JP5962161B2 - Eustachian tube treatment - Google Patents

Description

  The present invention relates to a prophylactic, therapeutic and / or symptom improving agent for eustachian tube.

  The ear is an organ that controls hearing and balance, and is roughly divided into an outer ear, a middle ear, and an inner ear. The eustachian tube is a mucosal tube that connects the nasopharynx and middle ear cavity. It takes outside air into the middle ear and equalizes the air pressure inside and outside the eardrum.

  Eustachian tube is a disease in which the normally closed ear canal remains open, and causes symptoms such as self-voice enhancement, ear closure, and self-breathing listening. Causes of eustachian tube are thought to be stress, blood flow disturbance, rapid weight loss, etc., but the mechanism is unknown and has not yet been elucidated. Depending on the symptoms and severity, drug therapy, injection of fat or silicon into the ear canal, conservative treatment such as spraying a chemical solution to the opening of the ear canal to cause inflammation and constriction, silicon ear tube pins, Although a surgical operation such as insertion of a cartilage fragment into the ear canal is performed, an effective treatment method has not yet been established.

  In pharmacotherapy, Kampo Shikito and other Chinese medicines, anxiolytics, vitamin preparations, adenosine triphosphate preparations (hereinafter referred to as ATP preparations), etc. are used. There is no.

On the other hand, Limaprost Alphadex is already used in clinical practice as an oral PGE ₁ preparation having an effect of improving peripheral circulation and is known as a safe pharmaceutical product. Limaprost Alphadex tablets, which are preparations containing Limaprost, are useful as a preventive and / or therapeutic agent for peripheral circulatory disturbance and are very useful for improving symptoms such as obstructive thromboangiitis and lumbar spinal canal It is a drug. In addition, limaprost, which is an active ingredient of limaprost alphadex tablets, is known to have a vasodilatory action, a platelet aggregation inhibitory action, etc., and improve peripheral circulation.

  It has been reported that compounds having PGE receptor binding activity such as limaprost are effective for inner ear diseases and effective for inner ear dizziness or inner ear deafness (see Patent Document 1). However, the inner ear and the ear canal are completely separate tissues, and so far there has been no report that limaprost is effective for open ear canal.

JP 2007-023028 A

  Currently, there is no established therapeutic agent for open ear canal. An object of the present invention is to provide a prophylactic, therapeutic and / or symptom-ameliorating agent for eustachian tube which is effective and safe and can be administered orally.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that limaprost can be a therapeutic agent for eustachian tube. Furthermore, Limaprost has been found to be effective for patients with open ear canal, for which Kampo medicines and ATP preparations currently used in clinical practice have been ineffective, and completed the present invention.

That is, the present invention is as follows.
1. A prophylactic, therapeutic and / or symptom-ameliorating agent for eustachian tube, comprising limaprosts,
2. The agent according to 1 above, wherein the limaprost is limaprost alphadex;
3. Symptoms of eustachian tube are one or more selected from self-emphasis, ear tightness, listening to self-breathing, dizziness, dizziness, hearing loss, hearing loss, tinnitus, neck stiffness, stiff shoulders, headache, and depression The agent according to 1 or 2,
4). The agent according to any one of the above 1 to 3, wherein the eustachian tube is eustachian tube disease in a patient for whom Chinese medicine, anxiolytic drugs, vitamin preparations and / or ATP preparations are ineffective,
5. 5. Any one of 1 to 4 above, wherein an amount of 5 μg to 10 μg per dose is orally administered 3 times a day for 1 to 52 weeks to a patient with eustachian tube. Agent,
6). The agent according to 5 above, wherein the eustachian tube patient is a patient for whom Chinese medicine, anxiolytic drugs, vitamin preparations and / or ATP preparations are ineffective,
7). Furthermore, the agent according to any one of 1 to 6 above, which is a combination of at least one drug selected from the group consisting of traditional Chinese medicine, anxiolytic drugs, vitamin preparations and ATP preparations,
8). Use of limaprosts for the prevention, treatment and / or manufacture of symptom-ameliorating agents for eustachian tube,
9. 9. limaprosts used to prevent, treat and / or improve symptoms of eustachian tube, and The present invention relates to a method of treating and / or ameliorating symptoms of open canal, characterized by administering an effective amount of limaprost to a patient with open canal.

  Limaprosts are effective as preventive and / or therapeutic agents for eustachian tube. Various symptoms such as self-voice emphasis, ear closure, self-breathing listening, dizziness, dizziness, hearing loss, hearing loss, ear pain, tinnitus, neck stiffness, stiff shoulders, headache, depression, etc. It is also effective as a symptom improving agent.

  Limaprost is also effective for patients for whom Chinese herbal medicine or ATP preparations used in clinical settings are ineffective.

  In addition, limaprosts are other drugs that are used for the treatment of eustachian tube (eg, Kampo medicines (Kamikishou-to, Hanka Hyakuten Tento, Hochuekkito, etc.), anxiolytics , Vitamin preparations, ATP preparations, etc.).

  In the present invention, the term “treatment” refers to not only completely curing a disease state, but also suppressing the progression / aggravation of symptoms without completely healing, and stopping the progression of the disease state, or part or all of the disease state `` Prevention '' means preventing, suppressing, or delaying the onset of pathological conditions, and `` improving symptoms '' means relieving symptoms. To do.

Limaprosts As used herein, “limaprosts” means one or more selected from the group consisting of limaprost, a salt thereof, and an inclusion compound containing limaprost.

  The agent of the present invention contains at least one member selected from the group consisting of an inclusion compound containing limaprost, a salt thereof and limaprost as an active ingredient, and limaprost as an active ingredient is administered to a patient with eustachian tube. In terms of 5 to 50 μg, preferably 15 to 30 μg, more preferably 15 or 30 μg per day, it is not particularly limited as long as it is an agent for oral administration for 1 day to 52 weeks. As the limaprost, limaprost may be contained as it is or in the form of an inclusion compound such as a salt thereof or a cyclodextrin inclusion compound thereof. The agent of the present invention only needs to contain one or more of the inclusion compounds containing limaprost, a salt thereof and limaprost.

  In this specification, limaprost means the following formula (I)

The chemical name is (E) -7-[(1R, 2R, 3R) -3-hydroxy-2-[(3S, 5S)-(E) -3-hydroxy-5-methyl- 1-nonenyl] -5-oxocyclopentyl] -2-heptenoic acid (Registry No. 74397-12-9).

  Examples of the cyclodextrin inclusion compound of limaprost include, for example, α-cyclodextrin inclusion compound, β-cyclodextrin inclusion compound, and γ-cyclodextrin inclusion compound of limaprost. II)

A compound in which limaprost is clathrated with α-cyclodextrin is preferred. The chemical name of this compound is (E) -7-[(1R, 2R, 3R) -3-hydroxy-2-[(3S, 5S)-(E) -3-hydroxy-5-methyl-1-nonenyl. ] -5-Oxocyclopentyl] -2-heptenoic acid [alpha] -cyclodextrin inclusion compound (Registry No. 100459-01-6), generally known as limaprost alphadex. This is synonymous with “Limaprost Alphadex” listed in the 15th revision Japanese Pharmacopoeia.

  In the present invention, unless otherwise specified, symbols will be apparent to those skilled in the art.

Represents binding to the other side of the page (ie α-configuration),

Indicates that it is bonded to the front side of the paper (that is, β-configuration).

  The salt of limaprost is a non-toxic salt, particularly a pharmaceutically acceptable salt, and examples of such a salt include sodium salt and potassium salt.

  In the present invention, limaprost is preferably used in the form of an α-cyclodextrin inclusion compound of limaprost represented by the above formula (II), that is, limaprost alphadex.

Eustachian tube is a disease in which the normally closed eustachian tube remains open, and the symptoms include various symptoms of eustachian tube, such as self-voice emphasis, ear closure. Listening to self-breathing sounds, dizziness, dizziness, hearing loss, hearing loss, earache, tinnitus, neck stiffness, shoulder stiffness, headache, depression, etc.

  Any method can be used for evaluating the eustachian tube as long as it is a generally known method. For example, it is possible to make a diagnosis by listening to subjective symptoms or using an eustachian function test apparatus. Examples of the diagnosis using the eustachian tube function test apparatus include an eustachian tympanic airflow dynamic method (TTAG), an acoustic eustachian tube method, a pressurized / depressurized method, an eustachian catheter ventilation method, and an impedance method.

Dosage and Administration Method The dosage of the limaprost used in the present invention is not particularly limited as long as it is effective in improving the eustachian tube and its symptoms. It is preferable to administer 15 μg or 30 μg as the amount converted to the compound represented by the above formula (I) (Limaprost). In addition, the dose of limaprost per administration is preferably 5 μg to 10 μg, particularly 5 μg or 10 μg in terms of limaprost. When limaprost is administered as a cyclodextrin inclusion compound of limaprost (eg, limaprost alphadex), the limaprost contained in the cyclodextrin inclusion compound of limaprost is 5 μg to 50 μg, preferably 15 μg to 30 μg per day. Preferably, it may be administered in terms of such an amount that 15 μg or 30 μg is administered.

  As an administration method, it is preferable to administer once to three times a day, and it is particularly preferable to administer three times a day in the morning, noon, evening, preferably after each meal. In addition, the administration period may be any period as long as it is effective, and varies depending on the type and severity of symptoms. For example, it is preferably 1 to 52 weeks, more preferably 3 to 26 weeks. preferable. More preferably, it is 1 week to 12 weeks, and particularly preferably 2 weeks to 8 weeks. During the administration period, the above amount of limaprost may be administered daily or intermittently, but is preferably administered daily.

  In the present invention, the route of administration of limaprost is oral administration, and the dosage form for oral administration is preferably a solid preparation (eg, tablet, granule, capsule, etc.). In the solid preparation, limaprost may be contained as limaprost alphadex. More preferred are tablets (for example, uncoated tablets, dry-coated tablets, coated tablets, trilayer tablets, etc.). The tablet may be a sustained-release preparation such as an intraoral rapidly disintegrating tablet. Tablets containing limaprost include, for example, Opalmon Tablets (trade name), Prolenal Tablets (trade name), Opaprosmon Tablets (trade name), Optilan Tablets (trade name), Zeflop Tablets (trade name), Limalmon Tablets (trade name) And Limaprost Alphadex tablets containing Limaprost as Rimaprost Alphadex, such as 5 μg “F” (trade name) of Limaprost Alphadex tablets. Furthermore, the tablet containing limaprost may be other than the above-described tablet as long as it contains limaprost.

  The amount of limaprost in the tablet is preferably 5 μg to 10 μg, particularly 5 μg or 10 μg in terms of limaprost per tablet. In the tablet, when limaprost is contained as a cyclodextrin inclusion compound of limaprost (for example, limaprost alphadex), the limaprost contained in the cyclodextrin inclusion compound of limaprost is 5 μg or 10 μg in one tablet. What is included in terms of conversion is preferable. As the tablet containing limaprost, limaprost alphadex tablet containing limaprost as limaprost alphadex is preferable.

  In addition, limaprost can be used for other drugs used for the treatment of eustachian tube, such as Kampo medicines (Kamiki-spa-to, Hanka-moen Tenma-to, Hochuekki-to, etc.), anxiolytics , And may be administered in combination with vitamin preparations, ATP preparations and the like. Limaprosts and the above other drugs may be formulated into a single preparation containing both and administered simultaneously. Alternatively, both may be formulated separately and administered separately or simultaneously.

Method for producing compound used in the present invention Limaprost or limaprost alphadex used in the present invention can be produced by a known method, for example, the method described in JP-A No. 55-100300. The salt and inclusion compound of limaprost can be obtained from limaprost by a known method. As described above, a drug containing an α-cyclodextrin inclusion compound of limaprost (Limaprost alphadex) is commercially available.

Toxicity The toxicity of limaprosts used in the present invention, in particular, limaprost and its cyclodextrin inclusion compounds (such as limaprost alphadex) is extremely low and is sufficiently safe for use as a medicament.

Application to medicines Limaprosts used in the present invention are useful as prophylaxis, treatment and / or symptom improving agents for eustachian tube. Specifically, limaprosts are converted to limaprost, and are orally administered at 15 μg or 30 μg per day for 1 to 52 weeks. Furthermore, by converting orally limaprost into limaprost and orally administered at 15 μg or 30 μg per day for 1 to 52 weeks, various symptoms of eustachian canal, such as voice emphasis, ear closure, listening to self-breathing sounds It also improves lightheadedness, dizziness, hearing loss, hearing loss, ear pain, tinnitus, neck stiffness, shoulder stiffness, headache, and depression.

In order to use the administration target limaprost for the above-mentioned purpose, the limaprost is orally administered to a patient with eustachian tube. Limaprost is preferably administered in combination with the above-mentioned preferable dosage, administration method, administration period, administration route, dosage form and the like.

  In addition, limaprosts are drugs used for the treatment of eustachian tube (for example, Chinese herbal medicine (Kamikishouyu, Hanka Hyakuen Tento, Hochuekkito, etc.), anxiolytics, vitamins It is also effective for patients in whom preparations, ATP preparations, etc.) are ineffective.

Formulation In the present invention, a solid formulation containing limaprost is produced by adding a pharmaceutically acceptable additive to limaprost, if necessary, and using a technique widely used as a single formulation or a combination formulation. Can do. In formulating, limaprost may be used as limaprost alphadex.

  In the case of producing a solid preparation containing limaprosts, an additive may be further contained in addition to the limaprosts. The additive may be any one that is generally used in the production of solid preparations, for example, excipients, binders, lubricants, disintegrating agents, flavoring agents, flavoring agents, surfactants, A fragrance, a colorant, an antioxidant, a concealing agent, an antistatic agent, a fluidizing agent, a wetting agent, or the like can be appropriately used in combination of one or more.

  Examples of the excipient include glucose, fructose, maltose, lactose, isomerized lactose, reduced lactose, sucrose, D-mannitol, erythritol, maltitol, xylitol, palatinose, trehalose, sorbitol, corn starch, potato starch, wheat Starch, rice starch, crystalline cellulose, talc, anhydrous silicic acid, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate, dextran (eg, dextran, dextran 40, dextran 70, etc.), pullulan, dextrin, β-cyclodextrin, alphalation Examples include starch. Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, polyvinylpyrrolidone, methylcellulose, polyvinyl alcohol, carboxymethylcellulose, partially pregelatinized starch, pregelatinized starch, sodium alginate, pullulan, gum arabic powder, gelatin, dextrin and the like. One or two or more of these may be appropriately blended and used. Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate, stearic acid, talc, polyethylene glycol and the like. Examples of the disintegrant include low-substituted hydroxypropylcellulose, carmellose, carmellose calcium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, hydroxypropyl starch, and corn starch. Examples of the corrigent include sucrose, D-sorbitol, xylitol, citric acid, ascorbic acid, tartaric acid, malic acid, aspartame, acesulfame potassium, thaumatin, sodium saccharine, dipotassium glycyrrhizin, sodium glutamate, 5'-sodium inosinate, 5 ' -Sodium guanylate etc. are mentioned. Examples of the flavoring agent include trehalose, malic acid, maltose, potassium gluconate, anise essential oil, vanilla essential oil, cardamom essential oil and the like. Examples of the surfactant include polysorbate (polysorbate 80 and the like), polyoxyethylene / polyoxypropylene copolymer, sodium lauryl sulfate, and the like. As a fragrance | flavor, lemon oil, orange oil, menthol, brackish oil etc. are mentioned, for example. Examples of the colorant include titanium oxide, food yellow No. 5, food blue No. 2, iron sesquioxide, yellow iron sesquioxide, and the like. Examples of the antioxidant include sodium ascorbate, L-cysteine, sodium sulfite, vitamin E and the like. Examples of the masking agent include titanium oxide. Examples of the antistatic agent include talc and titanium oxide. Examples of the fluidizing agent include light anhydrous silicic acid, talc, hydrous silicon dioxide and the like. Examples of the wetting agent include polysorbate 80, sodium laurate sulfate, sucrose fatty acid ester, macrogol, and hydroxypropyl cellulose (HPC). These additives are generally blended in proportions usually used for oral preparations. In addition to the above, additives such as those described in publicly known documents, for example, “Pharmaceutical Additives Encyclopedia” (edited by Japan Pharmaceutical Additives Association) published in 2000, etc., may be used.

  A solid preparation containing limaprost can be produced by a known method, for example, using a rolling granulator, a stirring granulator, a fluid granulator, a centrifugal rolling granulator, a dry granulator, etc. The granules can be produced by granulation.

  For the solid preparation, for example, the granules obtained by the above method can be used as granules as they are. The solid preparation also includes a capsule containing the granule. Capsules can be produced by a known method. For example, the above-mentioned granules, and those to which additives are added as necessary are hard capsules (for example, gelatin capsules, hydroxypropylmethylcellulose (HPMC) capsules, pullulan capsules, polyvinyl alcohol) (PVA) capsule or the like) can be filled by using a capsule filling machine. The solid preparation includes a tablet containing the granule. The tablet can be produced by a known method. For example, the above granules and additives as necessary may be mixed evenly, and compression-molded by a rotary tableting machine to obtain an uncoated tablet, which may be used as a tablet as it is, Furthermore, you may coat | cover using a coating base. It is also possible to prepare a mixed powder containing a drug or the like without granulation and tablet it with a rotary tableting machine or the like. Furthermore, a lyophilized product obtained by dissolving limaprost and an excipient in a solvent (for example, water, an organic solvent (for example, ethanol, acetone, or the like), or a mixed solvent thereof) instead of the granule, and lyophilizing according to a conventional method. May be used to produce tablets. That is, after lyophilized product containing limaprost is pulverized, additives may be added and mixed as necessary to form tablets by tableting.

  Hereinafter, although an example explains the present invention in detail, the present invention is not limited to these.

Example 1 Effect of limaprost on eustachian tube <Case 1>
(1) Patient background A 76-year-old woman. Eustachian tube was diagnosed by subjective symptom such as self-voice enhancement and eustachian tympanic airflow dynamics method (TTAG) using an eustachian function test device.
(2) Effects of Limaprost administration Patients are given Opalmon (Limaprost Alphadex Tablets containing 5 μg of Limaprost in one tablet), once a tablet, 3 times a day (in combination with vitamin B12 preparations, methicobar and ATP preparation). That is, 15 μg / day in terms of limaprost was administered for 28 days. As a result, subjective symptoms disappeared, and an improvement in the findings of open ear canal due to TTAG was observed.

<Case 2>
(1) Patient background A 62-year-old male. Eustachian tube was diagnosed based on subjective symptoms such as ear closure and TTAG.
(2) Effect of administration of limaprost Patients were treated with opalmon (Limaprost alfadex tablet containing 5 μg of limaprost in 1 tablet), 2 tablets at a time, 3 times a day (ie, 30 μg / day in terms of limaprost), 62 Administered for 1 day. As a result, the subjective symptoms improved in 20 days, the subjective symptoms disappeared in 62 days, and the findings of opening the eustachian tube by TTAG improved.

<Case 3>
(1) Patient background A 46 year old male. Open tube was diagnosed based on subjective symptoms such as ear closure and ear pain and TTAG.
(2) Effect of Limaprost Administration The patient was administered Chinese herbal medicine (Kamiki Kaito, Hanka Hyakuten Tento) and Depass, an anxiolytic drug, for 2 weeks, but the symptoms did not improve. Therefore, Opalmon (Limaprost alphadex tablet containing 5 μg of limaprost in one tablet) was administered once a month, 3 times a day (ie, 15 μg / day in terms of limaprost) for 1 month. As a result, subjective symptoms disappeared, and the findings of opening the eustachian tube by TTAG improved.

<Case 4>
(1) Patient background A 60-year-old male. Eustachian tube was diagnosed based on subjective symptoms such as ear closure and TTAG.
(2) Effect of Limaprost Administration The patient received steroid preparation prednin, vitamin B12 preparation methicobar, ATP preparation and Kamijosui, but the symptoms did not improve. Therefore, when predonin was switched to opalmon (15 μg / day in terms of limaprost) and used in combination with methicobar, ATP preparation, and Kamijosui, subjective symptoms such as ear closure improved after 2 weeks and 45 days The disappearance of subjective symptoms and improvement of the findings of open ear canal due to TTAG were observed.
Note that the steroid preparation is prescribed in anticipation of an effect on inner ear diseases such as Meniere's disease suspected of being accompanied.

<Case 5>
(1) Patient background 71 years old male. Eustachian canal was diagnosed based on subjective symptoms such as ear closure and TTAG.
(2) Effect of administration of limaprost When a patient was administered metikobar, which is a vitamin B12 preparation, an ATP preparation, Kamijosuito and Opalmon (15 μg / day in terms of limaprost), two weeks after the administration, such as ear closure Improvement in subjective symptoms and findings of open ear canal due to TTAG were observed, and subjective symptoms disappeared one month after administration.

  As described above, it was confirmed that limaprosts are effective for eustachian tube and its symptoms. In clinical practice, it was confirmed that Kampo medicines, anti-anxiety drugs, vitamin preparations and ATP preparations used for patients with open ear canal were also effective for patients who were ineffective.

[Formulation example]
The typical formulation example used for this invention is shown below.
Formulation Example 1
350 g of dextran 40 was weighed and dissolved in 1875 g of purified water. 50 g of limaprost alphadex was dissolved in this, and then lyophilized according to a conventional method. 4 g of the obtained powder was mixed with 26 g of dextrin, 252.9 g of lactose, 15 g of corn starch, 0.6 g of light anhydrous silicic acid, and 1.5 g of stearic acid, and mixed using a rotary tableting machine. The compound represented by the above formula (I) per tablet (100 mg, 6.5 mmφ) was obtained by tableting at a tablet pressure of 800 kg / cm ² and drying under conditions of 60 ° C. and 0.1 kilopascal or less for 2 hours. 2000 tablets containing 5 μg were obtained.

<Composition in one tablet (100 mg)>
Limaprost Alphadex 0.167 mg
(5 μg as a compound represented by the formula (I))
Dextran 40 1.167 mg
Dextrin 8.67 mg
Lactose 84.3 mg
Corn starch 5.0 mg
Light anhydrous silicic acid 0.20 mg
Stearic acid 0.50 mg
100 mg total

  Limaprosts are effective as preventive and / or therapeutic agents for eustachian tube. Various symptoms such as self-voice emphasis, ear closure, self-breathing listening, dizziness, dizziness, hearing loss, hearing loss, ear pain, tinnitus, neck stiffness, stiff shoulders, headache, depression, etc. It is also effective as a symptom improving agent.

  Limaprost is also effective for patients for whom Chinese herbal medicine, anxiolytics, vitamin preparations and ATP preparations used in clinical practice are ineffective.

  Therefore, it is possible to provide a new preventive, therapeutic and / or symptom-ameliorating agent for Eustachian tube for which an effective treatment method has not been established.

Claims (7)

A prophylactic, therapeutic and / or symptom-improving agent for eustachian tube opening, comprising limaprosts. The agent according to claim 1, wherein the limaprost is limaprost alphadex. Symptoms of eustachian tube are one selected from self-emphasis, ear-closedness, listening to self-breathing, dizziness, dizziness, hearing loss, hearing loss, ear pain, tinnitus, neck stiffness, stiff shoulders, headache and depression It is the above, The agent of Claim 1. The agent according to claim 1, wherein the eustachian tube is eustachian tube in a patient for whom Chinese medicine, anxiolytics, vitamin preparations and / or ATP preparations are ineffective. The agent according to claim 1 or 2, wherein an amount of 5 to 10 µg per dose is orally administered to a patient with eustachian tube 3 times a day for 1 to 52 weeks in terms of limaprost. . 6. The agent according to claim 5, wherein the eustachian tube patient is a patient for whom Chinese medicine, anxiolytic drugs, vitamin preparations and / or ATP preparations are ineffective. Furthermore, the agent of Claim 1 formed by combining at least 1 sort (s) of medicine chosen from the group which consists of a Chinese medicine, an anxiolytic, a vitamin preparation, and an ATP preparation.