JP5030553B2 - Pharmaceuticals for treating dry mice and / or salivary secretion disorders - Google Patents

Description

  The present invention relates to a medicament for treating an exocrine disorder, and particularly to a medicament for treating a dry mouse and / or salivary secretion disorder.

  Exocrine secretion refers to secretions that are released directly from glandular cells or into the body surface or lumen through conduits or the like. Tear and saliva are typical exocrine secretions, including secretion from the nasal mucosa and airway mucosa, secretion from the stomach or intestine, secretion from the vagina, sweat and the like. Diseases resulting from exocrine disorders include “dry eye” (dry eye), “dry mouse” (dry mouth), “dry nose” (nasal dryness), “dry skin” (dry skin) and “ Examples include dry symptoms such as “Driver Jain” (vaginosis) and dryness of various parts of the body such as chronic pancreatitis, chronic gastritis and chronic bronchitis due to reduced exocrine secretion.

  In particular, a dry mouse (xerostomia) is mentioned as a disease associated with a salivary secretion disorder. Dry mice dry the lips and mouth due to a decrease in saliva secretion for some reason, causing various disorders such as dry mouth, dry mouth mucosa, burning sensation, mastication disorder, swallowing disorder, In addition, there is also a harmful effect such as causing the growth of tooth decay because food residue tends to remain. The causes of dry mice are various, including those that are unknown, but therapies include coping therapies such as drinking liquids all day long, chewing gum, and using artificial saliva. However, non-patent literature 1: Lancet 366: 321-331 2005), there is an eager desire to establish a drastic treatment for improving the decrease in salivary secretion.

  D-β-hydroxybutyric acid is a kind of ketone body, and is an alternative energy source when the human body cannot use sugar as energy, such as in starvation. It has been reported that administration of D-β-hydroxybutyric acid activates the ATP-producing ability of intracellular mitochondria in model mice with Parkinson's disease, thereby protecting the nerve from degeneration (non-patented). Reference 2: J Clin Invest 112: 892-901 2003). In addition, it has been reported that apoptosis in the corneal epithelium can be suppressed by instilling a D-β-hydroxybutyric acid aqueous solution (Non-patent Document 3: Invest Ophthalmol Vis Sci 44: 4682-4688 2003).

Lancet 366: 321-331 2005 J Clin Invest 112: 892-901 2003 Invest Ophthalmol Vis Sci 44: 4682-4688 2003

  An object of the present invention is to provide a medicament effective for treating an exocrine disorder.

  The present inventors considered that the action of suppressing the tissue damage of the ketone body would lead to the improvement of the pathology of the mucosa and salivary gland tissue even in the oral region. As a result, the present inventors have surprisingly found that a ketone body or a salt thereof has an action of improving an exocrine disorder and completed the present invention. That is, according to one aspect of the present invention, there is provided a medicament for treating an exocrine disorder comprising a ketone body or a pharmaceutically acceptable salt thereof as an active ingredient.

  As will be described in detail below, according to the present invention, an effective medicament for treating an exocrine disorder is provided.

  Embodiments of the present invention will be described below. However, the following description is for specifically explaining the present invention, and is not intended to limit the technical scope of the present invention.

  As described above, according to one aspect of the present invention, a medicament for treating an exocrine disorder is provided. According to another aspect of the present invention, a method for treating an exocrine disorder in a subject suffering from an exocrine disorder is provided. Moreover, according to the other aspect of this invention, use of the ketone body for manufacturing the pharmaceutical for treating an exocrine disorder is provided.

  The medicament according to the present invention contains a ketone body or a pharmaceutically acceptable salt thereof as an active ingredient. The ketone body is a general term for acetone, acetoacetic acid and β-hydroxybutyric acid. In particular, the ketone body is preferably β-hydroxybutyric acid (HBA), and the β-hydroxybutyric acid is more preferably D-β-hydroxybutyric acid.

  The pharmaceutically acceptable salt is preferably a conventional non-toxic salt. Specific examples of pharmaceutically acceptable salts include salts with inorganic bases such as alkali metal salts (sodium salt, potassium salt, etc.), alkaline earth metal salts (calcium salt, magnesium salt, etc.), and ammonium salts. Can be mentioned. Further, as a pharmaceutically acceptable salt, a salt with an organic base, for example, an amine salt (for example, methylamine salt, dimethylamine salt, cyclohexylamine salt, benzylamine salt, piperidine salt, ethylenediamine salt, ethanolamine salt, diethanolamine salt) , Triethanolamine salt, tris (hydroxymethylamino) ethane salt, monomethyl-monoethanolamine salt, lysine salt, procaine salt, caffeine salt, etc.), basic amino acid salt (eg arginine salt, lysine salt etc.), tetra Examples include alkyl ammonium salts.

  The ketone body or a pharmaceutically acceptable salt thereof can be obtained commercially, or can be prepared by any known method (see, for example, Invest Ophthalmol Vis Sci 44: 4682-4688 2003).

  The medicament according to the present invention can be used for subjects of mammals including humans and mice suffering from exocrine disorders. Exocrine disorder means an abnormal (decreased or stopped) exocrine secretion caused by some cause. Specifically, the exocrine disorder includes exocrine disorders in mucous membranes such as oral mucosa, vaginal mucosa, lung mucosa and nasal mucosa. In particular, exocrine disorders include salivary secretion disorders, tear secretion disorders and dry mice, dry skins, dry eyes, dry noses, and driver gynas. Dry mice and / or salivary secretion disorders may be thirsty or rough throat symptoms.

  In addition, systemic factors such as dry mice with exocrine disorders include cold, heat disease, dehydration, endocrine abnormalities (such as myxedema, Basedoo disease, diabetes insipidus), metabolic disorders (diabetes, uremia, cirrhosis, etc.) ), Vitamin A, B deficiency, autoimmune diseases (Sjogren's syndrome, progressive scleroderma, etc.), hypertension, kidney disease, anemia, bleeding, aging, menopause, drugs (sedatives, parasympathetic blockers, antihistamines, etc.) ) And the like. In addition, local factors that cause exocrine disorders such as dry mice include salivary glanditis, salivary gland atrophy (including those caused by aging), side effects of radiation gland treatment, congenital anomalies (ectodermal malformation, etc.), salivary gland-related Examples include nervous system disorders. The medicament according to the present invention can be used to treat an exocrine disorder associated with (eg resulting from) at least one of these.

  In the present specification, “treatment” includes controlling symptoms in all aspects, and specifically includes prevention, treatment, symptom reduction, symptom reduction, progression stoppage, and the like.

  The medicament according to the present invention comprises a therapeutically effective amount of a ketone body or a pharmaceutically acceptable salt thereof. The effective amount should be determined appropriately according to the target disease and its symptoms, the subject's (patient) age, weight, dosage form (including administration route and dosage form), treatment period, desired therapeutic effect, etc. Can do. In general, the effective amount is preferably 0.01 g / day to 2 g / day, and particularly preferably 0.11 g / day to 0.21 g / day.

  The medicament according to the present invention can be administered to a subject (patient) by any administration route including oral administration, local administration to a disease site such as in the oral cavity, and intravenous administration. In particular, the medicament according to the present invention is preferably administered by oral intraoral administration when applied to dry mice and / or salivary secretion disorders. Depending on the route of administration, the medicament according to the present invention can take any dosage form. In particular, the medicament according to the present invention is preferably in a dosage form suitable for local oral administration when applied to dry mice and / or salivary secretion disorders. More specifically, the medicament according to the present invention can be, for example, a sublingual agent, a troche, a chewing gum, a mouthwash, a spray, an ointment, a powder, a granule, a tablet, a capsule, an injection or the like. . These formulations can be formulated by various known methods.

  The medicament according to the present invention may contain various pharmaceutically acceptable additives in addition to the active ingredient, depending on the administration route and dosage form. Additives include excipients, carriers, diluents, extenders, solvents, lubricants, adjuvants, binders, disintegrants, coating agents, encapsulating agents, ointment bases, suppository bases, aerosol materials, emulsifiers , Dispersants, suspensions, thickeners, tonicity agents, buffers, soothing agents, preservatives, antioxidants, flavoring agents, fragrances, colorants, coating agents, stabilizers and functional agents Including. Those skilled in the art can appropriately select these additives from known materials according to the dosage form and the like.

  It is known that ketone bodies or pharmaceutically acceptable salts thereof do not show cytotoxicity in a therapeutically effective amount.

  Embodiments of the present invention will be described below with reference to the accompanying drawings. However, the following description is for explaining the present invention more specifically, and is not intended to limit the technical scope of the present invention.

[Experimental Example 1-1: Usefulness of D-β-hydroxybutyric acid in the treatment of dry mice]
[Target]
The subjects were 7 dry mouse patients and 4 healthy subjects who visited a special clinic for dry mice at Tsurumi University School of Dentistry. The dry mouse patient was 1 male and 6 female, with an average age of 57.4 +/− 15.4 years. The healthy subjects were 4 women and the average age was 59.8 +/- 12.5 years. The average amount of saliva during stimulation for dry mouse patients was 0.47 +/− 0.32 g on average, and 3.00 +/− 1.22 g for healthy subjects.

〔Method〕
Over a period of 2 weeks, a 3% by weight aqueous solution of D-β-hydroxybutyric acid was administered to the oral cavity five times a day, and subjective symptoms of dry mouth feeling before and after administration, changes in the water content of the oral mucosa and saliva secretion were observed. evaluated. One dose was 0.6 mL. The subjective symptoms of dry mouth were evaluated using a VAS (Visual analog scale) as 0 when no dry mouth was felt, and 100 when severe and unbearable. The moisture content of the oral mucosa was evaluated by the value of moisture checker / mucus (MCM) (manufactured by Life Co., Ltd.) in the buccal mucosa. The MCM measurement site was the buccal mucosa 10 mm behind the right mouth corner, and the probe was applied at 200 g / cm ² . A 12 μm thick sensor cover was used in all cases so that the probe did not directly contact the oral mucosa. The measurement was performed 3 times and the average value was calculated. Saxon test was used to measure salivary secretion. A 5 × 5 cm gauze was chewed for 2 minutes, and the difference in the weight of the gauze before and after chewing was measured as the amount of saliva secretion.

〔result〕
(1. Subjective symptoms of dry mouth)
FIG. 1 shows changes in dry mouth feeling (VAS) before and after administration with D-β-hydroxybutyric acid in the healthy subject group and the dry mouse patient group. As shown in FIG. 1, in the healthy subject group, the VAS average value of dry mouth feeling was 64.0 +/− 43.2 before administration, and changed to 62.5 +/− 43.9 after administration. In the dry mouse patient group, this value was 85.0 +/− 20.2 before administration and 80.4 +/− 21.0 after administration. The dry mouse group tended to show a higher VAS value than the healthy group. In each group, the VAS average value decreased after administration of D-β-hydroxybutyric acid.

(2. Moisture content of oral mucosa)
In FIG. 2, the change of the average value of MCM before and behind administration by D-beta-hydroxybutyric acid in a healthy subject group and a dry mouse patient group is shown. As shown in FIG. 2, in the healthy subject group, the average value of MCM was 29.8 +/− 9.1 before administration, and changed to 31.4 +/− 8.2 after administration. In the dry mouse patient group, this value is 31.5. It was +/- 5.1 and changed to 36.2 +/- 1.9 after administration. Thus, in the dry mouse patient group, the tendency for MCM value to increase was recognized by administration of D-β-hydroxybutyric acid. FIG. 4 (a) shows changes in the value of MCM before and after administration of D-β-hydroxybutyric acid in each case (dry mouse patient and healthy subject).

(3. Salivary secretion during stimulation)
FIG. 3 shows changes in salivary secretion during stimulation before and after administration with D-β-hydroxybutyric acid in healthy subjects and dry mice patients. As shown in FIG. 3, in the healthy subject group, the average value of the salivary secretion during stimulation was 3.00 +/− 1.22 g before administration, and changed to 3.16 +/− 1.08 g after administration. In the dry mouse patient group, this value was 0.47 +/− 0.32 g before administration and changed to 1.19 +/− 1.35 g after administration. Thus, in the dry mouse patient group, the tendency for saliva secretion amount to increase by administration of D-beta-hydroxybutyric acid was recognized. FIG. 4 (b) shows changes in the salivary secretion during stimulation before and after administration of D-β-hydroxybutyric acid in each case (dry mouse patient and healthy subject).

[Discussion]
From the above results, it was recognized that the administration of D-β-hydroxybutyric acid increased the water content of the oral mucosa and the amount of saliva during stimulation in the dry mouse patient group. From this, it can be seen that β-hydroxybutyric acid is effective in the treatment of dry mice and / or salivary secretion disorders.

[Experimental Example 1-2: Usefulness of D-β-hydroxybutyric acid in the treatment of dry mice]
For the purpose of verifying the results, cases were added and the amount of saliva secretion was measured by the Saxon test in the same manner as in Experimental Example 1-1. FIG. 5 shows changes in the salivary secretion during stimulation before and after administration with D-β-hydroxybutyric acid in 9 healthy subjects including additional cases and 12 dry mice patients. As a result, similar to the above, in the dry mouse patient group, there was a tendency that the amount of saliva secretion increased by administration of D-β-hydroxybutyric acid.

[Experimental Example 2: Effect of D-β-hydroxybutyric acid on ATP production ability of human salivary gland cells (HSY)]
〔Method〕
The influence of D-β-hydroxybutyric acid on the ATP production ability of human salivary gland cells (HSY) was examined. Intracellular ATP activity was measured in the presence (1, 5, 20 mM) and absence (0 mM) of D-β-hydroxybutyric acid. ATP activity was performed using an ATPlite kit (PerkinElmer) according to the instruction manual attached to the kit. Each cell of 1x10 ^4/100 [mu] L each were plated in 96-well plates, after cells were lysed mammalian cell lysis solution 50μL a (mammalian cell lysis solution) was added 24 hours after seeding, substrate solution 50μL a (Substrate solution) Ten minutes after the addition, the fluorescence intensity of each well was measured. The addition of D-β-hydroxybutyric acid was performed 2.5 minutes, 5 minutes, 10 minutes, or 15 minutes before adding the mammalian cell lysate.

〔result〕
FIG. 6 shows changes in ATP activity by D-β-hydroxybutyric acid in human salivary gland cells (HSY). Compared with the control (0 mM), high ATP activity was observed at each concentration by addition of D-β-hydroxybutyric acid for 2.5 minutes.

[Discussion]
From these results, it was suggested that D-β-hydroxybutyric acid has an action of promoting ATP production in cells when added for a short time. Since the enhancement of the ATP production ability of salivary gland epithelial cells is involved in the promotion of salivary secretion, the data is powerful basic data that can explain that D-β-hydroxybutyric acid is effective as a therapeutic agent for dry mice. Conceivable.

[Experimental Example 3: Influence of D-β-hydroxybutyric acid on the preventive effect against free radicals in human corneal epithelial cells (HCEC)]
〔Method〕
It was investigated whether pretreatment with D-β-hydroxybutyric acid suppresses the cytotoxic action of free radicals caused by ultraviolet irradiation in human corneal epithelial cells (HCEC). HCEC cells were seeded in a 96-well plate at a cell number of 20,000 / well, then cultured for 24 hours, and D-β-hydroxybutyric acid was added. The final concentration of D-β-hydroxybutyric acid is 0%, 0.1%, 1% or 10% (all by weight), the pretreatment time is 1 hour, and after the pretreatment, the medium does not contain HBA. Returned to the thing. Immediately thereafter, DAPI (4 ′, 6-Diamidino-2-phenylindole, dihydrochloride) was added and irradiated with ultraviolet rays. The number of DAPI-positive dead cells was counted over time at each time point of 30, 40, 50, or 60 minutes after UV irradiation.

〔result〕
FIG. 7 shows a fluorescence micrograph of human corneal epithelial cells (HCEC) that have been pretreated with D-β-hydroxybutyric acid and irradiated with ultraviolet light. As shown in FIG. 7, the number of cells killed by UV irradiation increased in a time-dependent manner as compared to unirradiated controls. By adding D-β-hydroxybutyric acid to this model, the number of dead cells in each irradiation time group tended to decrease depending on the concentration of D-β-hydroxybutyric acid.

[Conclusion]
As described above, the examination of the ultraviolet irradiation model using HCEC cells suggested that D-β-hydroxybutyric acid may have a preventive effect on free radicals generated by ultraviolet irradiation. Dry mice are a disease that causes a decrease in saliva and qualitative abnormalities, and the cause of this disease is complex and often develops due to various environmental factors such as drug side effects, stress, and lifestyle. Although it is said that there is relatively little due to organic damage of glandular tissue, the mechanism of these salivary secretion disorders is not clear. In recent years, oxidative stress is thought to be caused by increased production of active oxygen in vivo due to infection, ischemia, tobacco, drugs, etc., and it is known that it is related to various diseases and aging. Its involvement is also assumed in dysfunction. From this, the results of studying the drug having a preventive effect on free radicals as useful for the treatment of dry mice led to the present invention. In particular, in Sjogren's syndrome, which is one of the causes of dry mice, the eyes and mouth are the main lesions and the same symptoms appear, so the results shown with HCEC cells were thought to be reduced to the oral cavity.

It is a graph which shows the change of a mouth dry feeling (VAS) before and behind administration by D- (beta) -hydroxybutyric acid in a healthy subject group and a dry mouse patient group. It is a graph which shows the change of the average value of MCM before and behind administration by D-beta-hydroxybutyric acid in a healthy subject group and a dry mouse patient group. It is a graph which shows the change of the saliva secretion amount at the time of irritation | stimulation before and behind administration by D- (beta) -hydroxybutyric acid in a healthy subject group and a dry mouse patient group. It is a graph which shows the change of the value of (a) MCM and (b) the amount of saliva secretion at the time of stimulation before and after D-β-hydroxybutyric acid administration in each case (dry mouse patient and healthy subject). The change of the saliva secretion amount at the time of stimulation before and after the administration by D-β-hydroxybutyric acid in the healthy subject group and the dry mouse patient group including additional cases is shown. It is a graph which shows the change of ATP activity by D-beta-hydroxybutyric acid in a human salivary gland cell (HSY). It is the fluorescence-microscope photograph of the human corneal epithelial cell (HCEC) which performed the pre-processing by D- (beta) -hydroxybutyric acid and ultraviolet irradiation.

Claims (3)

A medicament for treating dry mice and / or salivary secretion disorders , comprising β-hydroxybutyric acid or a pharmaceutically acceptable salt thereof as an active ingredient. The medicament according to claim 1 , wherein the β-hydroxybutyric acid is D-β-hydroxybutyric acid. The medicament according to claim 1 or 2 , wherein the dry mouse and / or salivary secretion disorder includes a thirsty or rough throat symptom.