 2-cyano acrylate (NBCA), and the like.
  • NBCA N-butyl 2-cyano acrylate
  • Typical examples of commercial PVA particles which are most widely being used are Contour ® (PVA, Target Therapeutics, USA) and Ivalon ® (Laboratories Ingenor Inc., Paris), which occupies more than 80% of the world market.
  • These kind of embolic materials are the permanent particle embolic materials, which are nonabsorbable in the human body, and due to the irregularity of particle size and shape, it is difficult to obtain their distribution of a relatively exact average particle size compared to a spherical body, which makes it more difficult to accomplish an embolization to the blood vessel at the treatment site.
  • the embolic materials had moved to a distant organ (mainly pulmonary artery) and aroused any embolization, which resulted in a patient's death.
  • the solid particle embolic material which is biodegradable, are auto-thrombus, gelform, and the like, whereas the permanent embolic materials, which are non-biodegradable, are PVA particle, silicon sphere, glass, and the like.
  • the solid particle embolic materials has several problems such as clogging in the catheter, obstruction ofthe catheter, irregularity of particle size, and the like.
  • the first object of the invention is to prepare oval or spherical embolic materials having relatively uniform particle size, which have a perfect and efficient embolic effect in any blood vessels.
  • the second object ofthe invention is to prepare embolic materials with high biocompatibility without any adverse reactions because it is not possible to induce tumor.
  • the third object of the invention is to prepare embolic materials which can be suspended as respective particles without agglutination in a salt solution in order to be easily injected through a catheter.
  • the fourth object of the invention is to prepare embolic materials which may be easily delivered through a catheter in a solution as a carrier.
  • the fifth object of the invention is to prepare embolic materials which may efficiently occlude the blood vessel to be embolized.
  • the sixth object of the invention is to provide embolic materials which do not pass through capillary vessels.
  • the seventh object of the invention is to provide blood vessel embolic materials which can cause more or less inflammation in any vessels and as a result, easily perform embolization.
  • the eighth object of the invention is to provide blood vessel embolic materials which are degradable and absorbable with the embolic materials, or not, with the lapse of time after embolization.
  • the ninth object of the invention is to provide functional embolic materials which can immobilize contrast media and/or anticancer agent.
  • the tenth object of the invention is to provide a method for preparing the embolic material according to the foregoing first to ninth objects.
  • substantially spherical embolic materials comprising of chitosan.
  • embolic materials comprising of chitin and/or chitosan particles.
  • substantially spherical functional embolic materials comprising of chitosan and/or chitin, which are solidified with contrast media and/or anticancer agent.
  • a method for preparing chitosan beads comprising the step of: passing chitosan solution of lactic acid, acetic acid, or hydrochloric acid through a capillary blowing air under pressure to obtain chitosan microdroplet of a desired size, and then precipitating it into a solidifing solution to form chitosan beads, which solidify the chitosan into the uniform particle size and shape.
  • Fig. 1A and Fig. IB are, respectively, a whole and an essential part schematic view for explaining the method for preparing embolic materials according to the invention.
  • Fig. 2 is an enlarged microphotograph of the conventional PVA particle
  • Fig. 3A and Fig. 3B are, respectively, an enlarged microphotograph of a
  • Fig. 4A and Fig. 4B are, respectively, a microphotograph and a naked eye
  • Fig. 5 is an enlarged picture of functional chitosan embolic material according to the invention with catheter and solidification of Doxorubicin • HC1 as an antineoplastic agent.
  • Fig. 6A and Fig. 6E are pathological report pictures of rabbit renal showing the results of experimental example 7, respectively.
  • Blood vessel embolic materials comprising of chitosan and/or chitin of the present invention are polymers derived from nature, which are harmless to human body, activation of immunity, and are gradually degradable in a blood vessel.
  • chitin and chitosan particles used in the present invention although it is not intended to be limited regarding chitin' s number average molecular weight, it is the range of about 400 thousand to 1 million and chitosan number average molecular weight is the range of about 20 thousand to 400 thousand, preferably about 100 thousand to 200 thousand although it is not intended to be limited regarding it. Also, it is desirable to use chitosan whose deacetylation
  • the viscosity of chitosan when forming chitosan beads is the range of 2 to lOOcps, preferable of 5 to 86cps, the most preferable of 5 to 20cps, and
  • the concentration of chitosan is the range of 0.5 to 10.0%(W/V), preferable of 1.5 to
  • the blood vessel embolic materials comprising of chitosan and/or chitin of the present invention are, in concrete terms, chitosan and/or chitin particles of a relatively uniform average diameter in specific ranges, preferably spherical chitosan beads of a relatively uniform average diameter in specific ranges, which are able to suspend for a constant time in a salt solution only or mixture with a contrast media or an anticancer agent, which the suspended particles do not clump up to each other, which pass through a catheter easily, which easily occlude the blood vessel to be embolized, and which do not pass through a capillary.
  • the blood vessel embolic materials comprising of chitosan and/or chitin of the present invention may be formed as chitosan and/or chitin particles having a uniform particle size range by sieving after grinding chitosan and/or chitin, preferably as spherical beads having a relatively uniform average diameter in specific ranges by dissolving chitosan in an appropriate solvent.
  • Such chitin and/or chitosan particles are able to be isolated in order to have an average particle size of a specific range by grinding and subsequent sieving, which can easily be performed by those skilled in the art; therefore, the specific explanation is omitted hereon.
  • the viscosity and the concentration of chitosan in preparing chitosan beads preferably used for the invention are important factors to form spherical embolic materials, and the range thereof are as mentioned above. It is desirable to wash the embolic materials of the form of beads according to the invention, with distilled water several times in order to remove solidification agents such as a sodium hydroxide solution.
  • the storage stability and the utility convenience of the embolic material, according to the invention may be improved by freeze-drying in a
  • Fig. 1A and Fig. IB are, respectively, a whole and an essential part of a schematic view for explaining the method for preparing embolic materials according to the invention and an apparatus for preparing the blood vessel embolic materials of the invention includes a solution storage bath (not shown in the drawings), a carrying conduit 3 of chitosan solution, an air carrying conduit 6, several micro needle-shaped capillaries 5 branched from the conduit 3, and a solidification bath 8.
  • the chitosan bead 1 for the embolization according to the invention is prepared by dissolving chitosan having specific ranges of the deacetylation rate and the viscosity in lactic acid, acetic acid or hydrochloric acid solution with a concentration of 1 to 10%(w/v) and filtering it, and then compulsorily transferring the solution 10 by a pump 2 through the conduit 3 and the micro needle-shaped
  • capillary 5 having the inside diameter of 50 to lOOO m, which is severally branched
  • the numeral number 4 denotes a capillary supporter.
  • the chitosan beads 1 for embolization according to the invention pass through the capillary 5 and then are loaded in the solidification bath 8.
  • the solidification solution in bath 8 it is necessary to select one or a mixed solvent, to show the high solidification speed of chitosan and to prepare more perfect spherical chitosan beads.
  • Such preferable examples are a mixture of water, ethanol and sodium hydroxide or potassium hydroxide, although the invention is not limited thereby, and it is possible to use these appropriate solvents individually, or mixing optionally.
  • the mixture ratio may be a range of 1 : 0 - 18 : 4 - 24.
  • the chitosan solution 10 is coagulated in the solidification bath 8 and formed as beads for embolization of the invention. Although the intention is not to be limited on the average diameter of
  • beads of the invention may be a range of 0 to lOOO m, or 150 to 500 ⁇ m, or 150 to
  • the chitosan beads of the invention are required to have a superior suspension in a salt solution, a mixed solution of a salt solution and a contrast media and/or an anticancer agent, which guarantees a good passing property in the catheter. It is desirable that the chitosan bead embolic materials of the invention are able to suspend in a physiological salt solution for longer than 30 minutes if the diameter of
  • a bead is 50 to 350jum, and for longer than 5 minutes if it is 350 to 500 m or more.
  • the preferable viscosity of chitosan liquid when preparing chitosan beads of the invention is a range of 5 to 86cps, and the preferable
  • concentration of chitosan is generally a range of 1.5 to 5.5% (W/V), although it
  • the embolic materials have weak cohesion in a physiological salt solution or a mixed solution with other substances, and the embolic materials ofthe invention do not clump up in a physiological salt solution and a mixed solution with the contrast media.
  • the chitin and/or chitosan particle of the invention is principally irregularity, but smoothly passes through a catheter in a carrying solution as a carrier and tend to clog the catheter, because, it is assumed, the penetration of water is noteasily into the inside of particles and, since the amino group is not positioned outside, the static electricity load is small.
  • HMDC hexamethylenediisocyanate
  • glutaraldehyde glutaraldehyde
  • epichlorohydrine hexamethylenediisocyanate
  • HDMC hexamethylenediisocyanate
  • the cross-linking agent can be used within a range of 10% of chitin and/or
  • the cross-linking process can be carried out by adding chitosan beads to acetic acid liquid, adding glutaraldehyde to the above solution, stirring it for 24 hours under room temperature, and then reducing the schiffe base by adding NaBH 4 until pH is adjusted to be neutral.
  • epichlorohydrine as the cross-linking agent, it is possible to cross-link by adding chitosan beads to sodium hydroxide solution and then adding epichlorohydrine to it and then stirring it for 24 hours under room temperature.
  • the chitosan and/or chitin embolic materials of the invention could be prepared to functional embolic materials, which absorbes various kinds of contrast media for angiography or anticancer agent.
  • the contrast media is absorbed and solidified to the embolic materials of the invention by partially cationizing the chitosan and/or chitin, substituting ethanol for it, adding a certain amount of contrast media, or anticancer agent to it and then removing ethanol from it under vacuum or reduced pressure, it is possible to obtain a radiograph of embolic materials by irradiation with radiation or to absorb and solidify the anticancer agent.
  • Chitin and chitosan which were purchased in a flake state were boiled in a sodium hydroxide solution to remove remaining protein, and to remove heavy
  • ethylenediaminetetraacetate(EDTA-4Na) washed by a neutral detergent, dried, intermittently ground by a grinder (Hoodmixer FM-681, Han-il Electricity Co., Ltd., Korea), and then sieved by a micro sieve (Chung-Kye Industries, Ltd., Korea) in order to obtain particles of a uniform size.
  • Polyvinylalcohol(PVA) (tread mark: Contour, Target Therapeutics,
  • PVA are represented in Fig 2A. As shown in Fig. 2 A, it was confirmed that PVA has an irregular size and shape.
  • Chitosan beads or chitosan coagulant were prepared by the apparatus for manufacturing chitosan beads as illustrated in Fig. 1A and Fig. IB, using various chitosan solutions whose chitosan number average molecular weight is more than
  • the mark X on the shape indicates a case of not forming beads while the mark O indicates a case of forming beads.
  • Suspending properties were decided by suspended time in a mixed solution of a physiological salt solution (2.5ml) and contrast media (2.5ml, Trade name: Hexabrix, containing ioxaglate sodium, 320mg
  • the mark O indicates a case of suspended time for longer than 30 minutes if the
  • average diameter is 50 to 350 m, and for longer than 5 minutes if it is more than
  • Catheter passage is decided on whether or not to pass without causing
  • Fig. 4A and Fig. 4B are a microphotograph and a naked eye photograph of chitosan beads of Example 13, respectively. Examples 19 to 25 and Comparative Example 2
  • chitosan solution having 9.8 cps of the chitosan viscosity, 4% (w/v) of the chitosan
  • CONTOUR® polyvinyl alcohol, Target Therapeutics
  • Example 2 particles of Example 2 in group 3, 150 to 250 m of chitosan beads of Example 7 in
  • the chitosan bead was cross-linked according to the method as described in Example 27.
  • Rabbits were anesthetized by an intramuscular injection of 35 mg/kg of Ketara®(Ketamine, Yuhan Corporation, Seoul, Korea), and 5 mg/kg of Rompun®(Xylazine, Bayer Korea, Seoul, Korea).
  • a 4F angiography cobra catheter (Terumo, Tokyo, Japan) was inserted through the right femoral artery and the right renal artery was selected.
  • the contrast media was injected into the renal artery under the irradiation of radiation to examine angiography.
  • the embolization of the renal artery was continued by the prepared embolic materials until complete occlusion of a blood vessel was accomplished.
  • lOOmg/kg of Ceftexole Sodium®(Shin Poong Pharm. Co., Ltd, Seoul, Korea) was daily injected by an intramuscular injection.
  • Biochemical examination was conducted on BUN, creatinine, total bilirubin, GOT, GPT, alkaline phosphatase, total protein, albumine, A/G ratio, LDH, CPK, glucose, total cholesterol, amylase, electrolyte (Na, K, Cl).
  • group 4 the cloggong of a catheter in examination on a catheter after the operation in one sample (16%) was observed.
  • Embolization was successful on all the 24 rabbits.
  • the pathological report with the naked eye indicated that in PVA (group 1) case, a hard and contracted renal was observed after the second week. With chitosan beads, it was observed on the fourth week in group 2, the eighth week in group 3, and the fourth week in group 4, respectively.
  • Embolic materials were not absorbed until the eighth week. It was observed that blood vessels were occluded by the embolic materials, and it showed an acute inflammation change and an organization, and then turned back to revascularization. The embolic materials showed a coagulation necrosis and were contracted making calcification and fibrosis. Compared with the case of PVA (group 1), the coagulation necrosis occurred later in the group of chitosan beads (groups 2, 3, 4), the beads became inflamed later and showed more severe vacuities than the case of PVA. There was no significant difference depending on the size of beads. Since chitosan beads have not been observed in the embolized renal after the tweentieth week, it was found that chitosan is degradable in blood vessels.
  • chitosan beads prepared by the aforementioned method it proved successful to intercept blood flow by inserting a catheter through the rabbit's right femoral artery and injecting embolic materials.
  • the embolized renal of the rabbit resulted from the test is shown in Fig. 6A to Fig. 6E, and the pathological findings on the rabbit renal is set forth in Table 3 and Table 4, respectively.
  • chitin and/or chitosan particles and chitosan beads which are natural biopolymers of the present invention are activation immunity, when they are injected into a blood vessel for embolization; it was observed that the leucocyte count increased between the fourth week and the eighth week, whilst it decreased in the case of PVA reversely.
  • embolic materials of the present invention especially chitosan beads, cause vasculitis, thickening of vessel wall occurs, which results in gradual stricture and occlusion of blood vessel lumen; therefore, it is possible to permanently occlude the desired blood vessel with the intention of embolic materials.
  • chitin and/or chitosan particles and chitosan beads are natural biopolymer, they are highly biocompatible, activation of immunity and biodegradable.
  • chitosan beads are spherical in shape, they seldom pass through a capillary vessel and may easily be embolized a designated portion due to their uniform size. Moreover, they have excellent catheter passage (utility).
  • Example 26 Method for preparing freeze-dried chitosan embolic materials
  • Example 17 shows the method for preparing wet chitosan embolic materials
  • Example 27 the preparation of cross-linked chitosan embolic materials Beads prepared in Example 26 have been washed by water to neutralize its pH and ethanol was substituted, and then 50ml of that has been dried, wherein its dry weight was 1.6g. It is necessary to cross-link this bead since it has weak intensity and is not easily restored to a round-shape after freeze-drying and it is dissolved in an acid solution.
  • beads which had been substituted with ethanol have been substituted DMF and added to 0.1 mol of HMDC per 1 mol of the amino group of chitosan. Then, it has been stirred slowly for 12 hours at room temperature. Any remaining have been removed by thorough washing using DMF and water.
  • Example 28 the preparation of chitosan embolic materials solidified to ioxaglic acid (trade name; Hexabrix, main ingredients; ioxaglic acid, contrast media for angiography, 320mg 1/ml, Taejoon Pharm., Co., Ltd, Korea)
  • Example 29 the preparation of chitosan embolic materials solidified to ioxitalamic acid contrast media for angiography (trade name; Telebrix, main ingredients; ioxitalamic acid, 300mg 1/ml, Taejoon Pharm., Co., Ltd, Korea)
  • Embolic materials of which ioxitalmic acid has been absorbed and solidified, have been obtained by adding 5ml of ethanol to lOOmg of chitosan embolic material of Examples 17, 26, and 27, substituting it twice under vacuum, adding 6ml of Telebrix thereto, and then removing ethanol and moisture under vacuum.
  • This contrast media for angiography is absorbed amino groups of chitosan and carboxyl groups of contrast media by ion exchange. It also applies to chitosan beads of Examples 17 and 27.
  • Example 30 the preparation of chitosan embolic materials solidified to Iohexol (trade name: Omnipaque, main ingredients: Iohexol, 350mg 1/ml, Nicomed Imaging A.S., Korea) contrast media for angiography
  • Embolic materials of which omnipaque has been absorbed and solidified, have been obtained by adding 3ml of ethanol to lOOmg of chitosan embolic material of Examples 17, 26, and 27, substituting it once under vacuum, adding 5ml of omnipaque thereto, and then removing ethanol and moisture under vacuum.
  • This contrast media for angiography is solidified by absorbing contrast media into chitosan molecular. It also applies to chitosan beads of Examples 17 and 27.
  • Example 31 the preparation of chitosan embolic materials solidified to Hydroiodic acid (Hydroiodic acid, Wacopure Chemical, Japan) Embolic materials, in which hydroiodic acid has been absorbed and solidified, have been obtained by adding 3ml of ethanol to lOOmg of chitosan embolic material of Examples 17, 26, and 27, substituting it three times under vacuum, adding 5ml of hydroiodic acid having a concentration of 320mg I/ml thereto, removing ethanol and moisture under vacuum, and then washing them by water until neutralized.
  • Hydroiodic acid Hydroiodic acid
  • This contrast media for angiography is solidified by ion exchange between iodine and amino group of chitosan from a combined amino group of chitosan and hydrogen ion of hydroiodic acid. It also applies to chitosan beads of Examples 17 and 27.
  • Example 32 Preparing chitosan embolic materials fixed to doxorubicin • HC1 (trade name: Ildong-Adriamvcin PFS Injection, main ingredients: doxorubicin • HC1, lOmg doxorubicin-HCl/5ml, Ildong Pharmaceuticals Co., Ltd, Korea) or epirubicin • HC1 (trade name: Ildong Pharmorubicin PFS Injection, main ingredients: epirubicin • HC1, lOmg epirubicin • HCl/5ml, Ildong Pharmaceuticals Co., Ltd, Inc..
  • Embolic materials in which doxorubicin • HC1 has been absorbed and solidified, have been obtained by adding 3ml of ethanol to lOOmg chitosan embolic materials of Examples 17, 26, and 27, substituting it twice under vacuum, adding 5ml of doxorubicin • HC1 thereto, and then removing ethanol and moisture under vacuum.
  • This contrast media for angiography is solidified by absorbing doxorubicin • HC1 into molecular chains of chitosan. It applies to chitosan bead of Examples 17 and 27 and doxorubicin • HC1 has been solidified by the same method.
  • chitin and/or chitosan embolic materials of the present invention are highly biocompatible blood vessel embolic materials, which may embody a perfect embolization without any adverse reactions and a good stability not to flow into the lungs through capillary vessels and which enable obtaining a radiograph for embolic materials themselves by absorbing contrast media into embolic materials, which may achieve revascularization with the lapse of time after embolization due to being degradable in the blood vessel, and which may efficiently occlude the desired size of blood vessels because they are able to be prepared in a relatively uniform size in the specific ranges. Further, they have no oncogenicity and they are favorable to embolization since they generate more or less inflammation in the blood vessels. If an anticancer agent is solidified to blood vessel embolic materials, blood vessel embolic materials which may be controlled the release of an anticancer agent into a uniform concentration for a long hour are prepared, and therefore it is expected to be effectively used for treatment of tumor.
  • Chitosan bead embolic materials according to the present invention can represent the embolization effect by occluding renovascular and inducing coagulation necrosis. Furthermore, compared with the conventional PVA particles, they show changes in an equal degree in blood test and biochemical examination, and they can be provided at a low cost.

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Abstract

L'invention concerne des matières d'embolisation utilisées pour l'embolisation du système vasculaire par insertion du cathéter dans le système vasculaire et injection des matières d'embolisation à travers le cathéter. L'invention concerne également une méthode de préparation desdites matières d'embolisation. Ces dernières contiennent des particules de chitine et/ou de chitosane ayant un diamètre moyen compris entre 50 et 1000 νm et des perles de chitosane sensiblement sphériques ayant un diamètre moyen compris entre 50 et 1000 νm. La méthode de préparation des perles de chitosane consiste à élaborer une solution de chitosane sous forme de micro-gouttelettes en pressurisant et en faisant passer un capillaire sous un flux de gaz inerte et à fabriquer des perles en précipitant lesdites micro-gouttelettes en un liquide de coagulation. Les matières d'embolisation selon l'invention sont des matières d'embolisation du système vasculaire sensiblement sphériques et à biocompatibilité élevée qui permettent de réaliser une opération d'embolisation parfaite entraînant une faible réaction aux corps étrangers, qui permettent d'adsorber et de fixer des agents médicinaux, tels que des milieux de contraste pour angiographie, ou un agent anticancéreux, sans faire passer de capillaire, qui sont dégradantes ou non dégradables dans le système vasculaire, qui présentent une taille relativement uniforme dans le cadre du champ régulé, qui ne présentent aucun pouvoir oncogène et qui sont plus ou moins inflammatoires.
PCT/KR2002/001443 2001-08-04 2002-07-30 Matières d'embolisation contenant de la chitine et du chitosane et méthode de préparation associée WO2003013552A1 (fr)

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US7449236B2 (en) 2002-08-09 2008-11-11 Boston Scientific Scimed, Inc. Porous polymeric particle comprising polyvinyl alcohol and having interior to surface porosity-gradient
US7501179B2 (en) 2005-12-21 2009-03-10 Boston Scientific Scimed, Inc. Block copolymer particles
CN101618021B (zh) * 2009-08-12 2011-04-06 河北科技大学 壳聚糖包覆药物缓释微球及其制备方法
CN102240268A (zh) * 2011-05-06 2011-11-16 河北科技大学 生物提取物京尼平交联壳聚糖包覆二苯乙烯类化合物的缓控释微球及其制备方法
CN102764456A (zh) * 2012-07-24 2012-11-07 上海交通大学 血管栓塞剂及其用途、制备方法
US20150224221A1 (en) * 2012-08-31 2015-08-13 Chung-Ang University Industry-Academic Cooperation Foundation Method for preparing microspheres for emboli, and method for preparing microspheres to which drug-containing carrier is bound
US9283035B2 (en) 2005-04-28 2016-03-15 Boston Scientific Scimed, Inc. Tissue-treatment methods
WO2016078339A1 (fr) * 2014-11-17 2016-05-26 中国科学院微生物研究所 Appareil, système et procédé pour générer des micro-gouttelettes de liquide et appareil d'analyse de cellule unique/molécule unique
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