JPS63203605A - Stoppering composition for tube and cavity of human body - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates generally to medicine and has particular application to the filling of ducts and cavities in the human organism, such as the filling of pancreatic ducts, blood vessels, bronchi, cysts, abscesses or dental canals. Regarding the composition.

Compositions for use in occluding ducts and cavities of the human body must meet a number of specific requirements.

Such a composition must have the following characteristics:

1. Biocompatible 2. Low initial viscosity (less than 50 centipoise) 3. Fluid in air for at least 10 or 15 minutes and solid state within 1 to 3 minutes when injected into a tube or cavity Ability 4. Adhesiveness to the walls of tubes or cavities 5. Ability to be destroyed and removed from the organism within 1 to 3 months 6. Radiopacity 7. Preservative properties Silicone-based human composition for the occlusion of body canals and cavities (D, F, Bl
The magazine “Kliniches” by Agovidov et al.
Kayakhirurgia” (1982) No. 1
No. 1, pages 10 to 14) are known today.

These compositions are biocompatible, non-locally irritating, remain fluid in air for long periods of time, and are radiopaque (radiographically visible). However, the aforementioned compositions are too viscous to be injected into canals or cavities. Additionally, silicone-based compositions have no adhesion to the walls of the tube or cavity, allowing the preformed plug to “stick” away from the tube.
This is not effective as a surgical method because the plug may be "excluded" and re-channeled, or a space or passage may be formed between the plug and the wall of the vessel.

The long polymerization time (10 minutes or more) upon contact with body tissue increases the complexity of handling silicone-based occlusive compositions, and the possibility of reflux of the composition through the accessory pancreatic duct during surgery, resulting in non-occlusion of the pancreatic duct. It becomes complete. Since silicone-based compositions do not have preservative properties, they cannot undergo biodestructive processes and, after performing their function, become foreign bodies and become centers of infection.

Other compositions for the occlusion of the ducts and cavities of the human body based on alcoholic solutions of amino acids, namely prolamins (or called ethibrots), are also known to those skilled in the art.

The composition is characterized by a low initial viscosity, remains fluid in air for a long time, is radiopaque, and has preservative properties (Gebhardt Ch.)
5torte M by.

(See the literature in Arch, Chir, (1978) Vol. 346, No. 3, pp. 149-166)
. However, Etiblock has a fairly long curing time (15-20 minutes) when in contact with human tissue, resulting in regurgitation of the composition and ineffective surgical procedures. Furthermore, since Etibrothus is not adhesive to the wall of the tube, if the plug thus formed is removed or a space or passage is created between the plug and the wall of the tube or cavity, the tube can be rechanneled. Surgery has no effect. The composition may be destroyed and removed from the organism so quickly (within 11 to 14 days) that the pancreatic duct system may be rechanneled before complete atrophy, or the pancreatic duct may become obstructed and the pancreas may become obstructed. exocrine (exocrine)
In some cases, the tissue may atrophy incompletely. Additionally, Ethibrox has a short shelf life of 3 months, further impeding its application.

There are also known compositions for the occlusion of the ducts and cavities of the human body based on rapidly polymerizing monomers, namely α-cyanoacrylates, in particular esters of α-cyanoacrylic acid (Little J.M. ,) by Lan
er C, Surgery (1977) Vol. 81, No. 3, pp. 243-249).

The composition is a low-viscosity liquid that rapidly polymerizes into a thin film when it comes into contact with body tissue, and is biocompatible and biodegradable. The application of compositions based on α-cyanoacrylates for the occlusion of pancreatic ducts targeting the embolization of blood vessels is also known. It is generally known that cyanoacrylates polymerize rapidly (within seconds) upon contact with body tissue, resulting in incomplete occlusion of the vessel or cavity.

Alpha-cyanoacrylate polymerizes so quickly that it cannot polymerize uniformly within the vessel or cavity, resulting in the formation of discrete polymer agglomerates along the length of the vessel, rendering the performed surgery ineffective. Furthermore, when cyanoacrylate is used, the catheter through which the composition is injected sticks to the vessel wall. The preservative nature of cyanoacrylates and the fact that they lack any radiopacity add to the difficulties in handling such compositions.

Therefore, none of the currently used compositions having the aforementioned properties meet all the requirements imposed on materials for the occlusion of ducts and cavities of the human body.

Biocompatible and radiopaque, with low initial viscosity,
Long polymerization time (at least 10 minutes) when exposed outdoors
, the polymerization time within body ducts and cavities is optimal (1 to 3 minutes);
It is an object of the present invention to provide a composition for occluding ducts and cavities of the human body which is characterized by biodegradation in 1 to 3 months, has antiseptic properties and adheres well to the walls of ducts and cavities. This is the main and essential object of the present invention.

According to the invention, in addition to α-cyanoacrylate, it contains dimethyl sulfoxide, dimethyl ketone and a radiopaque organic acid, or a mixture of such acids, the weight percentages of these components being as follows: The said object is achieved by the fact that compositions are provided for occluding the ducts and cavities of the human body.

α-cyanoacrylate 25-42 dimethyl sulfoxide 12-25 dimethyl ketone
20-24 Radiopaque Organic Acids or Mixtures of Such Acids Containing 9-43 To increase the period during which the stopper retains solids, compositions for occlusion of ducts and cavities of the human body may further include: Molecular weight 15,000 to 25,000
The polyvinyl acetate may be doped in an amount of 5 to 11% by weight based on the total weight of the α-cyanoacrylate.

The ingredients shown in the above table, used in the proportions mentioned above, provide all the required physicochemical and medico-biological properties of the composition.

The composition of the present invention uses α-cyanoacrylate such as ethyl α-cyanoacrylate, ethoxyethyl α
- cyanoacrylates, or mixtures thereof.

The composition for occluding the ducts and cavities of the human body contains α-phenyl-β-(3,5-diiodo-4-hydroxyphenyl)propionic acid, 3-acetylaminomethyl-5 as a radioactive organic acid. -acetylamino-2,4,6-
3-iodobenzoic acid, or α-(3-amino-2,4,
6-) short benzyl)butyric acid.

When the content of α-cyanoacrylate is less than 25% by weight, the composition has no adhesive properties and biodegradation occurs in 15 to 25 days. α-cyanoacrylate content is 42% by weight
, the composition hardens very quickly upon contact with body tissue, with hardening times of less than 1 minute.

If the content of dimethyl sulfoxide is less than 12% by weight, the curing time of the composition on contact with body tissue will be long (4 or 6 minutes) and the composition will flow back. When the content of dimethyl sulfoxide exceeds 25% by weight, the polymerization time of the composition in air becomes shorter (10%).
(minutes or less), the composition becomes troublesome to handle. If the content of the radiopaque organic acid in the resin is less than 9% by weight, the resulting stopper is no longer radiopaque. If the content of the acid exceeds 44% by weight, the solidification rate of the composition upon contact with human fabric is slow and the solidity of the resulting plug is rather rapidly lost. The use of dimethyl ketone in the foregoing amounts along with the other components of the composition provides the necessary length of polymerization time of the composition in air upon contact with human tissue.

The compositions proposed herein for occluding ducts and cavities of the human body have been tested experimentally in animals and clinically in humans.

The efficacy of the composition on pancreatic duct obstruction was investigated in untreated pancreatic glands of sexually mature mongrel dogs weighing 6 to 35 kg. The method is as follows. A supramedian artery (supraa+edian) laparotomy is performed under intravenous hexenal anesthesia. Ligate the smaller (accessory) pancreatic duct. A polyvinyl chloride catheter is introduced into the larger (main) pancreatic duct from outside the duodenum to a depth of 0.3 to 0.5 cm and secured with a ligature. Inject 0.6 to 1 ml of the composition of the invention into the catheter within 30 to 50 seconds, simultaneously withdrawing the catheter and ligating the duct. As a control, pancreatic duct obstruction was measured using silicone elastomer and ethyl α-sial-
It was carried out according to the same method using

After performing the surgery, changes in the amounts of amylase, trypsin, immunoreactive insulin, C-peptide, and glucose were measured. Macroscopic and histological experiments were performed at various postoperative periods to study the rate of atrophy of the pancreas, the rate of degradation of the formed polymer, and the rate of occurrence of positive results.

The proportion of positive results is determined by the following relationship: where A is the number of animals with completely atrophied pancreas, and A is the total number of animals tested. . The atrophy rate is expressed by the formula V = - (where ■ in the formula is the atrophy rate, and t is the elapsed time until complete atrophy of the exocrine part of the pancreas, which is characterized by the absence of antral cells according to histological experiments) Determined from

The degradation rate of a polymer is the elapsed time until the formed polymer plug is completely broken down and removed from the organism. The rate of degradation is determined macroscopically for the absence of polymer in the main pancreatic duct during cadaver examination of the experimental animals.

The results obtained are summarized in Tables 1 and 2.

trypsin, immunoreactive insulin, C-peptide,
When studying changes in glucose content, no statistically reliable differences were found between the aforementioned compositions.

In a study of polymer degradation rates, the primary and secondary ducts as well as the main pancreatic duct were completely filled with polymer 15 days after surgery. The polymer was observed to remain in the main pancreatic duct as several clusters 1 to 1.5 months after surgery. No polymer was detected in the main pancreatic duct at the time of cadaver examination 2 or 3 months after surgery.

In a separate experiment, the applicability of the compositions of the invention for endoscopic occlusion was investigated. In experiments for this purpose, the duodenum was incised immediately after laparotomy.

Introducing a catheter into the main pancreatic duct through the duodenum to occlude the ducts and cavities of the human body,
A volume equal to the volume of the entire pancreatic duct system was injected without ligating the accessory pancreatic duct. As a control, a similar surgical procedure was performed using a silicone elastomer as the occlusive composition. Complete pancreatic atrophy occurred in 6 out of 7 dogs treated with the composition of the invention for pancreatic duct obstruction (rate of positive results 86%), but not when silicone elastomer was used for obstruction. Complete pancreatic atrophy occurred in only two of the six dogs tested (rate of positive results 33%).

Thus, the compositions of the invention for the occlusion of pancreatic ducts experimentally atrophy the exocrine part of the pancreas by about 100%, but do not affect the islets of Langerhans.

This is even more statistically valid compared to other compositions. The rate of atrophy of the exocrine portion of the pancreas is intensified. That is, the time required for complete atrophy of the antral tissue is reduced.

This fact is of utmost importance from the point of view of the clinical use of the compositions of the invention. Furthermore, acute pancreatic swelling was significantly reduced after the pancreatic duct was occluded using the composition of the present invention. The compositions of the present invention for the occlusion of ducts and cavities of the human body are more effective than silicone elastomers in experimental endoscopic occlusion of pancreatic ducts and have a higher rate of positive postoperative results. .

Compositions of the invention were also tested for efficacy in experimental vascular occlusion. Experiments were performed on 10 male rabbits weighing 3-3.5 kg under general ether anesthesia. 5
〜I Qmj! The composition was injected into the femoral artery using a catheter with a length of 30 to 50 G and a diameter of 1111 mm. Experiments have shown that the compositions can be easily injected into blood vessels with catheters of the aforementioned caliber and length, thereby demonstrating that the compositions can be administered into a variety of medium and small caliber blood vessels. The experimental animals tolerated the surgical method of injecting the composition into the femoral artery well, and no symptoms of general toxic effects were observed. A clear thrombotic effect was obtained in 100% of cases.

The compositions of the present invention for occluding ducts and cavities of the human body were tested on 17 patients undergoing treatment at three hospitals. According to the diagnosis, patients can be divided into the following groups:

Pancreatic groove outside the incision wound 4 Chronic pancreatitis 7 Pancreatic head tumor 4 Total hemorrhagic pancreatic necrosis 2 The patients' ages ranged from 28 to 73 years.

Patients underwent a general clinical examination, endoscopic retrograde pancreatocholangiography, and sonography of the liver, bile ducts, and pancreas before and after surgery.

An X-ray of the abdominal organs was also taken.

One patient (one of four patients with partial occlusion of the pancreatic groove and duct) had the ductal system rechanneled during the postoperative period, which required repeated occlusions. No other postoperative complications were observed. After occlusion of the sulcus canal, the patient's condition did not show any change using standard clinical examination methods. Sonographic examination showed induration and gradual reduction of the pancreatic segment with ductus. Radiographs show that the radiopacity of the composition for occlusion of human body ducts and cavities is maintained for 10 to 15 days after surgery, and radiological follow-up shows that the composition for occlusion of sulcus and pancreatic ducts and human It is possible to have post-operative control over the positioning of the composition for occlusion of body vessels and cavities. The average length of hospital stay for patients after surgery is 5 to 7 days.

Glucose tolerance tests performed 6 and 12 months after surgery showed normal function of the islets of Langerhans.

Seven patients underwent occlusion with the composition of the invention for severe conditions of chronic and difficult hepatitis. It was performed within the surgical period in 5 patients and endoscopically in 2 patients. The surgery involves laparotomy, duodenotomy, papillary sphincterotomy, catheterization of the main pancreatic duct, and total occlusion of the pancreatic ductal system with the composition of the invention for occlusion of ducts and cavities of the human body; A saif string suture was applied to the opening of the main pancreatic duct, and the catheter was tied tightly after retrieval. Endoscopic occlusion was performed after pancreatography to confirm the correct positioning of the catheter. In all operated patients, moderate hyperamylasia was observed within the postoperative period for an average of 4 postoperative days. No other postoperative complications were observed. All patients were pain free. X in abdominal organs
Radiographs showed that the radiopacity of the composition of the invention was maintained for 10 or 15 days after surgery. No cyst formation was detected by sonography.

All operated patients underwent subsequent control studies of islet function (i.e., glucose tolerance test) and no diabetes mellitus was present. The patient who underwent endoscopic occlusion was followed for more than 1 year, and no recurrence was observed.

In four patients, the remainder of the pancreas was occluded after resection of the pancreaticoduodenum due to tumors in the head of the pancreas. No complications were observed in the rest of the pancreas during the postoperative period, and no liver juices were dripped from the drainage ducts from the abdominal cavity. In two patients, small focal fatty pancreatic necrosis was observed during surgery, which was prevented after occluding the remaining pancreatic ducts of the pancreas with the composition of the present invention for occluding ducts and cavities of the human body. .

Two patients underwent occlusion of the pancreatic duct due to total hemorrhagic pancreatic necrosis. Laparotomy, cholecystectomy, resection of the papillary sphincter that penetrates the duodenum, and obstruction of the pancreatic duct were performed.

General clinical tests were performed during the postoperative period, and amylase and trypsin tests showed that the inflammation was progressing rapidly (1 or 2
The symptoms were shown to subside (within a week).

Intoxication phenomena were observed within 2 or 3 days.

No complications were observed in the pancreatic segment during the postoperative period, neither suppuration of pancreatic necrosis nor flow of liver juice from the drainage duct from the abdominal cavity was detected. Glucose tolerance tests were performed at 6 and 12 months postoperatively, and one patient's diabetes mellitus was in a mild state.

Moderately short-term toxicology experiments have shown that the compositions of the present invention are suitable for the occlusion of human body ducts and cavities as biological experimental materials (i.e., isolated red blood cells, isolated frog hearts, isolated No negative effects were observed when extracted from bull sex cells. The organismal functions of the experimental animals were not substantially different compared to those of the control animals (ie, CNS, liver, kidneys, etc.).

The compositions of the invention therefore pass all the requirements imposed on compositions for the occlusion of ducts and cavities of the human body. The compositions of the present invention are biocompatible, characterized by a low initial viscosity, remain fluid in air, can polymerize within 1 to 3 minutes within canals and cavities, and are It is characterized by good adhesion to organisms, is degradable and is removed from organisms within 1 to 3 months, and has good radiopacity and preservative properties.

Clinical trials of the compositions of the invention for the occlusion of ducts and cavities of the human body conducted by the applicant have shown that the compositions are convenient to handle and apply.

Injection of the composition may be tracked with X-ray imaging. The radiopacity of the compositions of the invention is maintained for 10 to 15 days post-operatively, allowing continued visualization of the composition's location within the vascular system. A subsequent glucose tolerance test (within 1 year after surgery) showed that the function of the islets of Langerhans was normal. No cases of incomplete obstruction of the pancreatic duct, recanalization of the ductal system, or cyst formation were observed during the long postoperative period (up to 1 year). The composition can be easily injected into an endoscope and polymerizes immediately after injection because of its low viscosity and the optimal polymerization time of the composition of the invention upon contact with body tissue. Application of the composition to pancreatic duct obstruction in total hemorrhagic pancreatic necrosis subsided the progression of inflammation and caused atrophy of the exocrine portion of the pancreas without the formation of empyema or cysts.

The method for producing a composition for occlusion of ducts and cavities of the human body is technically simple and carried out as follows.

The steps for manufacturing the composition of the present invention are as follows.

Alpha-cyanoacrylate is prepared alone or in a mixture, and then 5 to 10% by weight of dimethyl ketone is added thereto. The first component of the composition is thus obtained. An ioprime-containing radiopaque organic acid, or a mixture of such acids, is then provided, to which are added the remainder of the dimethyl sulfoxide and dimethyl ketone (remainder of the ratios used above).

The second component of the composition is thus obtained. Both of the aforementioned components can be stored for long periods of time (more than 1 year) at a temperature of 0±5° C. in a sealed container.

To produce a composition for the occlusion of ducts and cavities of the human body, both components are mixed immediately before use.

In order to better understand the invention, the following representative specific examples are provided below.

Example 1 The composition produced is characterized by the following weight percentages of each component:

Ethyl α-cyanoacrylate 12.5 Ethoxyethyl α-cyanoacrylate 12.5 Dimethyl sulfoxide 15 Dimethyl ketone
22α-phenyl-β-(3,
5-diiodo-4-hydroxyphenyl)propionic acid To a mixture of 380, 125 g of ethyl α-cyanoacrylate and 0.125 g of ethoxyethyl α-cyanoacrylate was added 1 g of dimethyl ketone, Get one ingredient. 0.15 g of dimethyl sulfoxide and 0.12 g of dimethyl ketone were then added to 0.38 g of α-phenyl-β-(3,5-diiodo-4-hydroxyphenyl)propionic acid and the ingredients were mixed thoroughly. to obtain the second component of the composition. The components thus obtained are stored for a long period of time at O±5℃ in a sealed container (
Can be stored for more than 1 year). Both ingredients are carefully mixed immediately before use.

The polymerization time of the composition thus obtained at 25° C. in air is 12 minutes. The polymerization rate of the composition upon contact with body tissue is 1.5 minutes. The composition was tested experimentally on an 8 kg mongrel dog. A laparotomy above the median artery was performed under general hexenal anesthesia. The accessory pancreatic duct was ligated. A catheter with a diameter of 1 mm was inserted into the main pancreatic duct through the duodenum and fixed by ligation.

The aforementioned composition was introduced into the catheter for 45 seconds, at the same time the catheter was withdrawn and the duct ligated. Dogs were fed a standard diet during the postoperative period. No complications were observed in the pancreatic region. A cadaver examination 45 days after the surgery noted atrophy of the pancreas and the absence of a plug in the main pancreatic duct. Histological examination detected complete atrophy of the antral tissue, but the islets of Langerhans were unaffected.

Example 2 The resulting composition is characterized by the following weight percentages of each component:

Ethyl α-cyanoacrylate 21 Ethoxyethyl α-cyanoacrylate 21 Dimethyl sulfoxide 12 Dimethyl ketone
243-acetylaminomethyl-5-acetylamino-2,4,6-3-iodobenzoic acid 22
A composition was prepared according to the method described in Example 1.

The polymerization time of the composition in air at 25°C is 11 minutes. The polymerization rate of the composition upon contact with body tissue is 1 minute.

The composition was clinically investigated in a 60 year old male patient who underwent surgery for total hemorrhagic pancreatic necrosis. The patient underwent choledochotomy, papillary sphincterotomy, and retrograde occlusion of the pancreatic duct with 1 ml of the composition of the invention for occlusion of ducts and cavities of the human body. Gradual infusion therapy was performed during the postoperative period.

No complications were observed in the pancreatic region during the postoperative period. The radiopacity of the composition, as determined by radiographs of abdominal viscera, remained until 15 days post-operatively, allowing the location of the composition to be tracked.

Example 3 The resulting composition is characterized by the following weight percentages of each component:

Ethyl α-cyanoacrylate 10 Ethoxyethyl α-cyanoacrylate 12 Molecular weight 15000
polyvinyl acetate 8 dimethyl sulfoxide
25 dimethyl ketone
21α-(3-Amino-2,4,6-3-iodobenzyl)butyric acid 24 composition is prepared by the method described in Example 1.

The polymerization time of the composition in air at 25° C. is 10 minutes, and the polymerization rate of the composition upon contact with body tissue is 2.5 minutes.

The composition was used and clinically investigated on a 46-year-old male patient P who had undergone surgery for cancer in the head of the pancreas. A radical Whipple pancreatoduodenotomy was performed and occlusion of the remaining ductal system of the pancreas was performed by injecting 3ml of composition for occlusion of human body ducts and cavities. It is noteworthy that the surgery removed a small focus of fat necrosis in the pancreatic tail region. The postoperative period was uneventful. Excessive amylasesis during the postoperative period was 5.
It was for days. No release of liver juice by the drainage ducts was observed during the postoperative period. The patient remained unsatisfied for 17 days after surgery.

Example 4 The resulting composition is characterized by the following weight percentages of each component:

Ethyl α-cyanoacrylate 15 Ethoxyethyl α-cyanoacrylate 10 Molecular weight 25,000
polyvinyl acetate 11 dimethyl sulfoxide 18 dimethyl ketone
203-Acetylaminomethyl-5-acetylamino-2,4,6-3-iodobenzoic acid 9α-phenyl-β-(3,5-diiodo-4-hydroxyphenyl)propionic acid 17 Composition described in Example 1 Obtain according to the method. The polymerization time of the composition thus obtained is 14 minutes when exposed to air at 25°C. The polymerization rate upon contact with body tissue is 185 minutes. The composition was used and studied over time in a 20 kg mongrel dog according to the surgical procedure described in Example 1. A cadaver examination of the sacrificial animal performed 15 days after surgery showed that the polymer plug filled the main pancreatic duct and the secondary and secondary ducts as a solid layer. Significant atrophy of the antral pancreatic tissue and proliferation of fibrous tissue was noted.

The island of Langerhans was not affected.

Example 5 The resulting composition is characterized by the following weight percentages of each component:

Ethyl α-cyanoacrylate 17 Ethoxyethyl α-cyanoacrylate 17 Dimethyl sulfoxide 19 Dimethyl ketone
22α-Phenyl-β-(3,5-diiodo-4-hydroxyphenyl)propionic acid 25 The composition is obtained according to the method described in Example 1. The polymerization time of the composition is 12 minutes when exposed to air at 25°C and the polymerization time upon contact with body tissue is 2 minutes. The composition was clinically investigated using patient B, a 38 year old male suffering from a severe condition of chronic and difficult pancreatitis. Once the patient has undergone endoscopic retrograde pancreatocholangiography, which shows that the catheter remains in the main pancreatic duct, 5 m
The catheter was withdrawn from the pancreatic duct immediately after injection of the 0 composition, in which f was infused for 50 seconds. No backflow of the composition was observed. The composition was injected while being followed by X-ray imaging. The postoperative period was uneventful. Control radiographs performed 10 days after surgery detected the presence of polymer in the main pancreatic duct. The patient experienced immediate pain relief after surgery. The patient did not complain of pain and gained 5 kg of weight, which was not prescribed, within -years after surgery.

Example 6 The resulting composition is characterized by the following weight percentages of each component:

Ethyl α-cyanoacrylate 12.5 Ethoxyethyl α-cyanoacrylate 12.5 Dimethyl sulfoxide 12 Dimethyl ketone
203-Acetylaminomethyl-5-acetylamino-2,4,6-3-iodobenzoic acid 43 composition is obtained according to the method described in Example 1. The polymerization time of the composition is 10 minutes when exposed to air at 25°C, and the polymerization rate upon contact with body tissue is 3 minutes. The composition was clinically investigated using a 28 year old male patient suffering from an extra-incisional pancreatic tit duct draining from the head and tail of the pancreas. There was no communication between the pancreatic region and the duodenum. Before surgery, 500 to 600 ml of night sweat was released from the canal every day.

The composition of the present invention at 12 mz was injected for 30 seconds to occlude the ductal cavity and the pancreatic duct in the head and tail of the pancreas, and at the same time, the catheter was recovered from the lumen. Radiographs showed complete filling of the ductal system and lumen of the head and tail of the pancreas. When the catheter was removed, some of the composition flowed out. The postoperative period was uneventful and uneventful, and no night sweats were observed to be discharged from the false lumen. The patient did not feel groggy for 3 days after the surgery. He was examined for 1 year after the surgery and had no physical complaints. A scar remains at the groin canal. A glucose tolerance test showed no diabetes mellitus. Not done.X
Radiographs showed no radiopacity in the peritoneal cavity.

Example 7 The resulting composition is characterized by the following weight percentages of each component:

Ethyl α-cyanoacrylate 30 Dimethyl sulfoxide 15 Dimethyl ketone
21α-phenyl-β-(3,
The 5-diiodo-4-hydroxyphenyl)propionic acid 34 composition is obtained according to the method described in Example 1. The polymerization time of the composition is 14 minutes when exposed to air at 25°C. The polymerization rate upon contact with body tissue is 2 minutes. The composition was tested on a 10 kg dog according to the surgical procedure described in Example 1. l, 2 m 12 of the composition was injected into the pancreatic duct. No complications were observed in the pancreatic region within the postoperative period. The dog was sacrificed 30 days after occlusion. Postmortem examination showed significant atrophy of the pancreatic tissue. The polymer was found to be present in the main pancreatic duct in the form of several clumps. Histological examination revealed that many acini were replaced by continuous tissue, and the remaining acini were embedded in the underlying tissue of the continuous tissue. It was found that the amount of island-like tissue increased to some extent.

Example 8 The resulting composition is characterized by the following weight percentages of each component:

Ethoxyethyl α-cyanoacrylate 38 dimethyl sulfoxide 18 dimethyl ketone
20α-7enylβ-(3,
The 5-diiodo-4-hydroxyphenyl)propionic acid 24 composition is obtained according to the method described in Example 1. The polymerization time of the composition is 13 minutes when exposed to air at 25°C. The polymerization rate upon contact with body tissue is 1.5 minutes. The composition was tested on a 12 kg dog. The experimental animals underwent laparotomy above the median artery and the duodenum was incised. A catheter with a diameter of 1 mm was inserted into the main pancreatic duct through the duodenum. 1.4 mR of the above composition was injected into the catheter over 50 seconds. The accessory pancreatic duct was not ligated. The duodenal wound was sutured with a single row of sutures. The animal was fed a standard diet after surgery, but was sacrificed 60 days after surgery. Postmortem examination revealed that the pancreas was greatly reduced in size, but no lobulation was observed. The polymer was found to be present in the main pancreatic duct in the form of several clumps. Histological examination revealed the absence of antral cells, poor proliferation of continuous tissue, and isolated islands of endocrine (e.g.
ndocrinous) tissue is embedded;
It was shown that the amount increased somewhat.

For comparison, the formulations of typical compositions are shown below. In these, each component is selected so as to fall outside the scope of the invention.

Example 9 The obtained composition is characterized in that each component has the following weight percentages: ethyl α-cyanoacrylate 15 ethoxyethyl α-cyanoacrylate 15 dimethyl sulfoxide 32 dimethyl ketone
21α-(3-amino-2,4,6-3
-iodobenzyl) acetic acid 17
The composition is obtained according to the method described in Example 1. The polymerization time t of the composition is 7 minutes when exposed to air at 25°C. Polymerization time on contact with body tissue is 1.1 minutes. The composition was tested in a short term experiment on a 12 kg mongrel dog. The surgical method was described in Example 1. A cadaveric examination performed one hour after surgery showed that the composition in the form of a dense polymeric solid filled the main pancreatic duct as well as the secondary and secondary ducts.

The pancreas was somewhat hardened and foci of necrosis were detected. No long-term experiments were carried out on the composition since it did not meet the requirements imposed on its properties.

Example 10 The resulting composition is characterized by the following weight percentages of each component:

Ethyl α-cyanoacrylate 10 Ethoxyethyl α-cyanoacrylate 12 Dimethyl sulfoxide 20 Dimethyl ketone
213-Acetylaminomethyl-5-acetylamino-2,4,6-3-iodobenzoic acid 37 The composition is obtained according to the method described in Example 1.

The polymerization time of the composition is 15 minutes when exposed to air at 25°C. Polymerization time on contact with body tissue is 3 minutes. The composition was tested in a short term experiment on 26 kg dogs. A laparotomy above the median artery was performed under intravenous hexenal anesthesia. A duodenotomy is performed and a catheter is inserted through the duodenum into the main pancreatic duct while at the same time administering 50% of the aforementioned composition.
Injected into the catheter for 0 seconds. A portion of the composition leaked into the duodenum through the accessory pancreatic duct. The wound in the duodenum was sutured. The postoperative period was uneventful and uneventful. Dog after occlusion 1
He died in five days. A post-mortem examination showed that the pancreas had become more hardened and somewhat atrophied. Several clustered polymer plug fragments were present in the main pancreatic duct.

Patency of the pancreatic duct system was restored.

Example 11 The resulting composition is characterized by the following weight percentages of each component:

Ethyl α-cyanoacrylate 13 Ethoxyethyl α-cyanoacrylate 13 Dimethyl sulfoxide 8 Dimethyl ketone
20α-phenyl-β-(3,5-
diiodo-4-hydroxyphenyl)propionic acid 4
6 compositions are obtained according to the method described in Example 1. The polymerization time of the composition is 26 minutes when exposed to air at 25°C. Polymerization time on contact with body tissue is 8 minutes. No long-term experiments were carried out, since the composition did not pass the requirements imposed.

Example 12 The resulting composition is characterized by the following weight percentages of each component:

Ethyl α-cyanoacrylate 26 ethoxyethyl α-cyanoacrylate 26 dimethyl sulfoxide 16 dimethyl ketone
243-Acetylaminomethyl-5-acetylamino-2,4,6-3-iodobenzoic acid 8 composition is obtained according to the method described in Example 1. The composition thus obtained will polymerize within 14 minutes when exposed to air at 25°C. The polymerization time of the composition upon contact with body tissue is 35 seconds. A short term experiment was conducted using the composition on a 14 kg dog. The surgical procedure was as described in Example 1.

Radiographs of abdominal viscera showed no radiopacity in the pancreas. Upon examination of the animal cadaver 1 hour after surgery, numerous foci of hemorrhagic necrosis were observed, which was associated with the composition polymerizing too quickly and thus disrupting the small interlobular ducts. Long-term experiments were not carried out, since the composition did not pass the imposed requirements.

Claims (3)

[Claims] (1) A composition for occluding ducts and cavities of the human body comprising α-cyanoacrylate, wherein said composition further comprises dimethyl sulfoxide, dimethyl ketone, and an iodine radiopaque organic acid, or a mixture of such acids. and the weight percentages of these components are as follows: alpha-cyanoacrylate 25-42 dimethyl sulfoxide 12-25 dimethyl ketone 20-24 iodine-containing radiopaque organic acid, or mixtures of such acids 9-43 A composition characterized in that (2) α-phenyl-β-(3,5-diiodo-4-hydroxyphenyl)propionic acid, 3-acetylaminomethyl-5-acetylamino- as the iodine-containing radiopaque organic acid in the composition; The composition according to claim (1), wherein 2,4,6-3-iodobenzoic acid or α-(3-amino-2,4,6-triiodobenzyl)butyric acid is used. (3) The composition further has a molecular weight of 15,000 to 2,500.
The composition according to claims (1) and (2), comprising 0 polyvinyl acetate in a proportion of 5 to 11% by weight of α-cyanoacrylate.