Method for treating Meniere's disease

A medicine for the treatment of Meniere's disease containing, as an active ingredient, erythritol which is capable of significantly reducing the endolymphatic pressure by oral administration of a therapeutically effective amount of erythritol as an active substance.

DESCRIPTION
 1. Technical Field
 The present invention relates to a medicine for the treatment of Meniere's
 disease containing erythritol as an active ingredient.
 2. Background Art
 Meniere's disease is a disease of unknown cause, but it has been reported
 to be an endolymphatic hydrops by nature. It is believed that
 endolymphatic fluid accumulates due to excess production of endolymphatic
 fluid or due to disorders in absorption, whereby the endolymphatic hydrops
 is formed and the Reissner's membranes of the cochlear duct is risen and,
 as a result, symptoms such as ringing of the ears, hearing difficulties,
 dizziness, and a feeling of blocked ears are generated.
 In the past, as a medicine for the treatment of Meniere's disease, the
 osmotic pressure diuretic medicine, Isosorbide (i.e.,
 1,4:3,6-dianhydro-D-sorbitol) has been used as an oral administration
 agent for the purpose of alleviating the endolymphatic hydrops. However,
 the osmotic pressure diuretic medicine, Isosorbide currently, which is
 clinically applied as a medicine for the treatment of Meniere's disease
 has difficulties in the viewpoint of taste. Further, it is a liquid, and
 therefore, there is the problem of inconvenience in the transportation.
 DISCLOSURE OF THE INVENTION
 Accordingly, an object of the present invention is to provide a medicine
 for the treatment of Meniere's disease which is superior in the viewpoint
 of taste, is capable of reducing the amount of the medicine to be
 administered by improving the type of formulation, and is easy to take by
 patients.
 In accordance with the present invention, there is provided a medicine for
 the treatment of Meniere's disease comprising erythritol as an active
 ingredient.

BEST MODE FOR CARRYING OUT THE INVENTION
 The present inventors engaged in various studies to find a medicine for the
 treatment of Meniere's disease superior to Isosorbide in viewpoint of
 taste and, as a result found that by intraduodenum administration of an
 erythritol aqueous solution, the endolymphatic pressure could be decreased
 quickly and found that, when using an aqueous erythritol solution as an
 oral agent, there is an equivalent effect as with isosorbide in viewpoint
 of dosage, whereby the present invention was completed.
 According to the present invention, there is provided a medicine for the
 treatment of Meniere's disease having erythritol as an active ingredient.
 By orally ingesting a therapeutically effective amount of erythritol as an
 active ingredient, it is possible to significantly decrease the
 endolymphatic pressure.
 The medicine for treatment of Meniere's disease according to the present
 invention is used in an amount, converted to erythritol, of normally 0.5
 to 3 g/kg, preferably 0.8 to 1.5 g/kg, per kg body weight, and is taken
 one to three times a day depending on the symptoms.
 Erythritol has the characteristics of having a refreshing sweet taste,
 being noncarious, and having zero calories, and therefore, is used in
 various confectioneries and beverages as a sweetener (or food ingredient).
 The toxicity thereof is extremely low. This is clear from the results of
 pilot acute toxicity tests using rats (LD.sub.50 value (g/kg), oral
 administration: males 11.8, females 9.5, intravenous administration: males
 6.1, females 5.4) (see Japanese Examined Patent Publication (Kokoku) No.
 7-103017).
 The medicine for treatment of Meniere's disease according to the present
 invention may be administered by all types of preparations as oral agents
 such as, for example, liquids, powders, granules, suspensions, tablets,
 capsules, dry syrups, etc. However, since the amount to be administered
 becomes large, powders, granules, and suspensions are preferable. In this
 way, in a preferable aspect of the present invention, the medicine for
 treatment of Meniere's disease according to the present invention is
 composed of erythritol as an active ingredient and, if desired, a base
 material. The concentration of the erythritol in the medicine composition
 is not particularly limited, but preferably is 90 to 100% by weight of the
 composition.
 A suspension may be produced by adding and mixing to the erythritol,
 normally 0.1 to 10% by weight, preferably 0.2 to 1% by weight, per
 erythritol, of a suspension of one or more types of a suspending agent (or
 base material) selected from the group consisting of polyvinyl
 pyrrolidone, sodium carboxymethyl cellulose, carboxyvinyl polymer,
 hydroxypropyl cellulose, hydroxypropylmethyl cellulose, xanthane gum,
 gelatin, tragacanth gum, crystalline cellulose, alginate, agar, etc.
 Further, it is possible to add a flavor (e.g., 0.001 to 0.1% by weight) or
 a sweetener (e.g., 0.1 to 1% by weight) to the suspension to improve the
 ease of the administration.
 A granular preparation may be produced by, for example, adding water,
 ethanol, or a mixed solution thereof etc. to erythritol, mixing them in a
 kneader, extruding the resultant mixture by the means of an extrusion
 granulator etc., drying the extrudate and sieving it after drying to
 obtain granules, then adding a small amount of Carbopol 971P ("trademark"
 for carboxyvinyl polymer made by B.F. Goodrich) and magnesium stearate
 etc. followed by mixing to obtain the granules. The granular preparation
 thus obtained can be ingested as it is or by suspension in a suitable
 amount of water.
 A high density granular preparation can be produced, without using water,
 by mixing erythritol, a gum such as xanthane gum and tragacanth gum, and a
 lubricant such as calcium stearate and extruding the mixture under a high
 pressure, etc. The obtained high density granular preparation thus
 obtained may be administered as it is or after suspended in water.
 The medicine for treatment of Meniere's disease according to the present
 invention may have suitably compounded thereinto, to an extent as long as
 the object of the present invention is not impaired, other medicinal
 ingredients, for example, a sympathetic nerve .beta.-agonist, a
 vasodilative, or a cerebral circulation improving drug as a medicine
 having an action improving the circulation in the inner ear, a diuretic or
 adrenacortical steroid as a medicine for alleviating hydrolabyrinth, and a
 sedative, tranquilizer, antiemetic, anti-dizziness agent, or autonomic
 regulator as a medicine for sedation or control of nausea.
 EXAMPLES
 The present invention will now be explained in further detail to clarify
 the effects of the present invention with reference to pharmacological
 tests of the preparations and the Preparations Examples, but these are
 merely illustrations. The present invention is by no means limited
 thereto.
 Test Example 1 (Endolymphatic Pressure Reducing Action)
 Test Method
 (Animals)
 Guinea pigs (Hartley strain, body weights of 300 to 500 g) were used as
 groups each having 13 to 14 pigs.
 (Test Medicines)
 (1) Erythritol: The amounts of erythritol administered were three dosages
 of 0.7, 1.4, and 2.8 g/kg. These were dissolved in, and diluted with,
 distilled water to the administration volumes of 8 ml/kg.
 (2) Isosorbide: The amounts of isosorbide administered as well were three
 dosages of 0.7, 1.4, and 2.8 g/kg. These were dissolved in, and diluted
 with, distilled water to the administration volumes of 8 ml/kg.
 (Endolymphatic Sac Silver Nitrate Corrosion Method)
 According to the method of Yazawa (Daishiro Yazawa, Jibi Rinsho, 74: 2450
 to 2506 (1981)), a small amount (30 to 50 .mu.l) of a 10% aqueous silver
 nitrate solution was surgically injected into the endolymphatic sac and,
 then, the incision sewn closed. Individuals after more than 21 days from
 the surgery were made to fast for at least 18 hours and, then, orally
 given the test medicine. One hour after the administration, the existence
 of urination was confirmed, then the animal was fixed under perfusion
 under anesthesia and the degree of hydrops in the cochlear duct was judged
 according to the criteria of Paparella (Paparella, M. M. et al.:
 Laryngoscope, 89:43-54 (1979) as:
 None: 0, Slight: 1, Medium: 2, Severe: 3 The degree of advance of the eight
 Reissner's membranes in the cochlear duct which could be recognized as
 tissue sections was scored. The average was used as the result of the test
 of the individual.
 Results
 As a result of the test, the hydrops score of the distilled water
 administration group in the endolymphatic hydrops model was 1.66.+-.0.27.
 For erythritol, a dosage-dependent reduction in the hydrops score due to
 oral administration of 0.7 g/kg, 1.4 g/kg, and 2.8 g/kg to 1.45.+-.0.49,
 1.21.+-.0.31, 0.70.+-.0.25 was recognized. In the 2.8 g/kg administration
 group, the hydrops score was significantly decreased compared with the
 distilled water administration group. For Isosorbide, a dosage-dependent
 decrease in the hydrops score due to oral administration of 0.7 g/kg, 1.4
 g/kg, and 2.8 g/kg to 1.33.+-.0.32, 1.01.+-.0.38, and 0.72.+-.0.30 was
 recognized. In the 2.8 g/kg group, the edema score was significantly
 decreased compared with the distilled water group.
 FIG. 1 shows the results of the test for 0.7 g/kg, 1.4 g/kg, and 2.8 g/kg
 of erythritol and for 0.7 g/kg, 1.4 g/kg, and 2.8 g/kg of Isosorbide.
 Test Example 2 (Endolymphatic Pressure Reducing Action)
 Test Method
 (Animals)
 Guinea pigs (Hartley strain, body weights of 300 to 500 g) were used as
 groups each having three to five pigs.
 (Test Medicines)
 Erythritol: The amounts of erythritol administered were two dosages of 1.4
 and 2.8 g/kg. These were dissolved in, and diluted with, distilled water
 to the administration volumes of 8 ml/kg.
 (Endolymphatic Sac Silver Nitrate Corrosion Method and Endolymphatic
 Pressure Measurement Method)
 According to the method of Yazawa (Daishiro Yazawa, Jibi Rinsho, 74: 2450
 to 2506 (1981)), a small amount (30 to 50 .mu.l) of a 10% aqueous silver
 nitrate solution was surgically injected into the endolymphatic sac and
 then the incision sewn closed. Individuals after more than 21 days from
 surgery were anesthetized and the respiratory tract secured, then a
 cannula was inserted into the duodenum and the test medicine injected.
 The trunk was held in the prone position, the rear of the middle-ear cavity
 was cut open, and the cochlear duct was exposed. The cochlear basal
 rotatory tympanic wall or stria vascularis confirmed from the round window
 was cut open by a microdrill, then a glass capillary connected to a
 polyethylene tube was inserted into the basal rotatory cochlear duct using
 a micromanipulator and affixed air-tightly.
 The inside of the closed circuit was filled, in advance, with endolymphatic
 equivalent solution, the polyethylene tube was connected to a pressure
 transducer, and the results recorded in a recticorder through an
 amplifier.
 The test substance started to be administered after confirmation of the
 stability of the endolymphatic pressure.
 Results
 As a result of the above test, no change could be recognized in the
 endolymphatic pressure of the distilled water group. A dosage-dependent
 fall in the endolymphatic pressure due to the administration of 1.4 g/kg
 and 2.8 g/kg of erythritol into the duodenum was observed. In both the 1.4
 g/kg group and the 2.8 g/kg group, the endolymphatic pressure was
 significantly decreased, compared with the distilled water group.
 FIG. 2 shows the results of tests using distilled water and 1.4 g/kg and
 2.8 g/kg of erythritol.
 Test Example 3 (Action Raising Plasma Osmotic Pressure)
 Test Method
 (Animals)
 Guinea pigs (Hartley strain, body weights of 300 to 500 g) were used as
 groups each having five pigs.
 (Test Medicine)
 Erythritol: The amounts of erythritol administered were two dosages of 1.4
 g/kg and 2.8 g/kg. These were dissolved in, and diluted with, distilled
 water to the administration volumes of 8 ml/kg.
 (Method)
 Normal guinea pigs were each anesthetized and their respiratory tracts
 secured, then a canular was inserted in the left carotid artery and used
 to sample blood. Further, a cannula was inserted into the duodenum and
 used to inject the test medicine. The trunk was held in the supine
 position and the blood was sampled before administration (pre). The blood
 was then sampled 15 minutes, 30 minutes, 60 minutes, 120 minutes, and 180
 minutes after administration of the test substance. After sampling, to
 secure the amount of body fluid, physiological saline of the same amount
 as the blood sampled was injected from the blood sampling cannula. The
 sampled blood was separated by centrifugation, then the plasma was taken
 and the plasma osmotic pressure was measured using an osmotic pressure
 meter.
 Results
 As a result of the above test, no change could be recognized in the plasma
 osmotic pressure of the distilled water group. It was recognized by the
 administrations of 1.4 g/kg and 2.8 g/kg of erythritol that a
 dosage-dependent rise in the plasma osmotic pressure after 15 minutes from
 administration of the medicine into the duodenum peaked at 30 minutes and
 60 minutes after administration. In particular, in the 2.8 g/kg erythritol
 group, a significant increase in the plasma osmotic pressure continued
 until 180 minutes after administration.
 FIG. 3 shows the results of tests using distilled water and 1.4 g/kg and
 2.8 g/kg of erythritol.
 Example 1 (Suspension)
 2 g of Carbopol 971P (trademark) and 2 g of citric acid were added to 200 g
 of erythritol. These were mixed in a mixer for 15 minutes to form a
 preparation, whereby a suspension capable of being suspended and taken at
 the time of use is produced. This preparation can be ingested by
 suspending a suitable amount (for example, packets corresponding to 10 g
 or 20 g of erythritol) in water at the time of use.
 Example 2 (Granules)
 20 g of water was added to 200 g of erythritol and mixed in a mixer. The
 mixture was mixed in a kneader, then dried at 60.degree. C., then graded
 by 12 mesh and 16 mesh sieves. 2 g of Carbopol 971P (trademark) and 2 g of
 magnesium stearate were added to the granules thus obtained to form a
 granular preparation. The preparation can be ingested by suspending
 packets containing suitable amounts in water at the time of use.
 Example 3 (High Density Granules)
 A high density granular preparation was prepared without using water by
 extruding (1 mm diameter) 200 g of erythritol, 2 g of xanthane gum, and 2
 g of calcium stearate using an extruder (Kurimoto Tekko). The preparation
 can be ingested by suspending packets containing suitable amounts in water
 at the time of use.
 Example 4 (Preparation of Spherical Granules)
 75 g of ethanol was added to 285 g of erythritol (100 mesh sieved product)
 and 15 g of anhydrous citric acid (100 mesh sieved product) and the
 mixture kneaded using a Shinagawa type universal mixer to prepare a paste.
 Next, this paste was extruded and granulated in a basket type granulator
 equipped with a 0.6 mm screen (die) to prepare crude granules. The crude
 granules thus obtained were transferred to a high speed mixing, agitating,
 and granulating device (high speed mixer FS-GS-10J, Fukae Kogyo K. K.)
 having a spherical granulating disk attached to the agitator and a
 granulating blade attached to a chopper. The device was operated for 30
 seconds at a speed of 200 rpm of the agitator and 2000 rpm of the chopper
 to make the granules spherical. These were dried at 60.degree. C. for 2
 hours, then passed through a 14 mesh (1.18 mm) sieve and graded to a size
 remaining on a 42 mesh (0.35 mm) sieve to prepare a granular preparation
 (spherical granules).
 INDUSTRIAL APPLICABILITY
 The medicine for the treatment of Meniere's disease according to the
 present invention has the advantage of a much easier administration
 compared with isosorbide in terms of taste. Further, erythritol is
 noncarious and has zero calories, and therefore, there is the advantage
 that there is no concern over cavities or over administration of calories.
 Further, by formulating it as a powder, suspension, or granules, there is
 the advantage that less of an amount of the medicine should be
 administered compared with Isosorbide and the load on the patient can be
 lessened from this viewpoint as well.