JP4398651B2 - Coating material for aneurysm treatment - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a coating material for treating an aneurysm characterized by comprising a fibrinogen component and a thrombin component as active ingredients and a bioabsorbable synthetic fiber as a base material.
[0002]
[Prior art]
An aneurysm occurs in the arteries of the body such as the brain, aorta, various organs, and extremities in a state where the arterial wall is locally weakened and stretched and abnormally dilated. Once ruptured at any site, the disease has a high mortality rate.
[0003]
Regarding cerebral aneurysms, rupture of aneurysms is a disease that causes subarachnoid hemorrhage and has a high mortality rate or a high rate of the aftermath of neurological symptoms. In addition, the cause of cerebral aneurysm is still unknown. Although the prevalence of subarachnoid hemorrhage in Japan is about 20 per 100,000 people, the recent advancement of magnetic resonance imaging (MRI) is an opportunity to discover pre-rupture cerebral aneurysms Has also increased rapidly. Recent reports indicate that 2,000-5,000 people per 100,000 have cerebral aneurysms.
[0004]
For the treatment of cerebral aneurysms, clipping techniques that block the blood flow into the aneurysm by approaching the cerebral aneurysm by craniotomy and applying a clip to the neck of the cerebral aneurysm are still mainstream. However, there are many cases where clipping is difficult due to the size and shape of the cerebral aneurysm and the positional relationship with the mother blood vessel. Until now, in this case, in such cases, an attempt was made to prevent the enlargement or rupture of the cerebral aneurysm by applying a sterilized neurosurgical pad to the aneurysm surface and applying and hardening the cyanoacrylate surgical adhesive. The coating technique to do has been performed. In fact, even in daily clinical settings, it has been frequently practiced to use a coating technique on a portion that cannot be covered by clipping alone. However, there are not a few cases in which stenosis / occlusion due to an inflammatory reaction occurred in the mother blood vessel, or the cerebral aneurysm increased and ruptured after coating with this cyanoacrylate surgical adhesive and a sterile brain surgical pad. Have been reported (for example, see Non-Patent Document 1). More recently, the carcinogenicity of this cyanoacrylate surgical adhesive was pointed out, and production was discontinued in June 2002. Therefore, at present, coating materials for the treatment of cerebral aneurysms that have been scientifically proven to be safe and effective do not exist in Japan. There is an urgent need to make it available at the facility.
[0005]
As for an aortic aneurysm, if it ruptures, it causes major bleeding to the pericardium, thoracic cavity, abdominal cavity, etc., and it is a disease that often causes death. The mortality rate when ruptured is said to be 50-80% for thoracic aortic aneurysms and 25-50% for abdominal aortic aneurysms.
[0006]
As a treatment for an aortic aneurysm, an artificial blood vessel replacement method in which the aneurysm is excised and replaced with an artificial blood vessel is the current mainstream. During this operation, the anastomosis between the artificial blood vessel and the artery may be reinforced with GRF (Gelatin-Resolcinol-Folmaldehyde) glue and felt. In a dissecting aortic aneurysm, GRF glue is injected into the dissociation space, and felt is applied in a sandwich shape on the inside and outside to reinforce the thinned aorta and aortic stump formation is also performed. However, early results are good, but re-dissociation (about 10%) and formation of anastomotic pseudoaneurysm (about 4%) cannot be avoided in the remote stage. This is thought to be due to tissue damage caused by formaldehyde contained in the GRF glue. Therefore, there is a demand for a material that can be used for reinforcement with higher safety.
[0007]
[Non-Patent Document 1]
Ministry of Health and Welfare, Pharmaceutical Safety Bureau, “Safety Information on Drugs”, No. 150, October 1998, “3. About occlusive vascular lesions of cerebral arteries by combined use of cyanoacrylate surgical adhesive and sterilized brain surgical pad "
[0008]
[Problems to be solved by the invention]
Under such circumstances, development of a new coating material for an aneurysm has been eagerly desired. The necessary conditions for the coating material of the aneurysm are to adhere to the vessel wall for a long period of time, cover the aneurysm with the connective tissue guided to the surrounding area, reinforce the vessel wall, and prevent aneurysm enlargement, rupture and recurrence, Furthermore, it does not elicit excessive inflammatory and immune responses in surrounding nerve and vascular tissues. Ideally, it can be taken as a condition that it decomposes and absorbs over a certain period of time and replaces the connective tissue, or acts on a thinned aneurysm wall to thicken the wall. It is an object of the present invention to develop a novel coating material that satisfies such conditions.
[0009]
[Means for Solving the Problems]
In view of such a situation, as a result of intensive studies, the present inventors have found that a new biomaterial using a fibrin adhesive component and a bioabsorbable synthetic fiber is safe and high as a coating material for aneurysm treatment. It has been found that it has an effect, and the present invention has been completed.
[0010]
DETAILED DESCRIPTION OF THE INVENTION
The novel coating material for aneurysm treatment of the present invention comprises a fibrinogen component and a thrombin component as active ingredients and a bioabsorbable synthetic fiber as a base material.
The fibrinogen component and the thrombin component are main components of a fibrin adhesive known as a biological tissue adhesive.
[0011]
In addition to the fibrinogen component and the thrombin component, pharmaceutically acceptable stabilizers and additives may be added. Examples of such additives and stabilizers include, for example, blood coagulation factor XIII (preferably derived from human blood or obtained by genetic recombination techniques), calcium chloride, protease inhibitors (eg aprotinin), albumin Aminoacetic acid, polyethylene glycol, arginine, sodium hyaluronate, glycerin, and mannitol. In addition, blood coagulation factor XIII may be added to the fibrinogen component in advance.
[0012]
Fibrinogen, thrombin and blood coagulation factor XIII are preferably derived from human blood or obtained by gene recombination techniques.
[0013]
Fibrin glue composed of fibrinogen and thrombin used as a component of the coating material of the present invention is used in various digestive / general surgery, cardiac / vascular surgery, pulmonary surgery, neurosurgery, microvascular surgery, gynecology, etc. In the area, it is used for the purpose of tissue adhesion and closure, and its safety is also guaranteed.
[0014]
The bioabsorbable synthetic fiber used in the present invention is preferably processed into a nonwoven fabric. Here, the bioabsorbable synthetic fiber refers to a fiber that has low inflammation-inducing properties as a foreign substance and is absorbed and / or decomposed in the living body over time. Moreover, it is preferable that this nonwoven fabric has a moderate softness | flexibility and a stretching property so that any affected part can be reliably coat | covered. For example, as a synthetic fiber that can form such a nonwoven fabric, polyglycolic acid, polylactic acid, a copolymer of glycolic acid and lactic acid, or the like processed into a nonwoven fabric can be used. Above all, bioabsorbable synthetic nonwoven fabrics made by processing polyglycolic acid into nonwoven fabrics are already used for medical purposes, and after being absorbed by living bodies, they are decomposed into water and carbon dioxide, so safety has been demonstrated. This is a very preferable material for this purpose.
[0015]
The shape of the fiber is not particularly limited, but it is one of the preferable shapes from the viewpoint of ease of application to various uses.
[0016]
The coating material of the present invention is not particularly limited as long as the bioabsorbable synthetic fiber finally contains a fibrinogen component and a thrombin component as active ingredients.
[0017]
In consideration of ease of use in the surgical field, one component of thrombin or fibrinogen, or both components may be immobilized on a bioabsorbable synthetic fiber in advance. When both components are immobilized, each component is immobilized on the non-woven fabric in an environment where the components are blocked from each other or in an organic solvent so that the thrombin and fibrinogen do not react to form a stabilized fibrin. Processing such as suspending each powder and spraying it onto the nonwoven fabric is necessary.
[0018]
The specific kit for aneurysm treatment coating material of the present invention comprises a bioabsorbable synthetic fiber as a base material, a container containing a thrombin component as an active ingredient, and a container containing a fibrinogen ingredient as an active ingredient, This includes the above-described additives and stabilizers as appropriate. For example, a bioabsorbable synthetic fiber is sequentially added to a solution containing a thrombin component and a solution containing a fibrinogen component prepared in accordance with a method for preparing a commercially available fibrin adhesive (for example, Bolheel (product name: manufactured by Chemical and Serum Therapy Laboratory)). It is used after dipping or after each solution is simultaneously applied to the nonwoven fabric using a spray or the like.
[0019]
In the above structure, a blood coagulation factor XIII or a protease inhibitor may be added to a solution containing a fibrinogen component.
[0020]
EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples of the present invention, but the present invention is not limited thereto.
[0021]
【Example】
Example 1: Production of an aneurysm model rabbit
In order to investigate the effect of the new coating material on the aneurysm model, elastase was applied to the rabbit common carotid artery to chemically damage the vascular wall and create an aneurysm model.
[0022]
Nembutal 30 mg / kg was intravenously administered to 21 Japanese white rabbits (male, body weight 2.46 to 2.94 kg) for anesthesia. In the supine position, a midline incision was made in the neck to expose the right common carotid artery. Under the microscope, the common carotid artery outer membrane was removed in a range of 2 mm square using microtweezers. Place 2 mm square of Bensheets (product name: Kawamoto Sangyo Co., Ltd.) 100% cellulose cotton in the outer membrane removal part and dilute 4 times elastase (3.6 mg protein / ml, 4.9 units / ml; Sigma Chemical Co., St Louis) 10 μL was added dropwise. After leaving for 10 minutes, the cotton was removed to confirm the occurrence of an aneurysm.
[0023]
<< Example 2: Treatment with various coating materials >>
Using the aneurysm model rabbit obtained in Example 1, the aneurysm site was treated with various coating materials.
The aneurysm model rabbits were randomly divided into 3 groups (control group, cyanoacrylate group, fibrin adhesive group), and after each treatment, the wound was closed and awakened from anesthesia.
[0024]
<Control group>
In the control group (n = 6), an aneurysm was created with elastase and coating was not performed.
[0025]
<Cyanoacrylate group>
In the cyanoacrylate group (n = 6), a sterilized neurosurgical pad (sterilized Bensheets (product name): Kawamoto Sangyo Co., Ltd.), which is a six-layered sheet, is used as one sheet, and the size is 1.5 × 0.3 cm. A portion of the common carotid artery treated with elastase was covered, and 0.2 mL of a cyanoacrylate surgical adhesive (product name: Biobond / Mitsubishi Pharma Corporation) was added dropwise.
[0026]
<Fibrin adhesive group>
A fibrin adhesive (product name: Borhir / Chemical and Serum Therapy Laboratory) of the fibrin adhesive group (n = 9) which is an embodiment of the present invention is a fibrinogen freeze-dried powder (human fibrinogen and human blood). Coagulation factor XIII-containing) and thrombin lyophilized powder (JP Thrombin), which were dissolved in fibrinogen solution (external standard aprotinin solution) and thrombin solution (JP calcium chloride), respectively.
[0027]
Polyglycolic acid-based non-woven fabric (product name: Neobel / Gunze Co., Ltd., thickness 0.15 mm) is 1.5 x 0.3 cm in size, similar to the cyanoacrylate group, and only fibrinogen solution (A solution) of fibrin adhesive is used. After soaking, a portion of the common carotid artery treated with elastase was covered and thrombin solution (solution B) was dropped.
[0028]
<< Example 3: Follow-up observation >>
Two weeks, four weeks, and eight weeks after elastase treatment, the wound was reopened under Nembutal anesthesia, and the right common carotid artery was removed together with surrounding tissues after sacrifice of exsanguination. The excised specimen was fixed in a 10% neutral buffered formalin solution, and paraffin-embedded sections were prepared according to a conventional method. Thereafter, Hematoxylin-Eosin (HE) staining, Elastica Van Gieson staining, and Masson trichrome staining were performed to evaluate histological changes in blood vessels, surrounding tissues, and coating materials.
[0029]
As a result, in the control group, the outer membrane was removed and the elastase was applied, but there were changes such as tearing and disappearance of the elastic plate of the media during the entire observation period. . For this reason, there was an example in which the blood vessel wall was partially thinned and an aneurysm-like bulge was caused with the disappearance of the intima (FIG. 1). In contrast, in the cyanoacrylate group and the fibrin adhesive group, the change in the media was similar to that in the control group, but the outer membrane connective tissue augmentation was significant throughout the entire observation period (FIGS. 2 and 2). FIG. 3). This change was remarkable around the fibers of the sterilized pad in the cyanoacrylate group, and around the fibers of the polyglycolic acid-based non-woven fabric and the fibrin adhesive in the fibrin adhesive group. As a result, the vascular wall was thickened, and the occurrence of aneurysm-like changes as seen in the control group was suppressed in either group. However, the fibrin adhesive group was characterized in that the connective tissue formed covered the artery fairly densely compared to the cyanoacrylate group.
In any experimental group, there was no sign of death during the observation period or infection of the treated area.
[0030]
<< Example 4: Examination about safety in dog intracranial application >>
A new coating material was applied to the canine skull, and the effect on the surrounding brain and intracranial artery in the cerebrospinal fluid space was examined.
Five beagle dogs were anesthetized by halothane inhalation. An incision was made in the head skin in the prone position. The temporal muscle was removed and the zygomatic arch was dissected. Craniotomy was performed by drilling in the frontal temporal region, and the dura mater was opened. Polyglycolic acid-based non-woven fabric (product name: Neobel / Gunze Co., Ltd.), soaked in fibrinogen solution (solution A) of fibrin adhesive (product name: Borheal / Chemical and Serum Therapy Laboratory) Was inserted between the internal carotid artery and the optic nerve, and thrombin solution (solution B) was dropped. Closed and awakened from anesthesia.
[0031]
Nine and 16 weeks after treatment, the blood was sacrificed under Nembutal anesthesia and perfusion-fixed with 10% neutral buffered formalin solution. Craniotomy was performed, and the brain was removed with the dura mater attached. The excised specimen was immersed and fixed in a 10% neutral buffered formalin solution, and paraffin-embedded sections were prepared according to a conventional method. Thereafter, Hematoxylin-Eosin (HE) staining and Kluver-Barrera staining were performed, and the histological changes of the tissues around the application area, such as brain and blood vessels, and coating materials were evaluated.
[0032]
As a result, histological examinations at 9 and 16 weeks after treatment showed connective tissue growth near the application site, but no marked changes were observed in the brain and blood vessels. In addition, although Neobelt fibers remained slightly in the 9th week after the treatment, they were completely absorbed and not recognized in the 16th week.
There were no animals that showed neurological symptoms or died during the observation period.
[0033]
【The invention's effect】
A novel coating material for treating aneurysms according to the present invention comprises:
1) Excellent flexibility and stretchability, tightly attached to the blood vessel wall,
2) Covering an aneurysm, promoting connective tissue augmentation around the application site, preventing aneurysm enlargement, rupture and recurrence,
3) Does not cause excessive inflammatory reaction in nerves and vascular tissues around the application area.
4) absorbed over time,
It is a coating material that can be replaced with more effectiveness and safety than conventional materials. In addition, it is a medical material that can be easily used in any medical facility and serves as a gospel for patients with aneurysms.
[Brief description of the drawings]
FIG. 1 is a drawing-substituting photograph showing the formation of an aneurysm 4 weeks after treatment in a control group (untreated) in a study on the therapeutic effect of an aneurysm treatment coating material using an aneurysm model rabbit.
FIG. 2 is a drawing-substituting photograph showing an aneurysm therapeutic effect at 4 weeks after treatment with a cyanoacrylate group in a test on the therapeutic effect of an aneurysm treatment coating material using an aneurysm model rabbit.
FIG. 3 is a drawing-substituting photograph showing an aneurysm therapeutic effect at 4 weeks after treatment with a fibrin adhesive group in a test on the therapeutic effect of an aneurysm treatment coating material using an aneurysm model rabbit.

Claims (13)

A coating material for treating aneurysms, comprising a non-woven fabric composed of a fibrinogen component and a thrombin component as active ingredients and a bioabsorbable synthetic fiber as a base material.   The aneurysm coating material according to claim 1, comprising at least one additive selected from blood coagulation factor XIII, a protease inhibitor, and calcium chloride.   The coating material for aneurysm treatment according to claim 1 or 2, wherein the fibrinogen, thrombin and blood coagulation factor XIII are derived from human blood or produced by a recombinant technology. The aneurysm treatment according to any one of claims 1 and 3 , wherein the bioabsorbable synthetic fiber material includes a material selected from the group consisting of polyglycolic acid, polylactic acid, and a copolymer of glycolic acid and lactic acid. Coating material. Material of the bioabsorbable synthetic fibers, for treating aneurysms coating material according to any one of claims 1 to 4, characterized in that the polyglycolic acid and materials. The coating material for aneurysm treatment according to any one of claims 1 to 5 , wherein the aneurysm is a cerebral aneurysm. A kit for aneurysm treatment coating comprising a nonwoven fabric composed of bioabsorbable synthetic fibers as a base material, a container containing a thrombin component as an active ingredient, and a container containing a fibrinogen component as an active ingredient. The kit according to claim 7 , comprising at least one container selected from a container containing blood coagulation factor XIII, a container containing a protease inhibitor, and a container containing calcium chloride as an additive. The kit according to claim 7 or 8 , wherein the blood coagulation factor XIII is contained in a fibrinogen component. The kit according to any one of claims 7 to 9 , wherein the thrombin, fibrinogen and blood coagulation factor XIII are derived from human blood or produced by a gene recombination technique. The kit according to any one of claims 7 to 10 , wherein the material of the bioabsorbable synthetic fiber includes a material selected from the group consisting of polyglycolic acid, polylactic acid, and a copolymer of glycolic acid and lactic acid. The kit according to any one of claims 7 to 11 , wherein the bioabsorbable synthetic fiber is made of polyglycolic acid. The kit according to any one of claims 7 to 12 , wherein the aneurysm is a cerebral aneurysm.

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