CS272002B1 - Microembolization agent - Google Patents

Abstract

The present invention relates to microembolization which is particularly suitable for administration together with the drug in one system injection and infusion techniques, in human or animal veterinary medicine. The resource is formed polyanhydroglucuronic acid containing 1-24% by weight of carboxyl groups and / or its calcium, soda lime or potassium calcium or calcium potassium calcium salts in the form of highly porous particles o medium polymerization degree in the range of 10 to 200, a predetermined shape, and a size in the range 1.0. 10 ’to 5.0. 10 specific surface area ranging from 1 to 200 µg / g, physiological pH between 3.1 and 7.5 and controllable rate of their resorption in the body. The application of the composition is possible substantially shorten the treatment time and thereby reduce complications sometimes accompanying this treatment.

Description

The subject of the invention is a microembolizing agent, suitable in particular for administration together with a drug in one system by injection and infusion technique in human or veterinary medicine.

In the intra-arterial application of some drugs, especially highly concentrated cytostatics in the targeted treatment of cancer, locally focused on tumor tissue, it is necessary to slow vascular flow by blocking the vascular basin in order to reduce nutrition and significantly increase drug concentration in diseased tissue. This is achieved by embolization, especially microembolization of blood vessels. During temporary local blockage of the vascular basin by microembolization with simultaneous intraarterial drug administration, there is a temporary sudden local increase in the concentration of the drug in the blocked vascular bed and due to the transfer of the substance in the diseased tissue itself.

The choice of substances capable of embolizing the respective vascular system is quite wide, but most such materials show a number of unsuitable properties from the point of view of the organism's reaction or from the point of view of application.

Preparations usable for embolization must have high adhesion to the vascular endothelium, must not cause adverse reactions in the body, must have high hemostatic efficiency, suitable particle size and distribution, high sorption capacity and relatively easy degradability with the rate of degradation in the body as required, followed by time controllable resorption after function. In addition, it must allow the rapid removal of the embol formed and the restoration of bloodstream patency in the event of any symptoms of ischemia or the need to re-apply the cytostatic.

The literature mentions a number of polymeric substances, for example olefinic, acrylic polymers, polyvinyl chloride, polyacryloamide, polyacrylonitrile, polyurethanes, polyamides, polyesters, polysiloxanes, polyvinyl alcohol as well as cellulose derivatives, such as cellulose acetates or ethers. For example, V.P. Chuang: AJR 136: 729-733, April 1981 discloses the use of crushed polyvinyl alcohol-based foam. The current state is well documented by such patent document EP 0086 627, according to which it is suitable to combine the above-mentioned substances with plasma coagulation factors to ensure hemostasis.

A common disadvantage of these polymers is the fact that they are foreign to the organism, some irritating the tissues after application, so that they can cause a number of subsequent complications. They do not usually have a hemostatic effect on their own, which can be partially eliminated by the application of blood clotting factors, as mentioned above, but this leads to an increase in production operations and an increase in production costs. These materials are not resorbed by the body, which is another significant disadvantage.

It is also known to use biosorbable polymers, in particular based on polysaccharides, such as dextran, chitin, oxidized cellulose or on a protein basis, such as collagen or gelatin. The disadvantage of these preparations produced so far is the fact that it is difficult to prepare materials with the desired particle size distribution, usually with a low specific surface area, and thus with low sorption capacity, because they are mostly prepared by crushing and grinding solid homogeneous or foamed polymers. In use, they are difficult to disperse into the application solution, have a relatively high sedimentation rate, which makes use difficult. During the mechanical processing of solid polymers, they can also be contaminated with heavy metals by abrasion of the grinding device.

The rate of degradation of these materials by the body is usually random, so that imperfect closure of the arteries may occur due to rapid degradation, for example when using gelatin foam (V.P. Huang et al .: AJR 138: 289-294, February 1982). Sweat-based protein preparations can also cause adverse immunolagic reactions in the body.

Accompanying complications in microembolization techniques using some of the above-mentioned substances can be especially severe ischemic pain in overdose and sometimes their difficult elimination, then fever and transient change in liver function (VP Chuang and S. Wallace: Radiology 140: 51-58, July 1981).

CS 272 002 Bl

The use of autogenous tissue, such as autogenous blood clots, muscle tissue and the like, as a microembolizing agent is also known. The disadvantage of this method is again the relatively rapid dissolution of the formed thrombus, which leads to recanalization.

The above-mentioned drawbacks of the preparations themselves used for the given purpose, as well as the drawbacks occurring in the application of the microembolization technique, are eliminated by a microembolizing agent suitable especially for administration together with a drug in one system by injection technique in human or veterinary medicine. that the microembolizing agent consists of a polyanhydroglucuronic acid containing 1 to 24% by weight of carboxyl groups and / or its calcium, soda-calcium or dasalcium-calcium or sodium-potassium-calcium salt in the form of highly porous particles with a mean degree of polymerisation of 10 to 200, predetermined shape and size in -13 7 range 1.0. 10 to 5.0. 10 .mu.m, a specific surface area in the range of 1 to 200 m 2 / g, a physiological pH value in the range of 3.1 to 7.5 and a controllable rate of their resorption in the organism.

The term polyanhydroglucuronic acid in this context and in the following also means copolymers of anhydroglucuronic acid with anhydroglucose, characterized by the stated content of carboxyl groups and the value of the degree of polymerization.

Polyanhydroglucuronic acids and their calcium and calcium alkali salts for use for this purpose can be obtained by selective oxidation of cellulose with nitrogen oxides and another hydrolysis precipitation process according to MS. author's certificate No. 242 920. The microdisperse preparations prepared in this way show a number of excellent properties which predetermine them precisely for use in microembolization techniques, in particular for the treatment of cancer. Above all, they are easy to disperse into saline solutions and very low sedimentation rate, which allows easy application by both impact injection and infusion techniques. Another advantage is the fact that due to their inactivity to the drugs used, the microembolizing agent and the drug can be applied together in one system.

A great advantage confirmed by a number of tests is the full compatibility of the microdispersed hydrolyzed preparations to the organism in the doses that come into consideration during application.

A significant advantage of microdisperse polyanhydroglucuronic acid, prepared by a hydrolytic precipitation process with a high specific surface area of 1 to 200 m 2 / g, when used in microembolization techniques for the treatment of tumors is that due to their particle size, preferably 1 to 250 winter, they are safely embolized during application. arteries of minimal diameters. Over time, the microparticles agglomerate in the bloodstream, so that larger diameter arteries are blocked and when a sufficient number of preparations are applied, the total blood embolization of the tumor bloodstream with excellent embol adhesion and at the same time its inactivity to the vascular endothelium occurs. The river bed closure time also depends on the ratio of the extent of the saturated riverbed to the amount of agent applied. It can be controlled for several hours to several months.

The rate of degradation of the resulting embol can be influenced by the physicochemical properties of the preparation, in particular the degree of polymerization in the range of 10 to 200, preferably 10 to 50 and the content of carboxyl groups in the range of 24% by weight, so that microembolization can not an insignificant advantage of applying microdispersed hydrolyzed polyanhydroglucuronic acid.

Another significant advantage of these high specific surface area preparations with high sorption capacity is the high hemostatic efficiency, so they do not require anchoring of blood clotting factors, as evidenced by the cessation of bleeding in otherwise uncontrollable homorhagia in angiomatosis patients. to diethylammonium-1,4-dihydroxybenzenesulfonate (etamsylate) was the use of hydrolyzed microdisperse polyanhydroglucuronic acid in the form of calcium3

CS 272 002 Bl.

salt is safely stopped.

A very important property of the preparations applied for microembolization according to the invention is its high sorption capacity not only of body fluids but also other substances, for example contrast agents based on adduct formed by halogen addition, especially iodine to unsaturated fatty acids such as oleic, linoleic, linolenic, their esters, for example poppy seed oil. Sorption of these substances onto hydrolyzed microdisperse polyanhydroglucuronic acids used for microembolization facilitates X-ray monitoring of the course of treatment. These substances can be fixed to microdisperse preparations already during their preparation or, preferably, only during their application by introduction into a suspension system for microembolization together with drugs.

By applying hydrolyzed microdisperse polyanhydroglucuronic acid, the time of application of cytostatics to the tumor basin was significantly shortened and thus the complications that sometimes accompany long-term leaving of the vessel in the respective vascular bed were reduced.

The invention is the result of research work dealing with the selection of substances suitable for intra-arterial applications and the artificial obliteration of blood vessels in regional chemotherapy of cancer. The technique of angiographic and microangiographic examinations of patients and control injections showed high embolization efficiency and compatibility, further analysis of hydrolyzed microdispersed polyanhydroglucuronic acid by further analyzes of blood and urine.

The advantages of using hydrolyzed microdisperse polyanhydroglucuronic acid and its derivatives for the microembolization treatment technique according to the invention can be illustrated by the following examples, which give the specifications of the microembolizing agent and its complete use (% data represent% by weight):

Example 1

Specification: specific surface area particle size COOH group content Ca content pH of aqueous extract polymerization degree bound N _{2 content}

In a patient born in 1921 (63

98.5 m ² / g%: 2 to 10 μm%: 25 to 60 μm 12.38%

4.83% 4.92 42 '

0.09

t) a large tumor of unclear origin has been detected in the small pelvis. Angiography was performed, which showed that the tumor grows from the wall of the axial loop and fills the entire small pelvis in the range of 25 to 30 cm in diameter. The tumor was extremely hypervascularized and grew on the ureters and bladder wall. Microembolization of 0.15 g of the preparation in the form of a suspension in 10 ml of physiological solution together with a dose of 10 mg of the antibiotic cytostatic - Adriablastine was performed once. Already during the control injection, the disappearance of most of the pathological vascularization with blockade of the venous system for more than two hours was evident. Further targeted treatment was abandoned due to the need to first operatively record the finding. During surgery, the tumor was reduced to less than half its original size, a tissue sample was taken for histological examination, and due to its close relationship to the urinary tract, further targeted treatment was recommended. Histological examination revealed adenocarcinoma. As with surgery, new catheterization demonstrated tumor shrinkage, and further targeted treatment for 5 days with repeated microembolization resulted in tumor shrinkage such that only 8 cm of colon wall resection was performed during surgery, with residual tumor infiltration lining the intestinal wall to maximum width. 1 cm. The remaining ends of the large intestine could be connected to each other and ensure its normal function.

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Example 2

Specifications: specific surface 48.3 m ² / g particle size 40%: 2 to 10 .mu.m 50%: 40 to 60 .mu.m 10%: 80 to 90 .mu.m content of COOH groups 18.6% Ca content 3.7% sodium content 2.3% pH of the aqueous extract 3.8 • polymerization stage 33 bound N _{2 content} 0.19

A patient born in 1933 has been treated for real breast cancer since 1983. In May 1985, she was admitted for severe shortness of breath, which lasted for two months. She was treated with total cytostatics and hormones. The finding of problems gradually progressed. Upon admission, extensive changes in the lung parenchyma and hilums induced by tumor lymphongoitis were found on X-ray of the lungs. The patient was so short of breath that she was under oxygen for most of the day with repeated injections of bronchodilators. Targeted cytostatic treatment into the pulmonary veins with microembolization with a dose of 0.10 g of the above preparation in 5 ml of physiological saline was performed by a combination of three cytostatics. Extreme dyspnea gradually began to subside, the patient may have been without oxygen for some time, and later she was released for home treatment without signs of dyspnea.

Example 3

Specifications: specific surface area 7.1 m / g

particle size 20%: 59%: 8%: ' 13 % : 1 to 10 .mu.m 40 to 75 .mu.m 90 to 100 .mu.m 100 to 165, um content of COOH groups 9.0% Ca content 3.4% contents K 0.25 Oh, oh pH of the aqueous extract 4.1 polymerization stage 46

bound N _{2 content}

A patient born in 1900 was admitted for a large right forearm tumor evaluated histologically as histiocytoma. The tumor disintegrated and repeatedly bled massively from the arroded arteries and veins. A compression bandage was applied to stop the bleeding without much effect. The patient was severely anemic from repeated blood loss. Catheterization of the brachial artery was performed, and first, simple microembolization was performed by dispersing the above-specified microembolization preparation of the present invention in physiological saline. There was a rapid cessation of bleeding and later applied cytostatics led to tumor shrinkage without recurrence of repeated bleeding. · '

Example 4

Specifications: specific surface 74.5 m ² / g particle size 85% : 2 to 10 .mu.m 12% : 20 to 45 ZJm 3% : 70 to 90 zum content of COOH groups 13.9 O. * 0 Ca content 6.8 % pH of the aqueous extract 6.2

CS 272 002 B1 polymerization stage bound N _{2 content}

0.12%

A patient born in 1933 has been treated for angiomatosis for the past five years. He repeatedly bled uncontrollably mostly from the mucous membrane of the nasal cavity. In 1985, a mediastial tumor was identified, for which it was treated with actinotherapy and later cytostatics with microembolization. After the tumor had regressed, there was a long-term uncontrollable recurrence of bleeding, both from the nasal cavity and from the digestive tract. Targeted angiography showed involvement of small arterioles in the visceral region, and targeted microembolization by polyanhydroglucuronic acid microdispersion alone led to the cessation of bleeding in this location. Later, profuse bleeding from the nasal cavity occurred, which was resistant to all drugs that were still active. The above-specified hydrolyzed microdisperse polyanhydroglucuronic acid was administered in the form of a suspension in physiological saline repeatedly into a vein. The therapeutic effect was prompt with complete cessation of bleeding.

Example 5 Specifications: specific surface 1.5 m ² / g particle size 12.5 (μm) on average length 20 to 130 μm particle shape fibrous content of COOH groups 14.2% Ca content 5.6% content Na 0.6% contents K 0.2% pH of the aqueous extract 6.92 polymerization stage 48 bound N _{2 content} 0.04%

An 11-year-old boy developed hematuria lasting practically 6 months with fluctuations in bleeding intensity. Targeted angiography showed an arteriovenous shunt in the upper pole of the right kidney of clearly traumatic origin without signs of congenital malformations. After application of the above-specified microembolizing preparation according to the invention (approx. 0.5 g = 6 ml of preparation + 14 ml of physiological saline), the short-circuit angiographic disappearance occurred and hematuria disappeared within a clinical course within 48 hours. For 3 months, the kidney remained completely free of signs of hematuria.

The application of the above-described microembolizing agent according to the invention, illustrated by the above examples, is naturally not limited to the treatment of tumors. The range of treatments is quite wide, especially in cases of acute bleeding, whether bleeding with an inflammatory, traumatic or tumorous cause. The choice of the preparation, in particular as regards its specific surface area, salt type, carboxyl group content and particle size shape, which may be non-fibrous in nature with a basic particle size in the range of 0.1 to 15 .mu.m or in the range of 15 to 15,000 .mu.m. spherical or irregular in shape, formed by suitable agglomeration of basic particles or fibrous character with a fiber length in the range of 15 to 15,000 μm, depends on the angiographic finding determining the width of the vascular bed in which the bleeding occurs and the type of vascular basin needed for elimination, and from small arteries to arterioles, precapillary to capillaries.

In the course of research, it has also been found that microembolizing preparations based on hydrolyzed microdisperse polyanhydroglucuronic acid and their salts according to the invention can be used not only for targeted intraarterial obliteration, but in bleeding conditions bleeding can also be affected by general application.

Claims (1)

OBJECT OF THE INVENTION Microembolizing agent, particularly suitable for administration together with a drug in one system by injection and infusion technique in human or veterinary medicine, characterized in that it consists of polyanhydroglucuronic acid containing 1 to 24% by weight of carboxyl groups and / or its calcium, soda-calcium or potassium-calcium or a sodium potassium calcium salt in the form of highly porous particles with a mean degree of polymerisation in the range of 10 to 200, a predetermined shape and size in the range of 1.0. 10 - to 5.0. 10 .mu.m, 2 specific surface area in the range of 1 to 200 m 2 / g, physiological pH values in the range of 3.1 to t 7.5 and controllable rates of their resorption in the organism.