WO2018207929A1 - 動脈血中酸素飽和度の向上剤 - Google Patents
動脈血中酸素飽和度の向上剤 Download PDFInfo
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- WO2018207929A1 WO2018207929A1 PCT/JP2018/018409 JP2018018409W WO2018207929A1 WO 2018207929 A1 WO2018207929 A1 WO 2018207929A1 JP 2018018409 W JP2018018409 W JP 2018018409W WO 2018207929 A1 WO2018207929 A1 WO 2018207929A1
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- orotic acid
- oxygen saturation
- decrease
- arterial oxygen
- arterial
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
Definitions
- the present invention is an arterial blood oxygen saturation improver comprising orotic acid or a salt thereof (hereinafter sometimes referred to as “orotic acids”) as an active ingredient, wherein the orotic acid or a salt thereof is obtained from the oral mucosa.
- orotic acids orotic acid or a salt thereof
- the present invention relates to an enhancer for oral mucosal administration absorbed into the body.
- Orotic acid also called orotic acid, uracil 6-carboxylic acid, orotic acid, or vitamin B13
- orotic acid is a major intermediate in the pyrimidine nucleotide biosynthesis system and is derived from dihydroorotic acid by dihydroorotic acid dehydrogenase, and orotic acid phospho It becomes orotidylic acid by ribosyltransferase (PRPP).
- PRPP ribosyltransferase
- Orotidylic acid is more rapidly converted to uridine monophosphate (UMP), and then pyrimidine nucleotides such as uridine triphosphate and cytidine triphosphate are synthesized.
- UMP uridine monophosphate
- pyrimidine nucleotides such as uridine triphosphate and cytidine triphosphate are synthesized.
- orotic acid has a blood uric acid level lowering action (Patent Document 1), orotic acid has an endurance improving action (Patent Documents 2 and 3), and orotic acid reduces oxygen consumption and energy consumption. (Patent Document 3) and the like have been reported.
- Patent Document 1 blood uric acid level lowering action
- Patent Documents 2 and 3 endurance improving action
- Patent Document 3 orotic acid reduces oxygen consumption and energy consumption.
- Patent Document 3 Patent Document 3 and the like have been reported.
- these documents only disclose the effect of orotic acid after oral administration for a relatively long period (10 days to 3 weeks) by animal experiments using mice and rats. It is known that when administered so as to be absorbed from the oral mucosa into the body, a decrease in arterial oxygen saturation is suppressed, or a reduced arterial oxygen saturation or decreased tissue oxygen sufficiency is improved. It was not done.
- Non-patent Document 4 increased uric acid levels in hypoxic cases of chronic obstructive pulmonary disease (COPD) (Non-patent Document 4), increased liver oxygen consumption by alcohol consumption (Non-patent Document 5), alcohol consumption Affects the respiratory disturbance and pulse rate during sleep (Non-patent Document 6).
- COPD chronic obstructive pulmonary disease
- the problem of the present invention is that it can be ingested by a relatively simple method, and has excellent immediate effect and sustainability, suppresses the decrease in arterial oxygen saturation, or decreases the arterial oxygen saturation or decreased tissue It is in providing the improver used in order to raise oxygen sufficiency.
- orotic acid or its salt is administered to the subject whose arterial blood oxygen saturation or tissue oxygen sufficiency is reduced or is expected to be absorbed by the oral mucosa instead of oral administration.
- decreased arterial oxygen saturation or decreased tissue oxygen sufficiency increases rapidly, or decrease in arterial oxygen saturation or tissue oxygen sufficiency is suppressed, and arterial oxygen saturation or tissue oxygen sufficiency is suppressed.
- the present invention was completed by finding that symptoms related to a decrease in the degree of symptoms were promptly improved and that the physical condition (state) improved / recovered thereafter was stably maintained.
- the present invention is as follows.
- An arterial oxygen saturation improving agent containing orotic acid or a salt thereof as an active ingredient for suppressing a decrease in arterial oxygen saturation or increasing a decreased arterial oxygen saturation An agent for improving oxygen saturation in arterial blood for oral mucosal administration, wherein the orotic acid or a salt thereof is absorbed into the body from the oral mucosa.
- the improver according to [1] above, wherein the decrease in arterial oxygen saturation is caused by drinking.
- [10] orotic acid or a salt thereof absorbed into the body from the oral mucosa, or a subject whose arterial oxygen saturation may decrease, or arterial oxygen saturation A method for suppressing decrease in arterial oxygen saturation, or increasing decreased arterial oxygen saturation, comprising a step of administering to a reduced subject so that it is absorbed into the body from the oral mucosa, [11 ] Orotic acid or its salt used as an agent for suppressing decrease in arterial oxygen saturation or increasing decreased arterial oxygen saturation for oral mucosal administration, [12]
- Orotic acid or its salt thereof used as an agent for suppressing decrease in arterial oxygen saturation or increasing decreased arterial oxygen saturation for oral mucosal administration
- Examples thereof include use of orotic acid or a salt thereof for producing an improving agent that suppresses a decrease in arterial oxygen saturation or increases a decreased arterial oxygen saturation.
- the arterial oxygen saturation improving agent of the present invention is a preventive or ameliorating symptom or disease caused by a hypoxic state, for example, a subject before exercise or drinking that may decrease arterial oxygen saturation.
- a hypoxic state for example, a subject before exercise or drinking
- orotic acid or a salt thereof is administered to a person so as to be absorbed into the body from the oral mucosa (for example, sublingual administration)
- the decrease in arterial oxygen saturation is suppressed, or the arterial oxygen saturation is increased.
- the (Persistence), long-term suppression of the symptoms associated with hypoxia reduction and tissue in arterial blood oxygen saturation (prophylaxis or improvement) it becomes possible to.
- the excellent immediate effect and persistence of such orotic acid or a salt thereof is exhibited when administered so as to be absorbed into the body from the oral mucosa rather than orally administered.
- FIG. 3 shows the results of measuring subject's percutaneous arterial blood oxygen saturation (SpO2) (Fig. 1A) and heart rate (bpm) (Fig. 1B) before and after sublingual administration of orotic acid in a normal-pressure hypoxic chamber.
- SpO2 percutaneous arterial blood oxygen saturation
- Fig. 1A percutaneous arterial blood oxygen saturation
- bpm heart rate
- FIG. 1B shows the results of measuring subject's percutaneous arterial blood oxygen saturation
- FIG. 1A shows the result of having made test subject A enter a normal-pressure hypoxic chamber, and measuring SpO2 (FIG. 2A) and heart rate (FIG. 2B) before and after oral administration of orotic acid.
- the broken line in the figure indicates when orotic acid was orally administered.
- FIG. 2A percutaneous arterial blood oxygen saturation
- bpm heart rate
- “*” Represents that the orotic acid administration group (OA group) has a significant difference with respect to the control group (CTL group) at a risk rate of less than 5%.
- CTL group control group
- “*” Represents that the orotic acid administration group (OA group) has a significant difference with respect to the control group (CTL group) at a risk rate of less than 5%. It is a figure which shows the result of having analyzed the respiratory quotient / RER of the mouse
- FIG. “*” And “**” indicate that each group has a significant difference with respect to the control group (CTL group) at a risk rate of less than 5% and a risk rate of less than 1%, respectively.
- the improving agent of the present invention has a use (purpose) for “suppressing a decrease in arterial blood oxygen saturation or an increased arterial oxygen saturation” and a use (use) for “oral mucosal administration”. ) Is an arterial blood oxygen saturation improver containing orotic acid or a salt thereof as an active ingredient, and is administered so that orotic acid or a salt thereof is absorbed into the body from the oral mucosa. There are features. Further, the “preventive agent for increasing uric acid level” and the “preventing or improving agent for diseases associated with a decrease in arterial blood oxygen saturation” of the present invention contain the above-described improver of the present invention as an active ingredient.
- improvers, preventive agents, preventive or improvers of the present invention are pharmaceuticals (pharmaceutical compositions), health foods consumed for the purpose of maintaining health, etc. (functional foods, nutritional supplements, health supplements, nutrition enhancements) Foods, nutritionally adjusted foods, supplements, etc.) and health function foods (specific health foods, nutrient function foods, functional indication foods, etc.).
- arterial blood oxygen saturation is an index indicating how much oxygen is contained in blood
- SpO2 is the percentage of hemoglobin in blood (arteries) that contains oxygen. It can be measured using a simple device called a pulse oximeter.
- decrease in arterial oxygen saturation means a state in which arterial oxygen saturation (SpO2) is lower than a normal value in arterial blood due to some factor, and includes muscle, liver, brain Such a state that the body tissue is in an oxygen-deficient state and the blood lactic acid level or uric acid level is higher than the normal level is also included in the “decrease in arterial blood oxygen saturation” for convenience.
- a decrease in oxygen saturation preferably means a state that is at least 2% lower than the normal value. Since the normal value of SpO2 differs depending on the normal state of the subject, it cannot generally be specified, but is usually at least 93% or more, preferably at least 94%, more preferably at least 95%, most preferably at least 96% or more. Therefore, “decrease in arterial oxygen saturation” includes, for example, SpO2 values of 70% to less than 96%, 80% to less than 96%, 90% to less than 96%, and the like.
- increasing decreased arterial oxygen saturation means that SpO2 is increased from a state where it is lower than the normal value in arterial blood, or in tissues such as brain and liver. It means improving oxygen deficiency.
- the cause of SpO2 being lower than the normal value in arterial blood or in tissues such as the brain and liver (being oxygen deficient) is caused by exercise (for example, climbing, swimming, long-distance running [marathon], short-distance running, skating competition, Soccer, basketball, tennis, bicycle competition, etc.), insufficient blood flow due to some reason, decrease in oxygen concentration in the air (altitude, altitude training, low oxygen training, insufficient arousal in closed space, etc.), anaerobic condition, lungs Decreased function (chronic obstructive pulmonary disease [COPD; chronic obstructive pulmonary disease], asthma, idiopathic pulmonary fibrosis, aging, etc.), respiratory arrest (sleep apnea syndrome, conscious respiratory arrest during diving, etc.), etc.
- exercise for example, climbing, swimming, long-distance running [marathon], short-distance running, skating competition, Soccer, basketball, tennis, bicycle competition, etc.
- insufficient blood flow due to some reason, decrease in oxygen
- causes other than the above include sensory abnormalities, numbness, dyspnea, coldness, stiff shoulders, headache, fatigue, poor concentration, glaucoma, epilepsy, emphysema, respiratory acidosis, pressure ulcers, cardiac edema, hepatic edema, Premenstrual tension, Meniere's disease syndrome, cardiovascular disease (eg, hypertension, arrhythmia, angina, myocardial infarction, stroke, cerebrovascular disorder), diabetes, frequent urination, rash, fever, dementia, drinking Can do.
- the improver of the present invention is particularly effective for lowering the oxygen concentration in the air, lowering the lung function, breathing arrest, exercising, and drinking alcohol.
- the above “reduction of oxygen concentration in the air” means a condition (state) in which the oxygen concentration in the air is lower than the normal value (about 21%).
- a specific example of a symptom or disease associated with a decrease in oxygen concentration in the air is altitude sickness.
- Non-patent Document 4 Since it is known that blood uric acid levels increase due to hypoxia (Non-patent Document 4), when a decrease in SpO2 (tissue oxygen deficiency) is a cause of blood uric acid levels increasing, for example, exercise In drinking, etc., the decrease of SpO2 is suppressed (improvement of oxygen deficiency in the tissue) or the decreased SpO2 is increased by the absorption of the improver of the present invention and the preventive agent for increased uric acid level into the body As a result, the increase in blood uric acid level is suppressed.
- SpO2 tissue oxygen deficiency
- “increase in blood uric acid level” means that the uric acid concentration in blood, plasma or serum increases from a normal value.
- the normal value of blood uric acid concentration varies depending on the gender and the normal condition of the subject, so it cannot be specified unconditionally, but it is usually within the range of 2.0 to 7.0 mg / dL, and the subject is male. In this case, it is preferably 3.8 to 7.0 mg / dL, and preferably 2.4 to 5.8 mg / dL when the subject is female.
- the reduction of arterial blood oxygen saturation is suppressed by absorption of the improver of the present invention into the body from the oral mucosa, or the reduced arterial blood oxygen saturation increases, resulting in efficient training.
- sports for which the above-described high altitude training or low oxygen training is effective include sports (exercises) such as mountain climbing, swimming, marathon, sprinting, skating, soccer, basketball, tennis, and cycling.
- the form or dosage form of the improver, preventive agent, preventive or ameliorating agent of the present invention may be any form as long as orotic acid or a salt thereof is absorbed into the body from the oral mucosa.
- the retention method in the oral cavity is not particularly limited.
- the improver, prophylactic agent, preventive or ameliorating agent of the present invention slows the release of orotic acid or a salt thereof, so that the surface of the improving agent of the present invention gradually dissolves and disappears by saliva, and orotic acid after administration Alternatively, those having an action of retaining the salt in the oral cavity for a long time (sustained release agent applied to the oral mucosa) are preferable.
- the size, form, etc. of the improver, preventive agent, preventive or ameliorating agent of the present invention are preferably adjusted so that they cannot be swallowed quickly.
- a granule tablet wrapped in an edible film such as a troche tablet, a sublingual tablet, a buccal tablet, an oblate (edible starch film)
- examples include jelly tablets and chewable tablets (chewable tablets).
- the powder of the ingredient to enhance the solubility of orotic acid or its salt described later and orotic acid or its salt are used. Can be mixed and used.
- the time during which orotic acid or its salt stays in the oral cavity after administration is the dose of orotic acid or its salt, the age, weight, sex, symptom of the subject, It can be appropriately selected depending on the sensitivity to orotic acid or a salt thereof, for example, at least 10 seconds, preferably at least 15 seconds, more preferably at least 20 seconds, more preferably at least 25 seconds, most preferably at least 30 seconds. It is.
- Orotic acid or a salt thereof which is an active ingredient of the improver, prophylactic agent, preventive or ameliorating agent of the present invention, can be configured as a safe food ingredient, and can be easily and continuously ingested on a daily basis because it is inexpensive. .
- foods and supplements are preferable as the improver, preventive agent, preventive or ameliorating agent of the present invention.
- Such food is not particularly limited.
- a sustained-release agent applied to the oral mucosa specifically, (throat) rice cake, chewing gum, gummy, jelly, chewing candy, jelly Beans etc. can be mentioned.
- the orotic acid includes orotic acid hydrates such as orotic acid-free monohydrate in addition to orotic acid free form (anhydrous).
- the salt of orotic acid may be a salt with a physiologically acceptable base, for example, an alkali metal salt such as sodium salt or potassium salt; an alkaline earth metal salt such as calcium salt or magnesium salt; Examples include heavy metal salts such as zinc salts; ammonium salts; salts with basic amino acids or basic peptides described below.
- a physiologically acceptable base for example, an alkali metal salt such as sodium salt or potassium salt; an alkaline earth metal salt such as calcium salt or magnesium salt; Examples include heavy metal salts such as zinc salts; ammonium salts; salts with basic amino acids or basic peptides described below.
- the improver, prophylactic agent, preventive or ameliorating agent of the present invention further contains components (for example, amino acids, peptides, etc.) that further increase the solubility of orotic acid in order to improve the absorption of orotic acid into the oral mucosa.
- components for example, amino acids, peptides, etc.
- those are preferred.
- the component that enhances the solubility of orotic acid include lysine, histidine, arginine, ornithine, carnitine, choline, carnosine, anserine, and valenin.
- carnitine can be preferably exemplified.
- the component that enhances the solubility of orotic acid includes L-form, D-form, or a mixture thereof.
- the improver, prophylactic agent, preventive or ameliorating agent of the present invention includes, as necessary, usual pharmaceutically acceptable carriers, binders, stabilizers, excipients, diluents, pH buffering agents, disintegrations. Ingredients such as agents, isotonic agents, additives, coating agents, solubilizers, lubricants, lubricants, solubilizers, lubricants, flavors, sweeteners, solvents, gelling agents, nutrients, etc. It may be added.
- ingredients include water, physiological saline, animal fat, animal oil, vegetable oil, lactose, starch, gelatin, crystalline cellulose, gum, talc, magnesium stearate, hydroxypropyl cellulose, polyalkylene glycol, Examples thereof include polyvinyl alcohol and glycerin.
- the dosage of orotic acid or its salt contained in the improver, prophylactic agent, preventive or ameliorating agent of the present invention depends on the age, body weight, sex, symptom, sensitivity to orotic acid or its salt, etc. of the subject of administration. It is determined appropriately.
- the dosage of orotic acid or a salt thereof is, for example, in the range of 50 to 2000 mg / day, preferably 100 to 1000 mg / day, more preferably 150 to 800 mg / day, still more preferably 150 to 600 mg / day, particularly
- the dose is preferably 200 to 400 mg / day, and most preferably 200 mg / day.
- it may be administered once or a plurality of times (for example, 2 to 4 times) per day.
- a tablet containing 50 mg orotic acid or a salt thereof may be taken four times a day, and 100 mg orotic acid or a salt thereof may be taken. May be taken twice a day, and a tablet containing 200 mg orotic acid or a salt thereof may be taken once a day.
- the above orotic acids include orotic acid free monohydrate (manufactured by Kyowa Hakko Bio, Matsumoto Kosho), orotic acid anhydride (manufactured by Kyowa Hakko Bio), orotic acid monohydrate (manufactured by SIGMA-ALDRICH)
- Commercial products such as orotic acid monohydrate (manufactured by Wako Pure Chemical Industries, Ltd.) may be used, and the culture solution may be obtained by fermentation using various microorganisms into which mutations requiring pyrimidine requirement or pyrimidine analog resistance have been introduced. Produced and accumulated therein (for example, see Japanese Patent No.
- Example 1 Effect 1 of suppressing reduction in arterial oxygen saturation due to absorption of orotic acid from oral mucosa
- carnitine was used to improve the solubility of orotic acid in water (absorbability to the oral mucosa) (see JP-A-2015-43743). Subject A was asked not to change his / her breathing even after entering the room.
- the SpO2 value of the subject A was stably maintained at about 88% between 12.9 and 13.0%, the increase in SpO2 value due to sublingual administration of orotic acid It can be confirmed that this is not due to the rise in As a result of eating lunch at 13:00, the heart rate increased slightly after that, but since there was no significant disturbance in the heart rate throughout the whole (see FIG. 1B), the increase in the heart rate caused an increase in the SpO2 value. The possibility was denied.
- subject A had an uncomfortable feeling immediately after entering the room due to hypoxia such as mild sleepiness, but immediately after taking orotic acid, the uncomfortable feeling disappeared and the remaining time until leaving the room was completely unchanged. Spent. Based on the above results, when orotic acid is administered sublingually to humans with reduced arterial oxygen saturation, arterial oxygen saturation increases immediately, and then the increased arterial oxygen saturation lasts for a long time. It was confirmed.
- Example 2 Effect 2 of suppressing reduction in arterial oxygen saturation due to absorption of orotic acid from oral mucosa
- Three test subjects (a male in his 60s [subject A; the same subject as in Example 1], a male in his 50s [subject B], and a female in his 50s [subject C]) described in [Test Method 1] above The test was performed according to the method.
- subject A a method of swallowing 2 tablets (total 400 mg of orotic acid) containing 200 mg of orotic acid-free monohydrate (manufactured by Kyowa Hakko Bio) for comparison with sublingual administration ( Oral administration) was also examined.
- the indoor oxygen concentration was stable in the range of 12.4 to 12.7% throughout the test period.
- Subject C initially planned to administer orotic acid sublingually 30 minutes after entering the room, but the SpO2 value after entering the room dropped to 70%, and he felt headaches and poor mood. It was decided to administer 400 mg of acid sublingually. However, since it was ingested slightly, it was swallowed before the oblate dissolved, resulting in the same administration method as oral administration. After that, recovery of SpO2 level was not observed, and in the hypoxic chamber test, I was aware that my breathing did not change, but in the case of subject C, I did not feel well and often experienced mild headaches and yawning. However, it was in a situation where books could not be read.
- Example 3 Reduction of energy consumption after exercise and suppression of increase in post-exercise uric acid level due to absorption of orotic acid from oral mucosa
- Test Method 3 The composition comprising the ingredients shown in Table 1 was compressed into chewable tablets to produce orotic acid-containing throat jars and placebo throat jars.
- Peroxidase is allowed to act on hydrogen peroxide (H 2 O 2 ) generated when uric acid in a sample is oxidatively decomposed by the action of uricase, thereby producing 4-aminoantipyrine (4-AA).
- H 2 O 2 hydrogen peroxide
- 4-aminoantipyrine 4-aminoantipyrine
- a quinone dye produced by oxidative condensation with a color former, colorimetric measurement of uric acid concentration (mg / dL) immediately after the end of exercise and 4 hours after the end of exercise (uricase-POD method), plasma The change in uric acid level was calculated.
- exercise after ingesting orotic acid suppresses an increase in plasma uric acid levels after exercise, and this effect may be more pronounced in the oral intake of orotic acid than in the oral intake of orotic acid. found. It is presumed that the ingestion of orotic acid from the oral mucosa before the start of exercise suppresses the decrease in the SpO2 value due to exercise, resulting in the suppression of the increase in plasma uric acid level or the decrease in plasma uric acid level.
- Example 4 Inhibitory effect of reduction of arterial oxygen saturation due to absorption of orotic acid from oral mucosa
- Test Method 4 A 70-year-old woman with idiopathic pulmonary fibrosis ingested 2 tablets of orotic acid-containing throat produced in Example 3 and then continuously ingested 1 tablet of the throat daily for 4 weeks. SpO2 was measured.
- SpO2 immediately before ingestion of the throat was about 91%, but SpO2 after about 30 minutes from the ingestion of the 2 tablets of throat increased to about 93%.
- SpO2 was maintained at 93 to 94% after 2 weeks and 4 weeks from the intake of the 2 tablets of the throat, the amount of sputum was reduced by half, and the pulse was stable at 100 or less.
- Example 5 Inhibitory effect of reduction in arterial oxygen saturation due to absorption of orotic acid from oral mucosa
- SAS sleep apnea syndrome
- a 57-year-old woman suspected of having sleep apnea syndrome (SAS) has a placebo throat tablet manufactured in Example 3 before going to bed, and is loaned from the medical corporation Koushikai Ginza Taijiang Internal Medicine Clinic Maximum time during sleep apnea (state where breathing stops for 10 seconds or more) or hypopnea (state where ventilation due to breathing falls to 50% or less for 10 seconds or more) detected by a test device for sleep apnea syndrome SpO2 was measured for 2 nights by the method in Example 1 (these values are described in the diagnostic results analyzed by the clinic software).
- Each mouse in the other group (orotic acid administration group: OA group) was administered with orotic acid (50 mg / mL) suspended in a 0.5% by mass CMC solution at 10 mL per kg body weight of the mouse. These administrations were performed 5 times a week for 4 weeks (total 20 times) for each mouse. At 19 o'clock on the last administration day, each mouse was transferred to a metabolic measurement chamber to start fasting. Oxygen consumption (VO 2 [mL / min]) and carbon dioxide production from 20:00 in the dark period to 8 o'clock on the next day The amount (VCO 2 [mL / min]) was measured.
- FIG. 7 shows the oxygen consumption by the average value of each group
- FIG. 8 shows the carbon dioxide production by the average value of each group.
- the respiratory quotient / RER of each mouse was calculated as a value obtained by dividing the carbon dioxide production by the oxygen consumption.
- FIG. 9 shows the respiratory quotient as an average value of each group.
- FIG. 10 shows the oxygen consumption by the average value of each group
- FIG. 11 shows the carbon dioxide production by the average value of each group.
- FIG. 12 shows the respiratory quotient as an average value for each group.
- orotic acid has an action of reducing oxygen consumption regardless of whether it is resting or exercising, and does not change the respiratory quotient at that time.
- Each group was bred using roughage (CE-2), and orotic acid 250 mg / kg was orally administered to the OA 250 mg / kg group and orotic acid 500 mg / kg was orally administered to the OA 500 mg / kg group 5 times a week.
- the limit swimming time of each group was measured once a week while rearing for 3 weeks. The limit swimming time at this time is shown in FIG.
- the present invention is intended to prevent or improve symptoms or diseases associated with hypoxia or elevated blood uric acid levels, improve performance in sports where high altitude training or hypoxic training is effective, and recover fatigue and reduce feeling of fatigue due to exercise. It contributes to the field of production of target foods (for example, health foods, health functional foods) and pharmaceuticals.
- target foods for example, health foods, health functional foods
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Abstract
Description
他方、空気の通り道である上気道が物理的に狭くなり、呼吸が止まってしまう閉塞性睡眠時無呼吸患者は、夜間睡眠中に無呼吸あるいは低呼吸が繰り返し引き起こされるため、低酸素血症に曝される時間が多い病態であり、血清尿酸値は産生と尿中排泄とのバランスによって規定されているが、低酸素の条件下では、細胞レベルでは酸素供給不足によりATPの分解が充進され、プリン体の終末代謝産物である尿酸の産生が充進ずることが知られている(非特許文献1)。
また、酸素が不足すると、TCAサイクルでの好気的なATPの生成ができなくなり、解糖系の代謝に必要なNADの再生のためにピルビン酸から乳酸を生成することで解糖系からのATP生成を行う結果、乳酸が蓄積される。また、酸素が不足すると、ATPを再生するために、2分子のADPからATP1分子とAMP1分子が生成され、この生成したAMPは分解されて尿酸に変換されることが知られている。さらに、ATPを補うために解糖系が亢進され、嫌気的に生成した乳酸が尿酸の排泄を抑制することも知られている(非特許文献2及び3)。
その他、慢性閉塞性肺疾患(COPD)症例の低酸素状態で尿酸値が増加すること(非特許文献4)や、アルコール摂取による肝の酸素消費が亢進すること(非特許文献5)や、飲酒が睡眠時の呼吸障害と脈拍数に影響を及ぼすこと(非特許文献6)が知られている。
[1]オロット酸又はその塩を有効成分として含有する動脈血中酸素飽和度の向上剤であって、動脈血中酸素飽和度の低下を抑制するため、又は低下した動脈血中酸素飽和度を上昇させるために用いられ、前記オロット酸又はその塩が口腔粘膜から体内に吸収されることを特徴とする口腔粘膜投与用の動脈血中酸素飽和度の向上剤。
[2]動脈血中酸素飽和度の低下が、酸素濃度の低下した空気中での呼吸、心肺機能の低下、又は呼吸停止に起因することを特徴とする上記[1]に記載の向上剤。
[3]動脈血中酸素飽和度の低下が、運動により生じるものであることを特徴とする上記[1]に記載の向上剤。
[4]動脈血中酸素飽和度の低下が、飲酒により生じるものであることを特徴とする上記[1]に記載の向上剤。
[5]オロット酸又はその塩が、カルニチンとの混合物として含有されていることを特徴とする上記[1]~[4]のいずれかに記載の向上剤。
[6]舌下錠であることを特徴とする上記[1]~[5]のいずれかに記載の向上剤。
[7]オロット酸又はその塩の投与量が、200mg/日であることを特徴とする上記[1]~[6]のいずれかに記載の向上剤。
[8]上記[1]~[7]のいずれかに記載の口腔粘膜投与用の動脈血中酸素飽和度の向上剤を有効成分として含有することを特徴とする血中尿酸値上昇の予防剤。
[9]上記[1]~[7]のいずれかに記載の口腔粘膜投与用の動脈血中酸素飽和度の向上剤を有効成分として含有することを特徴とする動脈血中酸素飽和度の低下に関連する疾病の予防又は改善剤。
本明細書において、「動脈血中酸素飽和度の低下」とは、何らかの要因によって、動脈血中酸素飽和度(SpO2)が、動脈血中において正常値よりも低下した状態を意味し、筋肉、肝臓、脳等の体の組織が酸素不足状態になって、血中の乳酸値や尿酸値が正常値よりも上昇した状態も便宜上「動脈血中酸素飽和度の低下」に含まれる。また酸素飽和度の低下は、好ましくは正常値よりも少なくとも2%低下した状態を意味する。SpO2の正常値は、対象者の普段の状態で異なるため、一概に特定することはできないが、通常少なくとも93%以上であり、好ましくは少なくとも94%、更に好ましくは少なくとも95%、最も好ましくは少なくとも96%以上である。したがって、「動脈血中酸素飽和度の低下」には、例えば、SpO2値が70%以上~96%未満、80%以上~96%未満、90%以上~96%未満等が含まれる。
オロット酸の口腔粘膜からの吸収が、動脈血中酸素飽和度の低下を抑制する効果を有するか否かを確認する試験を実施した。
[試験方法1]
60才代男性(被験者A)を、ミウラドルフィンズの常圧低酸素室(酸素濃度12.4~12.7%、標高約4000m相当、23℃)に入室させ、その後、オロット酸フリー体(協和発酵バイオ社製)200mgと、L-カルニチン(ロンザジャパン社製)200mgとの混合物400mgをオブラートで包んだものを、舌下に置き、口内で少なくとも30秒間滞留させることを2回行う方法(舌下投与)により、計400mgのオロット酸を投与した後、SpO2と心拍数を、パルスオキシメーター PULSOX-300i(コニカミノルタ社製)を用いて測定した。なお、本実施例において、カルニチンは、オロット酸の水への溶解性(口腔粘膜への吸収性)を向上させるために用いた(特開2015-43743号公報参照)。被験者Aには、入室後も意識して呼吸を変えないようにお願いした。
入室後、被験者AのSpO2値は、速やかに83~84%まで減少したが、オロット酸の舌下投与(図1Aの点線の11時)後30分余りで、SpO2値は88%まで上昇した(図1A参照)。その後、SpO2値は、退出するまでの少なくとも5時間、約88%で安定に維持することが示された(図1A参照)。
なお、この試験において、常圧低酸素室の酸素濃度の調節不良により、12.4~12.7%に設定していた酸素濃度が、オロット酸の舌下投与後30分の時点で13.9%まで上昇した。しかし、その後、酸素濃度は1時間30分程度で12.9%まで低下し、12.9~13.0%で安定していた。被験者AのSpO2値は、酸素濃度が12.9~13.0%の間、約88%で安定に維持していたことから、オロット酸の舌下投与によるSpO2値の上昇は、室内酸素濃度の上昇によるものではないことが確認できる。また、13時に昼食を摂取した結果、その後若干の心拍数が増加したが、全体を通して心拍数に大きな乱れも認められないことから(図1B参照)、心拍数の増加によりSpO2値の上昇が生じた可能性が否定された。また、被験者Aは、入室直後は軽い眠気など低酸素に起因すると感じられる違和感があったが、オロット酸摂取後すぐに違和感も無くなり、普段とまったく変わらない状態で、退室までの残りの時間を過ごした。
以上の結果から、オロット酸を、動脈血中酸素飽和度が低下したヒトに舌下投与すると、動脈血中酸素飽和度は即効的に上昇し、その後上昇した動脈血中酸素飽和度は、長時間持続することが確認された。
[試験方法2]
3名の被験者(60才代男性[被験者A;実施例1と同じ被験者]、50才代男性[被験者B]、及び50代女性[被験者C])について、上記[試験方法1]に記載の方法にしたがって試験を行った。なお、被験者Aについては、舌下投与との比較のために、オロット酸フリー体一水和物(協和発酵バイオ社製)200mgを含む錠剤を、2錠(計400mgのオロット酸)飲み込む方法(経口投与)についても合わせて検討した。また、今回の試験においては、試験期間を通じて室内の酸素濃度は、12.4~12.7%の範囲で安定していた。
入室30分後(14時)の被験者Aに対して、オロット酸を経口投与したところ、84%まで低下したSpO2値は、ほとんど回復しなかった(図2A参照)。また、低酸素室に入室後に感じた低酸素に起因すると思われる違和感についての改善はわずかであった。なお、被験者Aは、試験期間を通じて、心拍数に大きな乱れは認められなかった(図2B参照)。
入室1時間30分後(15時)の被験者Bに対して、オロット酸400mgを舌下投与したところ、82%まで低下したSpO2値は、投与30分後ごろから上昇し、86%まで回復した後、退出するまでの少なくとも2時間30分間は、安定に維持することが示された(図3A参照)。また、被験者Bは、オロット酸の投与前は軽度の眠気や集中力の低下等の症状があったが、かかる症状は、オロット酸の舌下投与により解消した。なお、被験者Bの心拍数は、オロット酸の投与前後でほとんど変わらなかった(むしろ微減傾向にあった)ことから(図3B参照)、オロット酸投与によるSpO2値の上昇は、心拍数の増加による肺からの酸素取り込みの増加によるものではないことを示している。被験者Bの呼吸は、試験期間を通じてまったく変化はなかった(変化を感じなかった)。
被験者Cは、当初は入室30分後にオロット酸を舌下投与する予定であったが、入室後のSpO2値が70%まで低下し、頭痛や気分の不調を感じたため、急きょ入室20分後にオロット酸400mgを舌下投与することにした。ところが、やや慌てて摂取したために、オブラートが溶解する前に飲み込んでしまい、結果的に経口投与と同様の投与方法となった。その後、SpO2値の回復は認められず、低酸素室での試験においては、呼吸は変えない事を意識してもらったが、被験者Cの場合は、気分が優れず、軽い頭痛とあくびを頻発し、本も読めない状況であった。そこで入室2時間40分後に、オロット酸200mgの舌下投与を行った。舌下投与後、SpO2値は速やかに上昇し、80%を超えるまで回復し、被験者Cは、気分が回復し、頭痛や気分の不調等の高山病の症状は無くなり、クロスワードパズルも集中してできるようになった。
[試験方法3]
表1に示される配合成分からなる組成物をチュアブル錠に打錠し、オロット酸含有喉飴及びプラセボ喉飴を製造した。
運動終了直後、運動終了後2時間、3時間及び4時間経過後における呼気をミナト医科学社製 AERO MONITOR AE 300Sで分析し、酸素摂取量と二酸化炭素産生量を計測し、下記式(1)によりエネルギー消費量(kcal/day)を求め、エネルギー消費量の変化を計算した。
エネルギー消費量(kcal/day)=(3.9×酸素摂取量)+(1.1×二酸化炭素産生量) (1)
検体中の尿酸がウリカーゼの作用によって酸化分解されるときに発生する過酸化水素(H2O2)にペルオキシダーゼ(POD)を作用させ4-アミノアンチピリン(4-AA)及び発色剤で酸化縮合せしめることにより生じるキノン色素を比色測定することにより、運動終了直後及び運動終了から4時間経過後における尿酸濃度(mg/dL)を求め(ウリカーゼ-POD法)、血漿尿酸値の変化を計算した。
オロット酸の摂取により、バイク運動終了後2時間、3時間及び4時間経過後におけるエネルギー消費量は、バイク運動直後におけるエネルギー消費量に比べてより少なくなった。オロット酸を喉飴として口内吸収により摂取した場合のこの効果は、オロット酸を経口投与により摂取した場合の効果よりも顕著であった。運動開始前のオロット酸の口腔粘膜からの摂取により、運動によるSpO2値の低下が抑制される結果、代謝効率の低下も抑制され、運動後のエネルギー消費量が減少していると推量される。
オロット酸を摂取しなかった群の運動終了直後及び運動終了から4時間経過後における尿酸濃度変化は0.2mg/dLの上昇(図5左側)、オロット酸を経口投与により摂取した群の尿酸濃度変化は0.1mg/dLの上昇(図5右側)、オロット酸を喉飴として口内吸収により摂取した群の尿酸濃度変化は0.05mg/dLの減少であった(図5中央)。したがって、オロット酸を摂取してから運動すると運動後に血漿尿酸値の上昇が抑制され、この効果は、オロット酸の経口投与による摂取よりも、オロット酸の口内吸収による摂取においてより顕著であることが判明した。運動開始前のオロット酸の口腔粘膜からの摂取により、運動によるSpO2値の低下が抑制される結果、血漿尿酸値の上昇の抑制又は血漿尿酸値の低下が起きると推量される。
[試験方法4]
70才の突発性肺線維症女性が実施例3で製造されたオロット酸含有喉飴2錠を摂取し、その後、毎日上記喉飴を1錠ずつ4週間摂取し続け、実施例1における方法でSpO2を測定した。
[結果4]
上記喉飴摂取直前におけるSpO2は約91%であったが、上記喉飴2錠の摂取から30分経過後におけるSpO2は約93%に上昇した。上記喉飴2錠の摂取から2週間後及び4週間後におけるSpO2は93~94%で維持され、痰の量は半減し、脈拍は100以下で安定した。
[試験方法5]
57才の睡眠時無呼吸症候群(SAS)が疑われる女性に就寝前に実施例3で製造されたプラセボ喉飴1錠を摂取してもらい、医療法人光史会銀座泰江内科クリニックから貸与される睡眠時無呼吸症候群の検査機器で検出される睡眠中の無呼吸(呼吸が10秒以上止まる状態)又は低呼吸(呼吸による換気が10秒以上50%以下に低下する状態)時の最大時間とその時のSpO2を実施例1における方法により2晩測定した(これらの値は、クリニックのソフトが解析した診断結果に数値が記載される)。その後、この女性に就寝前に実施例3で製造したオロット酸含有喉飴1錠を摂取してもらい、睡眠中の無呼吸又は低呼吸状態の最大時間とその時のSpO2を同じ方法により2晩測定した。結果を図6に示す。図6において、プラセボ喉飴1錠を摂取時が丸形のプロット、オロット酸含有喉飴1錠を摂取時が菱形のプロットで示されている。
[結果5]
オロット酸を喉飴として口内吸収により摂取したときにおける無呼吸時間とオロット酸を摂取していないときにおける無呼吸時間が同じ場合、オロット酸を口腔粘膜から摂取したときにおけるSpO2が、オロット酸を摂取していないときにおけるSpO2よりも高いことが判明した。したがって、オロット酸の口腔粘膜からの摂取による低酸素状態の軽減効果が期待される。
オロット酸が、非運動時の酸素消費量を低減させる効果を有しているかを調べるために、以下の試験を行った。まず、12時間毎の明暗周期(8時~20時まで点灯)下に24±2℃の恒温動物室にて1週間以上飼育したddY雄マウス(6週齢)を32匹用意した。これらのマウスを2群に分け、一方の群(コントロール群:CTL群)の各マウスには、0.5質量%のカルボキシメチルセルロース溶液(CMC溶液)を、マウスの体重1kgあたり10mL投与した。もう一方の群(オロット酸投与群:OA群)の各マウスには、0.5質量%のCMC溶液に懸濁したオロット酸(50mg/mL)を、マウスの体重1kgあたり10mL投与した。これらの投与は、各マウスに対し、週に5回、4週間継続(合計20回)して行った。最後の投与日の19時に各マウスを代謝計測チャンバーに移して絶食を開始し、暗期である20時から翌日の8時までの酸素消費量(VO2[mL/分])及び二酸化炭素産生量(VCO2[mL/分])を測定した。図7には、その酸素消費量を各群の平均値で示し、図8には、その二酸化炭素産生量を各群の平均値で示す。なお、統計処理にはt-検定を用い、p<0.05で有意差を示した項目を*で示した。また、各マウスの呼吸商/RERは、二酸化炭素産生量を酸素消費量で除した値として算出した。図9には、その呼吸商を各群の平均値で示す。
オロット酸が、運動時の酸素消費量を低減させる効果を有しているかを調べるために、以下の試験を行った。まず、12時間毎の明暗周期(8時~20時まで点灯)下に24±2℃の恒温動物室にて1週間以上飼育したddY雄マウス(6週齢)を24匹用意した。これらのマウスを2群に分け、一方のCTL群の各マウスには、0.5質量%のCMC溶液を、マウスの体重1kgあたり10mL投与した。もう一方のOA群の各マウスには、0.5質量%のCMC溶液に懸濁したオロット酸50mg/mLを、マウスの体重1kgあたり10mL投与した。これらの投与は、各マウスに対し、週に5回、3週間継続(合計15回)して行った。最後の投与日の17時に各マウスの絶食を開始し、翌日の10時からマウス用トレッドミルを用いて強制運動を行い、運動中の酸素消費量及び二酸化炭素産生量を測定した。なお、強制運動は、0~5分を速度15m/min、6~10分を速度20m/min、及び11~30分を速度25m/minの計30分間行った。図10には、その酸素消費量を各群の平均値で示し、図11には、その二酸化炭素産生量を各群の平均値で示す。なお、統計処理にはt-検定を用い、p<0.05で有意差を示した項目を*で示した。また、各マウスの呼吸商は、二酸化炭素産生量を酸素消費量で除した値として算出した。図12には、その呼吸商を各群の平均値で示す。
被験物質としてオロット酸を用い、持久力向上効果を調べた。7週齢の雄ddYマウスを日本エスエルシー社より購入し、7日間馴化後、尻尾に重りをつけて強制遊泳させた。マウスが水上に上がってこられず、水面下に5秒間停滞した時点を限界遊泳時間とし、その時間を測定した。限界遊泳時間に群間差の無いように、以下のとおり群分けした。コントロール群(CTL群)(n=10)、オロット酸250mg/kg投与群(OA 250mg/kg群)(n=10)、オロット酸500mg/kg投与群(OA 500mg/kg群)(n=10)。各群共に粗飼料(CE-2)を用いて飼育し、OA250mg/kg群にはオロット酸250mg/kg、OA500mg/kg群にはオロット酸500mg/kgを週に5回経口投与した。群分け後、3週間飼育しながら各群の限界遊泳時間を週に1回測定した。この時の限界遊泳時間を図13に示す。
被験者Aへのオロット酸の投与方法について、1回目の舌下投与と、2回目の経口投与とを比較すると、(経口投与ではなく)舌下投与した場合に、低下した動脈血中酸素飽和度を即効的に上昇させる効果と、その効果の持続性が確認された(実施例1及び2参照)。また、被験者B、Cについても同様に、オロット酸の舌下投与により、低下した動脈血中酸素飽和度を即効的に上昇させる効果と、その効果の持続性が確認された(実施例2及び3参照)。被験者Cにおいては、被験者Aと同様に、オロット酸による即効的な効果が、最初の経口投与では認められず、次の舌下投与で認められた。
以上の結果は、オロット酸を、舌下投与等の方法により口腔粘膜から体内に吸収させると、動脈血中酸素飽和度低下を効果的に予防又は改善できることを示すとともに、その効果は長時間持続可能であることを示している。
マウスの実験においては、オロット酸の経口投与では有意差が得られるのに少なくとも3週間を要し、投与当日や1週間目での効果は認められなかった。オロット酸を口腔粘膜から体内に吸収させた場合の、低下した動脈血中酸素飽和度を即効的に上昇させる効果は、今回初めて見いだされたものである。このことは、マウスで確認された省エネ効果が、ヒトでも再現されただけでなく、オロット酸の舌下口内吸収により、即日に効果が得られることが見いだされた点で重要である。すなわち、運動前や睡眠時無呼吸症候群のヒトの睡眠前など、その後一時的な低酸素状態が予想される場面でも、事前のオロット酸の摂取が有効であることを示している。このような効果を有する生体成分やその摂取方法は、これまで見出されていなかった。
Claims (9)
- オロット酸又はその塩を有効成分として含有する動脈血中酸素飽和度の向上剤であって、動脈血中酸素飽和度の低下を抑制するため、又は低下した動脈血中酸素飽和度を上昇させるために用いられ、前記オロット酸又はその塩が口腔粘膜から体内に吸収されることを特徴とする口腔粘膜投与用の動脈血中酸素飽和度の向上剤。
- 動脈血中酸素飽和度の低下が、酸素濃度の低下した空気中での呼吸、心肺機能の低下、又は呼吸停止に起因することを特徴とする請求項1に記載の向上剤。
- 動脈血中酸素飽和度の低下が、運動により生じるものであることを特徴とする請求項1に記載の向上剤。
- 動脈血中酸素飽和度の低下が、飲酒により生じるものであることを特徴とする請求項1に記載の向上剤。
- オロット酸又はその塩が、カルニチンとの混合物として含有されていることを特徴とする請求項1~4のいずれかに記載の向上剤。
- 舌下錠であることを特徴とする請求項1~5のいずれかに記載の向上剤。
- オロット酸又はその塩の投与量が、200mg/日であることを特徴とする請求項1~6のいずれかに記載の向上剤。
- 請求項1~7のいずれかに記載の口腔粘膜投与用の動脈血中酸素飽和度の向上剤を有効成分として含有することを特徴とする血中尿酸値上昇の予防剤。
- 請求項1~7のいずれかに記載の口腔粘膜投与用の動脈血中酸素飽和度の向上剤を有効成分として含有することを特徴とする動脈血中酸素飽和度の低下に関連する疾病の予防又は改善剤。
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