Composition for treatment of perilymph fistula and method for treating perilymph fistula

Abstract

To provide a composition for treatment of perilymph fistula, as well as to provide a treatment method that includes administration of such a composition.SOLUTION: A composition for treatment of perilymph fistula contains a component that adheres biological tissue, and is used so as to be administered intratympanically.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] The present invention relates to a composition for treating a perilymphatic fistula, which comprises a component that adheres biological tissue. Further, the present invention relates to a method for treating a perilymphatic fistula, which uses a composition that comprises a component that adheres biological tissue. [Background technology]

[0002] Perilymph fistula is a condition in which a fistula develops between the inner ear lymphatic cavity and surrounding organs, disrupting the physiological functions of the inner ear and causing hearing and balance disorders. Fistulas can occur in the round window cochlea, vestibulocochlear window, microfissures, fractures, malformations, and areas of inflammatory destruction of the bony labyrinth (see page 72 of Non-Patent Document 1). Perilymph fistulas are classified into four categories based on their cause and trigger, as shown in Table 1. Perilymph fistulas often manifest as sudden hearing loss (acute sensorineural hearing loss in which the cause cannot be clearly identified). Perilymph fistulas have also been reported in patients diagnosed with Meniere's disease (a type of acute sensorineural hearing loss, similar to sudden hearing loss) (see Non-Patent Document 2).

[0003] [Table 1]

[0004] Symptoms of perilymphatic fistula are diverse and include sudden, fluctuating, and progressive hearing loss, tinnitus, water-running tinnitus, popping sounds, a feeling of ear fullness, dizziness, and dizziness due to pressure. If perilymph leaks from the fistula, symptoms worsen and fluctuate.

[0005] While there is no evidence-based treatment for sudden hearing loss, systemic or intratympanic administration of steroids is typically performed, with vasodilators, metabolic improvers, and vitamin preparations being used in combination. Because improvement is often not expected once hearing has stabilized, initiating drug treatment early after onset is recommended (see Non-Patent Document 1, pages 56-59). Perilymphatic fistula, one of the acute sensorineural hearing losses, is known to be treatable surgically. It has been reported that the earlier surgical treatment is performed after onset, the higher the rate of hearing improvement, while the longer the time since onset, the lower the rate of improvement (see Non-Patent Document 3, page 356; Non-Patent Document 4, page 1135; Non-Patent Document 5, pages 36-37, Table 10). Therefore, for patients diagnosed with perilymphatic fistula, surgical treatment is recommended as soon as possible after onset.

[0006] Traditionally, a definitive diagnosis of perilymphatic fistula in Japan was "confirmation of perilymph or cerebrospinal fluid leakage from either the cochlear window or the vestibulocochlear window, or both, or confirmation of a fistula by endoscopic examination or surgery (exploratory tympanotomy)." However, because the cochlear window fossa has a concave structure, tissue fluid and exudate flow in and accumulate from the surrounding area, making it difficult to determine whether this is perilymph or cerebrospinal fluid leaking from the inner ear, and even with exploratory tympanotomy, it is not easy to confirm a fistula. Therefore, surgical treatment is performed not only in cases where a definitive diagnosis of perilymphatic fistula has been made, but also in cases where a perilymphatic fistula has been diagnosed symptomatically based on physiological findings, symptoms, medical history, etc.

[0007] In recent years, biochemical tests using perilymph-specific proteins have been developed, and the latest Japanese diagnostic criteria define a definitive diagnosis of perilymphatic fistula as "a fistula between the middle ear and inner ear confirmed by a microscope or endoscope, or a perilymph-specific protein detected in the middle ear by biochemical testing." Currently, cochlear tomoprotein (CTP) is used as the perilymph-specific protein (see Patent Document 1 and Non-Patent Document 1, pages 19-21). However, even with these criteria, a definitive diagnosis requires procedures such as myringotomy to confirm the fistula or myringotomy to obtain a specimen for perilymph-specific protein (CTP) detection. Furthermore, detecting CTP in the specimen requires time, which can be prohibitively time-consuming in acute cases where preoperative diagnosis is urgently needed. For these reasons, even under the latest diagnostic criteria, cases strongly suspected of having a perilymphatic fistula based on physiological findings, symptoms, and medical history often undergo surgical treatment before a definitive diagnosis is obtained.

[0008] In the conventional cochlear window closure procedure, which has been performed as a surgical treatment for perilymphatic fistula, an incision is made in the skin of the external auditory canal, the tympanic ring is elevated, and the middle ear is examined. A fistula closure material, such as connective tissue, perichondrium, a small piece of fat or fascia, or a gelatin preparation, is placed in the area where a fistula is confirmed or, if no fistula is confirmed, in the area where the fistula is assumed to be present (centered around the round window and oval window), and then secured with a tissue adhesive. Recently, a modified cochlear window closure technique called round window reinforcement (RWR) has been reported, in which the middle ear mucosa is scraped or cauterized with a laser, and the cochlear window is firmly filled with cartilage in addition to fascia and connective tissue, in order to prevent migration or loss of the closure material and prevent recurrence (see Non-Patent Document 1, pp. 80-82, and Non-Patent Document 6).

[0009] There are various types of tissue adhesives used to adhere biological tissues, including cyanoacrylate, gelatin-aldehyde, fibrin, and alginate. However, fibrin glue, a fibrin-based tissue adhesive, is often used to fix the closure material to the fistula or suspected fistula site in conventional cochlear window closure surgery.

[0010] Conventional cochlear window closure surgery involves lifting the tympanic annulus to open the tympanic cavity and then closing the fistula with a sealing material, which is highly invasive to the tympanic membrane and middle ear. As a result, it takes time for the tympanic membrane to return to its pre-operative state, and combined with the conductive impairment caused by the connective tissue within the tympanic cavity, an air-bone gap occurs, which means it takes time for hearing to improve. Antibiotics must also be administered to prevent infection. Furthermore, because the procedure is often performed under general anesthesia, it places a heavy burden on the patient, requires a long hospital stay, and requires time for preoperative testing and hospitalization arrangements, which hinders treatment early after the onset of symptoms.

[0011] Therefore, there is a need for a method of treating perilymphatic fistula that is less invasive, simpler, and faster than conventional inner ear window closure procedures, and compositions for use in such a treatment. [Prior art documents] [Patent documents]

[0012] [Patent Document 1] Patent No. 4172777 published [Non-patent literature]

[0013] [Non-Patent Document 1] "Guide to the Treatment of Acute Sensorineural Hearing Loss 2018 Edition," edited by the Japan Audiological Society, Kanehara Publishing Co., Ltd., 2018 [Non-patent document 2] DC Fitzgerald, "Perilymphatic Fistula and Meniere's Disease: Clinical Series and Literature Review", Ann Otol Rhinol Laryngol, 110, p.430-436, 2001 [Non-patent document 3] Jungmin Ahn et al., “Surgical Outcomes on Hearing and Vestibular Symptoms in Barotraumatic Perilymphatic Fistula,” Otol Neurotol, Apr;40(4):e356-e363, 2019 [Non-patent document 4] Toru Seo et al., "Study on auditory and equilibrium function in cases of perilymphatic fistula surgery," Journal of the Oto-Rhino-Laryngological Society of Japan, Vol. 104, No. 12, pp. 1135-1142, 2001 [Non-patent document 5] Yoko Asano, "Diagnosis of Perilymphatic Fistula - Comparison of Probable and Suspected Cases," Otolaryngology Outlook, Vol. 34, No. 4, pp. 411-425, 1991 [Non-patent document 6] Silverstein H et al., “Round window reinforcement for superior semicircularcanal dehiscence : A retrospective multi-center case series,” Am J Otolaryngol, 35(3), p.286-293, 2014 Summary of the Invention [Problem to be solved by the invention]

[0014] An object of the present invention is to provide a composition for treating perilymphatic fistula, which comprises a component that adheres biological tissue. Another object of the present invention is to provide a method for treating perilymphatic fistula, which comprises administering into the tympanic cavity a composition that comprises a component that adheres biological tissue. [Means for solving the problem]

[0015] The present inventors discovered that perilymphatic fistula can be effectively treated by administering a composition containing a component that adheres biological tissue into the tympanic cavity, and thereby arrived at the present invention.

[0016] That is, the gist of the present invention is as follows. [1] A composition for treating perilymphatic fistula, comprising a component that adheres biological tissue, the composition being used to be administered intratympanically. [2] The composition described in [1], wherein no other material for closing the perilymphatic fistula is used in the treatment other than the composition. [3] The composition described in [1] or [2], wherein the treatment does not involve incision of the skin. [4] The composition according to any one of [1] to [3], wherein the composition is administered into the tympanic cavity through a perforation in the tympanic membrane during the treatment. [5] The composition according to any one of [1] to [4], which is a physiological tissue adhesive. [6] The composition described in [5], wherein the composition comprises a first liquid containing fibrinogen as a main component and a second liquid containing thrombin as a main component, and the treatment involves administering the first liquid into the tympanic cavity followed by administering the second liquid into the tympanic cavity. [7] The composition described in any of [1] to [6], wherein the treatment improves or cures hearing loss. [8] The composition described in [7], wherein the treatment improves the results of a pure tone audiometry test. [9] The composition described in [7], wherein the treatment improves the results of a speech audiometry test.

[10] The composition described in any of [1] to [7], wherein the treatment improves or cures dizziness.

[11] The composition described in [7], wherein the hearing loss has been present for more than 4 weeks.

[12] The composition described in

[10] , wherein the dizziness has been present for more than 4 weeks.

[13] The composition described in [8], wherein the treatment improves the results of a pure tone audiometry test in hearing loss that has been present for more than four weeks.

[14] The composition described in [9], wherein the treatment improves the results of speech audiometry tests in patients with hearing loss that has been present for more than four weeks.

[15] A composition described in any of [1] to

[14] , in which a perilymph-specific protein is detected in the middle ear of a patient to be treated.

[16] The composition according to any one of [7] to

[15] , wherein the patient to be treated is a patient whose hearing loss has not improved with the administration of steroid drugs.

[17] The composition according to

[10] ,

[12] or

[15] , wherein the patient to be treated is a patient whose dizziness has not improved with the administration of a steroid drug.

[18] The composition according to any one of [1] to

[17] , wherein the patient to be treated is 60 years of age or older.

[19] The composition according to any one of [1] to

[17] , wherein the patient to be treated is 70 years of age or older.

[20] A method for treating a perilymphatic fistula, comprising administering a composition containing a component that adheres biological tissue into the tympanic cavity of a patient in need of treatment for the perilymphatic fistula.

[21] The method of treatment according to

[20] , in which no other material for closing the perilymphatic fistula is used other than the composition.

[22] The method of treatment described in

[20] or

[21] , wherein the composition is administered into the tympanic cavity through a perforation in the tympanic membrane.

[23] A treatment method according to any one of

[20] to

[22] , in which no skin incision is made.

[24] The method of any one of

[20] to

[23] , wherein the composition is a physiological tissue adhesive.

[25] A method of treatment according to any one of

[20] to

[24] , wherein the composition comprises a first liquid containing fibrinogen as a main component and a second liquid containing thrombin as a main component, and wherein the first liquid is administered intratympanically followed by intratympanic administration of the second liquid.

[26] A method of treatment according to any one of

[20] to

[25] , in which hearing loss is improved or cured.

[27] The treatment method described in

[26] , which improves the results of pure tone audiometry.

[28] The treatment method described in

[26] , which improves the results of speech audiometry.

[29] A method of treatment according to any one of

[20] to

[25] , in which dizziness is improved or cured.

[30] The method of any of

[26] to

[28] , wherein the hearing loss has been present for more than four weeks.

[31] The method of treatment described in

[29] , wherein the dizziness has been present for more than 4 weeks.

[32] The treatment method described in

[27] improves the results of pure tone audiometry in patients with hearing loss that has been present for more than four weeks.

[33] A treatment method as described in

[28] , which improves the results of speech audiometry tests in patients with hearing loss that has been present for more than four weeks.

[34] A method of treatment according to any one of

[20] to

[33] , in which a perilymph-specific protein is detected in the middle ear of a patient to be treated.

[35] A method of treatment according to any one of

[20] to

[34] , in which the patient to be treated is a patient whose hearing loss has not improved with the administration of steroids.

[36] A method of treatment according to any one of

[20] to

[34] , in which the patient to be treated is a patient whose dizziness has not improved with the administration of steroids.

[37] A method of treatment according to any one of

[20] to

[36] , wherein the patient to be treated is 60 years of age or older.

[38] A method of treatment according to any one of

[20] to

[36] , wherein the patient to be treated is 70 years of age or older.

[39] A method of treatment according to any one of

[20] to

[38] , wherein after the first liquid is administered into the tympanic cavity, the patient's head is turned and then the second liquid is administered into the tympanic cavity. [Effects of the Invention]

[0017] The compositions of the invention and the treatment methods of the invention are useful in treating perilymphatic fistulas. [Brief explanation of the drawings]

[0018] [Figure 1] 1 is a table showing the age, sex, preoperative symptoms, etc. of 17 subjects who underwent intratympanic administration of fibrin glue. [Figure 2] 1 is a table showing the results of 17 subjects who underwent intratympanic administration of fibrin glue. DETAILED DESCRIPTION OF THE INVENTION

[0019] The present invention will be described in more detail below with reference to preferred embodiments, but the present invention is not limited to these in any way.

[0020] In one aspect, the present invention relates to a composition for treating perilymphatic fistula, comprising a component for adhering biological tissue, which is administered intratympanically. In this specification, the "composition for treating perilymphatic fistula, comprising a component for adhering biological tissue, which is administered intratympanically" according to the present invention may be referred to as the "composition of the present invention." In conventional cochlear window closure procedures, a closure material such as connective tissue or fascia is fixed to the fistula site with fibrin glue. However, in perilymphatic fistula treatment using the composition of the present invention, it is preferable that no other closure material for the perilymphatic fistula is used. Furthermore, the composition of the present invention is preferably administered intratympanically through a tympanic membrane perforation. This configuration eliminates the need to open the tympanic cavity to fix the closure material to the fistula site, thereby eliminating the need for highly invasive procedures for the tympanic membrane and middle ear, such as lifting the tympanic annulus, and significantly reduces the invasiveness to the tympanic membrane and middle ear. As a result, the degree of hearing impairment due to conductive disorders and other factors after surgery is reduced, and recovery is faster, compared to conventional cochlear window closure procedures. Since the procedure does not require incision of the external ear canal skin, it can be easily performed under local anesthesia, reducing surgical invasiveness and the risk of infection, making it widely applicable to patients with underlying diseases and the elderly. Compared to conventional cochlear window closure procedures, it shortens hospital stays, and requires less surgical time and equipment, making it economically advantageous. Furthermore, the composition of the present invention is preferably a physiological tissue adhesive such as fibrin glue, and it contains a first liquid containing fibrinogen as a primary component and a second liquid containing thrombin as a primary component. It is more preferable that the first liquid is administered intratympanically, followed by the second liquid. This configuration allows the first liquid to penetrate the fistula, and then the second liquid is administered and mixed with the first liquid to coagulate the fibrin glue, thereby effectively closing the fistula. The composition of the present invention may be administered to patients with hearing loss symptoms that have been present for more than four weeks since the onset of symptoms or dizziness symptoms that have been present for more than four weeks since the onset of symptoms. The composition of the present invention may also be administered to patients in whom perilymph-specific proteins have been detected in the middle ear.The compositions of the present invention may be administered to patients who are not responsive to treatment with steroids (e.g., dexamethasone, prednisolone, etc.), to patients aged 60 or over, or to patients aged 70 or over.

[0021] In another aspect, the present invention relates to a method for treating a perilymphatic fistula, comprising administering a composition containing a component for adhering biological tissue into the tympanic cavity of a patient requiring treatment for the perilymphatic fistula. In this specification, the "method for treating a perilymphatic fistula, comprising administering a composition containing a component for adhering biological tissue into the tympanic cavity" according to the present invention may be referred to as the "treatment method of the present invention." In the treatment method of the present invention, it is preferable that no perilymphatic fistula closure material other than the composition of the present invention is used. It is also preferable that the composition of the present invention is administered into the tympanic cavity through a perforation in the tympanic membrane. This configuration eliminates the need to open the tympanic cavity to secure the closure material to the fistula, thereby eliminating the need for highly invasive procedures to the tympanic membrane and middle ear, such as lifting the tympanic annulus, and significantly reduces the invasiveness to the tympanic membrane and middle ear. As a result, compared to conventional cochlear window closure procedures, the degree of hearing impairment due to conductive disorders and other factors after surgery is reduced and recovery is faster. Since the procedure does not require incision of the external ear canal skin, it can be easily performed under local anesthesia, reducing surgical invasiveness and the risk of infection, making it widely applicable to patients with underlying diseases and the elderly. Compared to conventional cochlear window closure procedures, it shortens hospital stays, and reduces the surgical time and equipment required, providing medical economic advantages. Furthermore, in the treatment method of the present invention, a physiological tissue adhesive such as fibrin glue is preferably used as the composition of the present invention. It is even more preferable to use a fibrin glue containing a first liquid containing fibrinogen as a primary component and a second liquid containing thrombin as a primary component, and administer the first liquid intratympanically before administering the second liquid. This configuration allows the first liquid to penetrate the fistula, and then administer the second liquid, which is mixed with the first liquid to coagulate the fibrin glue, thereby effectively closing the fistula. The treatment method of the present invention may also be used in patients with hearing loss symptoms that have been present for more than four weeks since the onset of symptoms or patients with dizziness symptoms that have been present for more than four weeks since the onset of symptoms. It may also be used in patients in whom perilymph-specific proteins are detected in the middle ear. The target patients may be those who are not responsive to treatment with steroids (for example, dexamethasone, prednisolone, etc.), or may be those aged 60 or over, or may be those aged 70 or over.

[0022] In the present invention, perilymph fistula refers to a disease in which a fistula develops between the inner ear lymphatic cavity and surrounding organs, impairing the physiological functions of the inner ear and causing disorders of hearing, balance, and the like. A definitive diagnosis of perilymph fistula in Japan is made when a fistula is confirmed between the middle ear and inner ear using a microscope, endoscope, or the like, or when a perilymph-specific protein is detected in the middle ear using a biochemical test. However, even when a perilymph fistula is present, it is not easy to confirm the fistula. Furthermore, if the amount of perilymph leakage is small at the time of sample collection due to factors such as intermittent perilymph leakage, minor leakage, or low cerebrospinal fluid pressure, the perilymph-specific protein may not be detectable. Currently, the positive concentration of CTP, a perilymph-specific protein, is 30 ng / ml (when a monoclonal antibody is used). However, the package insert for the CTP measurement kit also states that this value is only a reference standard value and may fluctuate due to various factors. Therefore, it is recommended that each facility set a standard value according to its purpose. Clinical diagnoses based on CTP measurement results should be comprehensively determined by the attending physician in conjunction with clinical symptoms and other test results (see the package insert for the CTP ELISA "Cosmic" (Cosmic Corporation, August 2020)). Therefore, the composition of the present invention may be administered to patients in whom CTP has been detected in the middle ear, or to patients with a CTP concentration of 8.9 ng / ml to 30 ng / ml (when a monoclonal antibody is used). The treatment method of the present invention may be administered to patients in whom CTP has been detected in the middle ear, or to patients with a CTP concentration of 8.9 ng / ml to 30 ng / ml (when a monoclonal antibody is used).

[0023] Patients with perilymphatic fistula who are eligible for the composition and treatment method of the present invention include patients in whom the presence of a fistula has been confirmed or a perilymph-specific protein has been detected, as well as patients in whom the presence of a fistula has not been confirmed or a perilymph-specific protein has not been detected, but who have been symptomatically diagnosed with perilymphatic fistula by their attending physician based on physiological findings, symptoms, medical history, etc. Patients who are eligible for the composition and treatment method of the present invention are determined, for example, by comprehensively examining items 1 to 6 listed in Table 2 below and their responsiveness to conservative treatment (oral medication, rest, etc.).

[0024] [Table 2]

[0025] In the present invention, the composition containing a component for adhering biological tissue may be any composition that can be used to adhere biological tissue in surgery, etc., and is generally called a biological glue, etc. Examples include cyanoacrylate-based biological tissue adhesives, gelatin-aldehyde-based biological tissue adhesives, fibrin-based biological tissue adhesives, and alginate-based biological tissue adhesives, but among these, physiological tissue adhesives are preferably used.

[0026] Fibrin-based biological tissue adhesives containing fibrinogen, thrombin, and the like are also known as "fibrin glues." They are physiological tissue adhesives that mimic the final stage of blood coagulation. Fibrin glue adheres and seals tissues by polymerizing fibrinogen under the catalytic action of thrombin to form a soluble fibrin clot, which is then activated by thrombin in the presence of calcium ions to form a stable, urea-insoluble fibrin clot with physical strength (see package insert for "Beriplast (registered trademark) P Combiset for Tissue Adhesion" (CSL Behring, August 2023)). Fibrin glues are highly biocompatible and have been used in various surgical procedures. They are also preferably used in the present invention.

[0027] When the composition of the present invention is a fibrin glue, it may further contain blood coagulation factor XIII, calcium chloride hydrate which provides calcium ions, etc. to promote the above-mentioned coagulation mechanism, and may also contain an antifibrinolytic drug such as aprotinin to prevent the generated fibrin clot from being gradually decomposed by fibrinolytic enzymes.

[0028] The composition of the present invention may contain various additives such as stabilizers, buffers, surfactants, tonicity agents, pH adjusters, preservatives, etc. When the composition of the present invention is a fibrin glue, the lyophilized product is generally dissolved in an aqueous medium for use, and therefore, for the purpose of improving solubility in an aqueous medium, for example, albumin, amino acids, sugars, sugar alcohols, etc., which are also used as stabilizers and excipients, may be added. The composition of the present invention may contain sodium chloride, etc. as an isotonicity agent, and may contain sodium citrate hydrate, sodium acetate hydrate, etc. as a buffer.

[0029] The composition of the present invention may further contain a pharmaceutical agent, drug, etc. The pharmaceutical agent, drug, etc. to be contained is preferably a water-soluble compound.

[0030] The method for producing the composition of the present invention is known, and the composition can be produced using known compounds and reagents. Commercially available products may also be used as the composition of the present invention. Commercially available fibrin glues include Bolheal (registered trademark) (KM Biologics Co., Ltd.) and Beriplast (registered trademark) (CSL Behring Co., Ltd.).

[0031] When the composition of the present invention is a fibrin glue, contact between its main components, fibrinogen and thrombin, rapidly accelerates the coagulation process described above, forming a fibrin clot. Therefore, it is preferable to store fibrinogen and thrombin separately until intratympanic administration. For example, a first liquid containing fibrinogen as a main component and a second liquid containing thrombin as a main component may be placed in separate syringes, and the first liquid may be injected into the tympanic cavity through a perforation in the tympanic membrane, followed by the second liquid, allowing the two to come into contact and mix within the tympanic cavity. Alternatively, the first liquid may be injected into the tympanic cavity through a perforation in the tympanic membrane, and then the second liquid may be applied or dropped over the perforation from the ear canal side, allowing the two to come into contact and mix through the perforation.

[0032] Therefore, "administering" the composition of the present invention into the tympanic cavity not only includes administering all of the components constituting the composition of the present invention into the tympanic cavity together, but also includes administering multiple components constituting the composition of the present invention into the tympanic cavity at different times to bring these components into contact and mix within the tympanic cavity. "Administering the composition of the present invention into the tympanic cavity through a perforation in the tympanic membrane" not only includes administering all of the components constituting the composition of the present invention into the tympanic cavity together through a perforation in the tympanic membrane together, but also includes administering multiple components constituting the composition of the present invention into the tympanic cavity at different times through a perforation in the tympanic membrane to bring these components into contact and mix within the tympanic cavity, or injecting some of the components constituting the composition of the present invention into the tympanic cavity through a perforation in the tympanic membrane with a syringe or the like, and then applying or dripping the other components onto the perforation site to bring the two components into contact and mix via the perforation.

[0033] In the present invention, it is preferable to make a perforation by incising the tympanic membrane of the affected ear, and then administer the composition of the present invention into the tympanic cavity through the perforation. For example, when fibrin glue is used as the composition of the present invention, the fibrin glue begins to coagulate rapidly upon contact with blood. Therefore, to avoid bleeding at the time of perforation, it is preferable to make the perforation small in the tympanic membrane, and it is also preferable to make the perforation using a laser electrocautery. The tympanic membrane may be perforated in one or two places. If two perforations are made, one place can be used to administer the composition of the present invention and the other can be used to vent the air from the tympanic cavity, making the administration of the composition of the present invention easier. In patients with a small ear cavity, a single perforation may be made.

[0034] If the presence or absence of perilymph-specific proteins in the middle ear has not been tested before the treatment method of the present invention is performed, body fluids may be collected from the middle ear before the biological tissue adhesive is administered into the tympanic cavity, and perilymph-specific proteins such as CTP contained therein may be detected. When collecting a sample to test for the presence or absence of perilymph-specific proteins before the biological tissue adhesive is administered into the tympanic cavity, a syringe or the like may be inserted through a perforation made in the tympanic membrane and body fluids may be collected by aspirating them directly from the middle ear, or a cotton swab or the like may be inserted and used to wipe off any body fluids present. However, it is preferable to insert a syringe or the like through the perforation and inject physiological saline into the tympanic cavity, and then use the collected middle ear washings as a sample.

[0035] To administer the composition of the present invention into the tympanic cavity through a perforation in the tympanic membrane, commercially available syringes and needles can be used. For example, a commercially available 1 ml syringe (such as Terumo Syringe 1 mL for Tuberculin (Terumo Corporation)) can be used with a commercially available indwelling needle (such as Surflow Indwelling Needle (Terumo Corporation)). Alternatively, a spray-type syringe or dual syringe can be used. If the composition of the present invention is a two-liquid type in which two liquids are mixed before use, the two liquids can be placed in separate inner barrels of a dual syringe, and the two liquids can be simultaneously extruded and mixed at the syringe tip while being administered into the tympanic cavity. Alternatively, the two liquids can be filled into separate syringes and injected into the tympanic cavity in turn, allowing the two liquids to come into contact and mix within the tympanic cavity. Alternatively, one liquid can be injected into the tympanic cavity, and then the other liquid can be brought into contact and mixed with the liquid administered into the tympanic cavity through a perforation in the tympanic membrane. When using commercially available biological tissue adhesives, syringes and needles, if included with the product, can be used.

[0036] For example, when fibrin glue is used as the composition of the present invention, a syringe filled with a first solution containing fibrinogen, human blood coagulation factor XIII, and aprotinin, and a syringe filled with a second solution containing thrombin and calcium chloride may be prepared prior to intratympanic administration. It is preferable to attach an injection needle to the syringe. When using commercially available fibrin glue, the first and second solutions may be prepared according to the instructions in the product package insert. The patient may be placed in a supine position with the neck twisted so that the affected ear is facing up, and then the first solution may be injected with the syringe into the tympanic cavity through the perforation in the tympanic membrane. After injection of the first solution, it is preferable to change the orientation of the middle ear cavity relative to the direction of gravity to spread the first solution throughout the tympanic cavity and allow it to penetrate the fistula. To achieve this, it is preferable to change the patient's body and head position, for example, by placing the patient in a lateral position, semi-lateral position, head-down position, raising or lowering the chin, or rotating the head left or right. It is preferable to change the body position and head position slowly, taking 5 to 10 minutes for each position. Furthermore, while changing the body position and head position, it is preferable to inject additional first fluid every 5 to 10 minutes while constantly observing the condition of the perforation site under a microscope.

[0037] After the first liquid has been injected into the tympanic cavity, the second liquid may be administered using a syringe filled with the second liquid. An injection needle is preferably attached to the syringe. The second liquid may be injected by inserting the tip of the syringe (or the tip of the injection needle if an injection needle is attached) into the tympanic cavity. Alternatively, the second liquid may be dripped or applied to cover the perforated part of the tympanic membrane without inserting the tip of the syringe (or the tip of the injection needle if an injection needle is attached) into the tympanic cavity. The second liquid is preferably administered within 1 hour, preferably within 45 minutes, and more preferably after about 30 minutes from the start of intratympanic injection of the first liquid.

[0038] After administration of the second liquid is complete, it is preferable to have the patient remain at rest and not swallow, even during surgery.

[0039] The present invention will be described in more detail below based on examples, but the present invention is not limited to these examples. [Example]

[0040] (Target of treatment) Seventeen subjects were diagnosed with perilymphatic fistula based on physiological findings, symptoms, medical history, etc., and were deemed suitable for surgical treatment of perilymphatic fistula after a comprehensive review of the items listed in Table 2 and their response to conservative treatment (oral medication, rest, etc.). Intratympanic administration of fibrin glue was performed on these subjects. Consent for treatment was obtained from the subjects before the procedure. None of the subjects had been confirmed to have a fistula before surgery, and none had undergone a CTP test.

[0041] (Intratympanic administration of fibrin glue) After topical anesthesia of the tympanic membrane with 4% lidocaine, the tympanic membrane was disinfected with isodine. Under a surgical microscope, a CO2 laser device (OtoLAM, ESC / Sharplan) was used to create two incisions (perforations) in the anterior and posterior quadrants of the tympanic membrane. For subjects with narrow ear openings, only one incision was made. The CO2 laser device OtoLAM irradiates the laser beam while rotating in a spiral pattern, resulting in a circular incision (perforation) in the tympanic membrane. The laser irradiation conditions were set to a diameter of 1.2 mm, single mode, and output power of 10–12 watts to achieve a perforation diameter of approximately 0.8–1.2 mm. However, for subjects with narrow ear openings, the diameter was set to 0.8–1.0 mm. If the tympanic membrane was too thick to be perforated in one irradiation, the laser was irradiated multiple times. Subjects were instructed not to swallow during or after surgery.

[0042] Prior to intratympanic administration of fibrin glue, samples for CTP testing were collected. Using a 1 mL syringe (Terumo Syringe 1 mL for Tuberculin (Terumo Corporation)) equipped with a Surflow needle (Terumo Corporation), 0.3 mL of saline was injected into the middle ear through a perforation in the tympanic membrane. The solution was then pumped in and out three times and collected as a middle ear lavage fluid. The CTP concentration in the samples was measured using ELISA with a monoclonal antibody.

[0043] Beriplast® P Combiset Tissue Adhesive (CSL Behring) was used as the fibrin glue. One to two 0.5 ml sets were used per subject. Solution A, prepared by dissolving vial 1 of Beriplast® P Combiset Tissue Adhesive (containing fibrinogen and human blood coagulation factor XIII as active ingredients) with vial 2 (containing aprotinin as active ingredient), was placed in a 1 mL syringe equipped with a Surflo indwelling needle. The subject was placed supine with the neck twisted so that the affected ear was facing up, and Solution A in the syringe was injected into the tympanic cavity through a perforation in the tympanic membrane. After intratympanic injection, the subject was positioned in various positions, such as lateral recumbent, semi-lateral recumbent, or head-suspended, with the chin raised or lowered, and the head rotated left and right, to distribute Solution A throughout the tympanic cavity. The orientation of the middle ear cavity relative to gravity was varied by positioning the subject in various positions, including lateral recumbent, semi-lateral recumbent, or head-suspended, with the chin raised or lowered, and with the head rotated left and right. These posture changes were performed slowly over a period of 5 to 10 minutes. During the posture changes, leakage or overflow of Solution A from the tympanic membrane was observed at any time using a surgical microscope, and additional Solution A was injected into the tympanic cavity every 5 to 10 minutes.

[0044] Once it was determined that Solution A had spread throughout the entire intratympanic cavity (usually approximately 30 to 60 minutes after the start of intratympanic administration of Solution A), Solution B, prepared by dissolving vial 3 of Beriplast (registered trademark) P Combiset tissue adhesive (containing thrombin as the active ingredient) in vial 2 (containing calcium chloride hydrate as the active ingredient), was placed into a 1 mL syringe equipped with a Surflo indwelling needle, and several to several tens of drops were dropped to cover the perforation, completing the surgery.

[0045] After the surgery, the subjects were asked to rest in bed for a while (usually about 3 hours). No antibiotics were administered to prevent infection before or after the surgery.

[0046] (Evaluation of treatment effect) The effectiveness of the treatment was evaluated based on hearing and dizziness (only for subjects who had dizziness symptoms before surgery). One day after surgery (inpatient), one week after surgery (outpatient), and two weeks after surgery (outpatient), all subjects underwent photographs of their eardrums and hearing tests, and subjects who had dizziness symptoms before surgery were asked to fill out a dizziness questionnaire. Similar tests were conducted at each outpatient visit thereafter, and the time at which maximum improvement or cure of hearing loss and dizziness symptoms was reached after surgery was used to assess the effectiveness of each treatment.

[0047] Pure-tone hearing was assessed using an audiometer (Rion AA-75 or AA-75N) according to the pure-tone audiometry method established by the Japan Audiological Society, and the average hearing level at five frequencies (250 Hz, 500 Hz, 1000 Hz, 2000 Hz, and 4000 Hz) was used to evaluate the hearing. A recovery of the test value from pre- to post-operatively to the same level as that of the normal ear or pre-onset was considered "cured," a recovery of 30 decibels (dB) or more across the five frequencies was considered "marked recovery," a recovery of 10 dB to less than 30 dB was considered "recovered," and a recovery of less than 10 dB was considered "unchanged."

[0048] Speech hearing was assessed according to the speech audiometry method established by the Japan Audiological Society (see Kanzaki Jin et al., "Establishment of the Audiology Testing Method (2003)" (AUDIOLOGY JAPAN 46 (6), 601-619, 2003)). The best speech intelligibility (%) was calculated by speech discrimination testing using the Japan Audiological Society's 67-S word list. A postoperative best speech intelligibility increase of 10% or more compared to preoperative was considered "improved," while a difference of 5% or less from preoperative best speech intelligibility was considered "no improvement." However, for subjects whose postoperative best speech intelligibility reached 100%, the upper limit of the test value, even if the increase in best speech intelligibility was only 5%, the subject was considered "improved."

[0049] Dizziness was evaluated using the DHI (Dizziness Handicap Inventory) score. If the DHI score was no impairment after treatment, the patient was rated as "cured," and if the DHI score improved after treatment, the patient was rated as "improved." However, there was one subject (subject number 9) who complained of dizziness symptoms despite having a preoperative DHI score of no impairment. This subject was treated as having "dizziness," and the presence or absence of postoperative dizziness symptoms was verbally confirmed during the examination. The DHI scores responses to 25 questions on a three-point scale (yes: 4 points, sometimes: 2 points, no: 0 points) and classifies responses into four levels: no impairment (0-14 points), mild (16-25 points), moderate (28-44 points), and severe (46 points or more) (see Masuda Kenako et al., "Study on the usefulness of the Dizziness Handicap Inventory" (Equilibrium Res 63:555-563, 2004)).

[0050] (Safety assessment) Safety was assessed one month after treatment for bone conduction threshold elevation, conductive hearing loss, and residual tympanic membrane perforation.

[0051] (result) The age, sex, preoperative symptoms, etc. of the 17 subjects are shown in Table A of Figure 1, and the results of intratympanic fibrin glue treatment are shown in Table B of Figure 2.

[0052] A. Effects on hearing impairment A-1 Overall Preoperatively, 12 patients had sudden hearing loss, 2 had recurrent / fluctuating hearing loss, 2 had acute mixed hearing loss, and 1 had recurrent hearing loss (Table A in Figure 1). As shown in Table B in Figure 2, pure-tone hearing was cured or significantly improved in 4 of 17 patients with intratympanic fibrin glue treatment, and recovered in 5 patients (treatment success rate: 24%, improvement rate: 53%). The mean pure-tone hearing test score (average of 5 frequencies) for the 17 patients improved from 62 dB preoperatively to 47 dB postoperatively, demonstrating a statistically significant improvement compared to preoperatively (paired t-test, p<0.001). Speech hearing improved in 14 of 17 patients (improvement rate: 82%). The average speech hearing test score for the 17 patients improved from 43% preoperatively to 67% postoperatively, demonstrating a statistically significant improvement compared to preoperatively (Wilcoxon signed-rank test, p<0.001). Furthermore, while 10 of the 17 patients had a best speech intelligibility of 50% or less preoperatively, 5 of them achieved a best speech intelligibility of over 50% postoperatively. Under the Act on Welfare of the Physically Disabled, a person whose "best speech intelligibility for normal speech in both ears is 50% or less" is classified as a Grade 4 disability. However, even if only one ear has a best speech intelligibility of 50% or less, conversation is considered difficult. Therefore, subjects whose best speech intelligibility improved were highly satisfied with their hearing recovery.

[0053] A-2 Relationship with CTP value Table 3 shows the relationship between CTP levels and the therapeutic effect of intratympanic fibrin glue administration. Even in subjects with CTP levels greater than 8.9 ng / ml but less than 30 ng / ml, excellent therapeutic effects were observed on pure tone and speech hearing. A CTP level of 8.9 ng / ml or less means that the CTP in the sample was below the detection limit of the ELISA test.

[0054] [Table 3]

[0055] A-3 Relationship with the period from onset to treatment Table 4 shows the relationship between the period from onset to intratympanic fibrin glue treatment and treatment effect. There were nine cases in which the period from onset to treatment was 28 days or less, of which six showed improvement in pure tone hearing (improvement rate 67%) and all showed improvement in speech hearing (improvement rate 100%). There were eight cases in which the period from onset to treatment was more than 28 days (all more than 42 days), of which three showed improvement in pure tone hearing (improvement rate 38%) and five showed improvement in speech hearing (improvement rate 63%).

[0056] [Table 4]

[0057] It has been reported that the therapeutic effect of conventional cochlear window closure surgery decreases in cases where time has passed since the onset of symptoms. For example, Non-Patent Document 4 reports that even in mid-frequency hearing, where improvement is most prominent, improvement was observed in only one of four cases in which surgery was performed more than 14 days after the onset of symptoms (see page 1137, Figure 3 of Non-Patent Document 4). Non-Patent Document 5 also reports that of 17 cases in which perilymph leakage was confirmed during cochlear window closure surgery more than 28 days after the onset of symptoms, only two cases showed improvement in pure tone hearing, a very low improvement rate of 12% (= 2 / 17) (see pages 36-37, Table 10 of Non-Patent Document 5). Non-Patent Document 3 also reports that there were very few cases in which improvement was observed more than 20 days after the onset of symptoms (see Figure 2 of Non-Patent Document 3). In contrast, the intratympanic fibrin glue treatment of the present invention showed excellent therapeutic effects, with a 38% (=3 / 8) improvement rate for pure tone hearing and a 63% (=5 / 8) improvement rate for speech hearing, even in cases where more than 42 days (6 weeks) had passed since the onset of symptoms. Moreover, as shown in Figure 1, the intratympanic fibrin glue treatment of the present invention improved pure tone hearing and speech hearing even in cases where a very long period of time had passed, such as 156 weeks and 48 weeks, since the onset of symptoms.

[0058] A-4 Relationship with age Table 5 shows the relationship between the effect of intratympanic fibrin glue treatment and the age of the subject. Non-Patent Document 5 reports that there were no cases in which cochlear window closure surgery was effective in improving pure tone hearing in patients aged 60 or older (see Table 7 in Non-Patent Document 5). However, with the intratympanic fibrin glue treatment of the present invention, excellent therapeutic effects were achieved, even in a group of subjects aged 60 or older, with an effectiveness rate of 25% for pure tone hearing, an improvement rate of 50%, and an improvement rate of 88% for speech hearing. Even in a group of subjects in their 70s, excellent therapeutic effects were achieved, with an effectiveness rate of 50% for pure tone hearing, an improvement rate of 50%, and an improvement rate of 100% for speech hearing.

[0059] [Table 5]

[0060] A-5 Relationship with steroid treatment As shown in Table A in Figure 1, all 17 cases had a history of oral steroid treatment (e.g., prednisolone), but 14 cases showed no improvement in symptoms. Even for these 14 subjects who did not respond to steroid treatment, intratympanic fibrin glue treatment resulted in recovery or a marked recovery of pure-tone hearing in 2 of the 14 cases, and recovery in 4 cases (treatment effectiveness rate: 14%, improvement rate: 43%), and speech hearing improved in 11 of the 14 cases (improvement rate: 79%), demonstrating excellent therapeutic efficacy. In the remaining 3 cases, the time between the start of oral steroid treatment and intratympanic fibrin glue treatment was short, making it impossible to determine whether steroids were effective in improving symptoms.

[0061] B. Effect on dizziness Of the seven patients with dizziness symptoms, five were cured and two improved (cure rate 71%, improvement rate 100%). In one of the five patients whose dizziness was cured, the patient complained of dizziness symptoms before surgery, but the results of the DHI test were within the normal range, and during the postoperative examination, it was confirmed through interview that the subjective symptoms of dizziness had disappeared.

[0062] C Safety One month after surgery, no subjects had elevated bone conduction thresholds, conductive hearing loss, or residual tympanic membrane perforations. Some subjects experienced temporary conductive hearing impairments due to the intratympanic injection of fibrin glue, but these symptoms disappeared within two weeks. Tympanic membrane findings also nearly normalized within two weeks. No subjects exhibited symptoms of infection. Some subjects complained of pain when the fibrin glue was administered intratympanically, but the pain disappeared within two hours without the need for medication. [Industrial Applicability]

[0063] The compositions and treatments of the present invention can be useful in treating perilymphatic fistulas.

Claims

1. A composition for treating a perilymphatic fistula, comprising a component that adheres biological tissue, the composition being used to be administered intratympanically.

2. The composition of claim 1 , wherein no other perilymphatic fistula closure material is used in the treatment other than the composition.

3. The composition of claim 1 or 2, wherein the treatment does not involve incision of the skin.

4. The composition according to claim 1 or 2, wherein the composition is administered into the tympanic cavity through a perforation in the tympanic membrane during the treatment.

5. 3. The composition of claim 1 or 2, which is a physiological tissue adhesive.

6. The composition according to claim 5, wherein the composition comprises a first liquid containing fibrinogen as a main component and a second liquid containing thrombin as a main component, and wherein the treatment involves administering the first liquid into the tympanic cavity and then administering the second liquid into the tympanic cavity.

7. 3. The composition of claim 1 or 2, wherein the treatment improves or cures hearing loss.

8. 8. The composition of claim 7, wherein the treatment improves pure tone audiometry results.

9. 8. The composition of claim 7, wherein the treatment improves speech audiometry results.

10. 3. The composition of claim 1 or 2, wherein said treatment improves or cures dizziness.

11. 8. The composition of claim 7, wherein the hearing loss is greater than 4 weeks old.

12. The composition according to claim 7, wherein the patient to be treated is a patient whose hearing loss has not improved with the administration of steroids.

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