JP7291380B2 - Immediate-acting agent for oral mucosa administration for runny nose or nasal congestion - Google Patents

Description

TECHNICAL FIELD The present invention relates to a rapid-acting improving agent for oral mucosa administration that improves runny nose or nasal congestion.

Orotic acid is a compound found in whey, also called orotic acid, orotic acid, uracil 6-carboxylic acid, and vitamin _B13 , and is a major intermediate in pyrimidine nucleotide biosynthesis. Dihydroorotate is induced by dihydroorotate dehydrogenase and converted to orotidylate by orotate phosphoribosyltransferase (PRPP). Orotidyl acid is further rapidly converted to uridine monophosphate (UMP), and then pyrimidine nucleotides such as uridine triphosphate and cytidine triphosphate are synthesized. Thus, orotic acid is a pyrimidine precursor and an important nutrient in rapidly dividing tissues. Orotic acid is known to be contained in foods such as root vegetables, wheat germ, and brewer's yeast, and is used to treat liver disease _. And anti-aging is also attracting attention. Furthermore, other physiologically active actions of orotic acid have been found, and anti-inflammatory agents for respiratory tracts, such as airway inflammation associated with hay fever, containing orotic acid, derivatives thereof, or salts thereof as active ingredients have been investigated (e.g. , see Patent Document 1). However, it has not been confirmed that ingestion of candies, drops, etc. manufactured as the anti-inflammatory agent for respiratory tract in a form in which active ingredients such as orotic acid are absorbed in the mouth is effective as an anti-inflammatory agent for respiratory tract. . In addition, oral ingestion of 3 g of orotic acid free form monohydrate per day for 14 days has been studied to improve hay fever symptoms such as runny nose and nasal congestion, and eye diseases such as itchy eyes due to hay fever. An eye drop containing orotic acid or a salt thereof for improving or preventing the disease has also been investigated (see, for example, Patent Document 2).

In recent years, many people suffer from allergic rhinitis symptoms caused by pollens, mites, house dust, viruses, bacteria, and the like. Therefore, a therapeutic agent for allergic diseases such as an egg white amino acid-bound water containing four proteins such as albumin as active ingredients (see, for example, Patent Document 3) has been investigated. Also, (A) pseudoephedrine or a pharmaceutically acceptable salt thereof, (B) phenylephrine or methoxyphenamine or a pharmaceutically acceptable salt thereof, and (C) Datura extract, belladonna total alkaloids, belladonna extract, Rohto extract A pharmaceutical composition for the treatment of rhinitis containing at least one selected from the group consisting of is investigated (see, for example, Patent Document 4). However, these therapeutic agents are expensive and may have side effects such as drowsiness, nausea, dizziness, and malaise.

WO 2002/100409 pamphlet JP 2016-153395 A JP 2017-114817 A JP-A-2004-269517

There has been a demand for an inexpensive, fast-acting ameliorating agent for nasal discharge or nasal congestion that does not cause serious side effects to the extent that it interferes with daily life, but such an ameliorating agent has not yet been provided. SUMMARY OF THE INVENTION An object of the present invention is to provide an ameliorating agent for runny nose or nasal congestion that has no side effects and has an immediate effect with a small dosage.

The inventor of the present invention has been extensively researching the effectiveness and amelioration of the body by ingesting orotic acid. Then, in a study of oral mucosal administration of orotic acid to improve arterial blood oxygen saturation that has decreased due to alcohol consumption, exercise, and apnea syndrome, tablets containing 200 mg of orotic acid were administered sublingually (oral mucosa). Surprisingly, the runny nose and stuffy nose caused by hay fever disappeared before the tablet no longer remained in the mouth, that is, within 2 to 3 minutes of oral mucosa administration. Therefore, we asked a woman in her 40s, who has been suffering from hay fever on a daily basis, to administer a tablet containing 200 mg of orotic acid to the oral mucosa without notifying the purpose. On top of that, it was said that the haze in the head was refreshing. Also, on the same day, two men in their 50s and 70s with hay fever were given oral mucosal tablets containing 200 mg of orotic acid, and their hay fever was significantly improved within 5 minutes. I got a reply saying yes.
At a later date, when a man suffering from sinusitis and a woman suffering from a cold were each given a tablet containing 200 mg of orotic acid through the oral mucosa, it was confirmed that the symptoms of runny nose and nasal congestion improved in both cases. bottom.
It was also confirmed that oral ingestion of tablets containing 600 mg of orotic acid did not improve symptoms of runny nose/stuffy nose as described above. In addition, previously, a clinical trial of 2-week intake of 1 g/day of orotic acid was conducted, but no ameliorating effect on runny nose and nasal congestion was observed.
The present invention has been completed based on the above findings.
That is, the present invention is as follows.
[1] A fast-acting ameliorating agent for runny nose or nasal congestion containing orotic acid or a salt thereof as an active ingredient, wherein the orotic acid or a salt thereof is administered so as to be absorbed into the body through the oral mucosa. The rapid-acting improving agent for oral mucosa administration characterized by:
[2] The immediate effect improving agent according to [1] above, which further contains carnitine.
[3] The immediate effect improving agent according to [1] or [2] above, wherein the orotic acid or a salt thereof is potassium orotate or magnesium orotate.
[4] The immediate effect improving agent according to any one of [1] to [3] above, wherein the dose of orotic acid or a salt thereof is 150 to 250 mg/day.
[5] The rapid-acting improving agent according to any one of [1] to [4] above, wherein the runny nose or nasal congestion is caused by sinusitis.
[6] The rapid-acting improving agent according to any one of [1] to [4] above, wherein the runny or stuffy nose is caused by a cold.
[7] The rapid-acting improving agent according to any one of [1] to [4] above, wherein the runny nose or nasal congestion is caused by hay fever.

In addition, as another embodiment of the present invention, [8] orotic acid or a salt thereof absorbed into the body through the oral mucosa is used in a subject who needs immediate improvement of runny nose or nasal congestion (e.g., having the above symptoms [9] Oral mucosal administration of runny nose or nasal congestion, comprising the step of administering to a patient or a subject who may have the above-mentioned symptoms) so that it is absorbed into the body through the oral mucosa. [10] Use of orotic acid or a salt thereof for producing a rapid-acting improving agent for oral mucosal administration of runny nose or nasal congestion can.

The rapid-acting improving agent for oral mucosa administration of the present invention improves runny nose or nasal congestion in a short time after ingestion, the improving effect lasts for 2 hours to 1 day, is inexpensive, and is serious enough to interfere with daily life. no adverse side effects.

The rapid-acting improving agent for oral mucosal administration of the present invention is effective for ameliorating the above-mentioned symptoms, limited to the use of "immediately improving runny nose or nasal congestion" and the use of "for oral mucosal administration". It is a drug containing orotic acid or a salt thereof as an ingredient, and is characterized in that orotic acid or a salt thereof is administered so as to be absorbed into the body through the oral mucosa. The rapid-acting improving agent for oral mucosal administration of the present invention includes pharmaceuticals (pharmaceutical compositions), i.e., preparations (pharmaceutical compositions) for the prevention or treatment of runny nose or nasal congestion, as well as those having specific functions such as health maintenance. Also included are pharmaceutical-like foods (food compositions) that are ingested for the purpose of preventing or treating runny nose or nasal congestion (food compositions). Such foods include, for example, health foods (functional foods, dietary supplements, health supplements, nutrient-enriched foods, nutrient-adjusting foods, supplements, etc.), foods with health claims (foods for specified health uses, foods with nutrient claims, functional labeling food, etc.).

Causes of runny or stuffy nose include sinusitis (empyema); eosinophilic sinusitis; sinus mycosis; common cold; influenza; allergic rhinitis caused by pollen, mites, house dust, etc.; specific examples include deviated nasal septum.

In the present invention, "immediate effect" means that a runny nose or nasal congestion is improved within 1 hour, preferably within 30 minutes, more preferably within 15 minutes, and most preferably within 5 minutes after ingestion of the improving agent. It means that you can be aware that you are.

As the form or dosage form of the rapid-acting agent for oral mucosa administration of the present invention, orotic acid or a salt thereof can be absorbed into the body through the oral mucosa. There are no particular restrictions on how to stay inside. Since the rapid effect improving agent for oral mucosal administration of the present invention slows down the release of orotic acid or a salt thereof, the surface of the rapid effect improving agent for oral mucosal administration of the present invention gradually dissolves and disappears with saliva, and administration of the rapid effect improving agent for oral mucosal administration is delayed. Those having the effect of allowing orotic acid or a salt thereof to remain in the oral cavity for a long period of time (sustained-release agent applied to the oral mucosa) are preferred. In addition, the size, shape, etc. of the rapid-acting agent for oral mucosal administration of the present invention are preferably adjusted so as not to be swallowed quickly.

Specific examples of the form or dosage form of the above-mentioned "sustained-release agent to be applied to the oral mucosa" include granules wrapped in an edible film such as a troche tablet, sublingual tablet, buccal tablet, and wafer (edible starch film). Orotic acid or a salt thereof can be absorbed through the oral mucosa, such as tablets, jelly tablets, and chewable tablets (chewable tablets).

In the above "sustained-release agent applied to the oral mucosa", the retention time of the solid component containing orotic acid or its salt after administration in the oral cavity depends on the dosage of orotic acid or its salt and the age of the subject of administration. , Body weight, sex, symptoms, sensitivity to orotic acid or its salt, etc. can be appropriately selected, 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. More specifically, in the case of a tablet containing 200 mg of orotic acid, it is preferable that the tablet completely dissolves in about 5 minutes.

Orotic acid or a salt thereof, which is an active ingredient of the rapid-acting agent for oral mucosal administration of the present invention, can be said to be a safe ingredient because orotic acid is synthesized in vivo. It can be easily and continuously taken on a daily basis. Therefore, the preferred fast-acting agent for oral mucosal administration of the present invention is food. Such foods are not limited to specific foods. For example, in the case of a form or dosage form of a "sustained-release agent applied to the oral mucosa", specific examples include (throat) lozenges, chewing gums, gummies, jellies, Chewing candies, jelly beans, etc.

Orotic acid in orotic acid or a salt thereof contained in the rapid-acting agent for oral mucosal administration of the present invention includes orotic anhydride (free form) and orotic acid hydrates such as orotic acid monohydrate. is included.

Specific examples of the orotic acid include free orotic monohydrate (Kyowa Hakko Bio Co., Ltd., Matsumoto Trading Co., Ltd.), orotic anhydride (Kyowa Hakko Bio Co., Ltd.), orotic acid monohydrate (SIGMA- ALDRICH, Wako Pure Chemical Industries, Ltd.), etc.; Produced and accumulated in the culture solution by fermentation using various microorganisms that have introduced mutations such as pyrimidine auxotrophy and pyrimidine analog resistance (for example, patented No. 2927882), from the above culture, whey containing orotic acid, etc., purified using a normal purification method, for example, a precipitation method, an ion exchange resin, a separation purification method such as a chromatography method using activated carbon, etc. It is taken.

The above-mentioned orotate is a salt with a physiologically acceptable base or the like. Specific examples of the orotate include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; heavy metal salts such as zinc salts; ammonium salts; and salt, etc. Preferred orotates are potassium orotate and magnesium orotate.

In order to improve the absorbability of orotic acid or its salt into the oral mucosa, the rapid-acting agent for oral mucosa administration of the present invention further contains components (e.g., amino acids, peptides, etc.) that increase the solubility of orotic acid or its salt. ) is preferably included. Examples of components that increase the solubility of orotic acid or salts thereof include lysine, histidine, arginine, ornithine, carnitine, choline, carnosine, anserine, and valenine. Among these, carnitine is a suitable example. Ingredients that increase the solubility of the orotic acid or salt thereof include the L-form, D-form, or mixtures thereof. In addition, the component that increases the solubility of the orotic acid or its salt may be used singly or in combination of two or more. The combination of orotic acid or a salt thereof, especially orotic acid and the above solubility-enhancing component improves the absorbability of orotic acid or a salt thereof in the oral mucosa, shortening the time that orotic acid or a salt thereof stays in the mouth. This makes it easier for children and the elderly to take.

The rapid-acting agent for oral mucosal administration of the present invention may contain, if necessary, conventional pharmaceutically acceptable carriers, binders, stabilizers, excipients, diluents, pH buffers, disintegrants, Ingredients such as isotonic agents, additives, coating agents, solubilizers, lubricants, lubricants, solubilizers, lubricants, flavoring agents, sweeteners, solvents, gelling agents, and nutrients are added. may Specific examples of such ingredients include water, physiological saline, animal fat and oil, vegetable oil, lactose, starch, gelatin, crystalline cellulose, gum, talc, magnesium stearate, hydroxypropylcellulose, polyalkylene glycol, Examples include polyvinyl alcohol and glycerin.

The dose of orotic acid or a salt thereof contained in the rapid-acting agent for oral mucosal administration of the present invention is appropriately determined according to the age, body weight, sex, symptoms, sensitivity to orotic acid or a salt thereof, etc. of the subject of administration. be done. 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 500 mg/day, still more preferably 150 to 250 mg/day, most preferably Preferably it is 200 mg/day. In addition, it may be administered in a single dose or in multiple doses (eg, 2 to 4 doses) per day. For example, if the daily dose of orotic acid or its salt is 200 mg, tablets containing 50 mg of orotic acid or its salt may be taken four times a day, and 100 mg of orotic acid or its salt may be taken four times a day. may be taken twice a day, and a tablet containing 200 mg of orotic acid or its salt may be taken once a day.

The duration of effect of the rapid-acting agent for oral mucosal administration of the present invention depends on the dosage of orotic acid or a salt thereof, the age, weight, sex, symptoms of the subject, sensitivity to orotic acid or a salt thereof, and the like. preferably 2 hours to 1 day, more preferably 4 hours to 1 day, even more preferably 6 hours to 1 day, most preferably 8 hours to 1 day.

The rapid-acting agent for oral mucosa administration of the present invention can also alleviate eye itching and malaise due to hay fever.

EXAMPLES The present invention will be described in more detail below with reference to examples, but the technical scope of the present invention is not limited to these examples.

[Production of immediate effect improving agent for oral mucosal administration containing orotic acid or its salt]
A composition comprising the ingredients shown in Table 1 was pressed into a chewable tablet to produce a lozenge containing free orotic acid monohydrate. Also, a composition comprising the ingredients shown in Table 2 was pressed into a chewable tablet to produce a laryngeal containing free orotic acid monohydrate and L-carnitine. A composition comprising the ingredients shown in Table 3 was also compressed into a chewable tablet to produce a lozenge containing potassium orotate. Furthermore, 200 mg of potassium orotic acid and 200 mg of free orotic acid monohydrate are each wrapped in wafer (edible starch film), and potassium orotic acid granules and free orotic acid monohydrate granules are prepared. manufactured.

１）オロット酸フリー体一水和物、（株）マツモト交商製ラクトセラム

1) Free orotic acid monohydrate, Lactoserum manufactured by Matsumoto Trading Co., Ltd.

２）オロット酸カルニチン混合粉末は、Ｌ－カルニチンの潮解性を無くすために、ラクトセラムとＬ－カルニチン（ロンザジャパン）の粉末を１：１で混合乾燥粉砕したもの
３）サプリメントのＯＥＭを受注するアピ株式会社で調製
４）サプリメントのＯＥＭを受注するアピ株式会社で調製

2) Carnitine orotate mixed powder is a 1:1 mixture of lactoserum and L-carnitine (Lonza Japan) powder to eliminate the deliquescence of L-carnitine. Prepared by Co., Ltd. 4) Prepared by Api Co., Ltd., which receives OEM orders for supplements

５）オロット酸カリウム塩（Potassium 0rotate）Bulk Supplement.com（米国）
から購入

5) Potassium Orotate Bulk Supplement.com (USA)
buy from

Six healthy female subjects in their 20s to 50s and four healthy male subjects in their 40s to 70s showing symptoms of hay fever were given laryngeal drops containing free orotic acid monohydrate and free orotic acid monohydrate. and L-carnitine-containing throat lozenges, and potassium orotate granules as sublingual preparations on separate days, and the effects on runny nose, nasal congestion, itchy eyes, and malaise within 1 hour of ingestion were evaluated. confirmed. Table 4 shows the results.

At least one of intake of free orotic acid monohydrate through oral mucosa, intake of L-carnitine-containing free orotic acid monohydrate through oral mucosa, and intake of potassium orotic acid potassium salt through oral mucosa, It was confirmed to be effective in alleviating runny nose or stuffy nose caused by hay fever within 1 hour of ingestion. These effects were felt several minutes after ingestion of the active ingredient through the oral mucosa and lasted for 2 hours to 1 day. Most people felt pain in the tongue when taking the throat lozenge containing free orotic acid monohydrate as a sublingual tablet, but did not feel pain when taking the potassium orotic acid granules as a sublingual tablet. I hardly felt it. Furthermore, most people feel little or no pain when ingesting L-carnitine-containing free orotic acid monohydrate throat lozenges as sublingual tablets and ingesting potassium orotate granules as sublingual tablets. I didn't feel it. Therefore, when the orotic acid-free monohydrate-containing laryngeal candy, which requires a long period of time for elution, is taken as a sublingual tablet, it is preferably taken as a mixture with L-carnitine.

Ingestion of free orotic acid monohydrate from the oral mucosa, intake of L-carnitine-containing free orotic acid monohydrate from the oral mucosa, and intake of potassium orotic acid from the oral mucosa were 1 hour after the intake. It was confirmed that it is also effective in relieving itchy eyes and malaise caused by hay fever.

A healthy male subject in his 60s who had a severe runny nose and nasal congestion due to a cold ingested one tablet of the potassium orotate salt-containing laryngeal candy prepared in Example 1 through the oral mucosa, and finished ingesting it. From around the time, I felt a decrease in runny nose, and after one hour, the number of times I had to blow my nose was reduced to less than half, and I could spend the whole day in that state. The next day, the cold symptoms were gone.

A woman in her thirties diagnosed with sinusitis was asked to take one tablet of the orotic acid-free monohydrate-containing laryngeal prepared in Example 1 through the oral mucosa. He said that he felt that his nasal passages had improved and that he could actually feel that oxygen was being sent to his brain.

A 14-type (39-item) IgE antibody test did not identify any allergens, but a 62-year-old pediatrician who usually gets itchy nose around autumn felt itchy nose. Sometimes, as a result of ingesting one tablet containing the free orotic acid monohydrate prepared in Example 1 after dissolving it in the oral cavity, the symptoms disappeared completely within 1 hour. After that, when he felt a sign of itching, he took one tablet of the above-mentioned throat lozenge, and halfway through, he ingested one tablet of the potassium orotate-containing throat lozenge prepared in Example 1. I was never bothered.

The subject was a man in his 80s who had been suffering from nasal polyps for many years. This man was diagnosed as neither hay fever nor eosinophilic sinusitis, and had a history of cerebral infarction and angina pectoris. In the past, he had taken several anti-allergic drugs, but they were discontinued because they were not particularly effective. Currently, he is taking Xyzal tablets, which are not particularly effective. continued. When this man in his 80s dissolved one tablet of the potassium orotate-containing laryngeal prepared in Example 1 in his mouth and ingested it, two hours later, he smelled plum blossoms at the venue of the plum festival. He said that he was very surprised because he had not felt the scent of flowers for many years. After that, one tablet of the above-mentioned laryngeal was taken a day, and from the middle of the day, one tablet a day of the laryngeal containing free orotic acid monohydrate prepared in Example 1 was dissolved in the oral cavity and ingested. At that time, I felt several odors that I had never felt before, such as citrus and seaweed, and experienced the immediate effect of orotic acid tablets on restoring the sense of smell. In addition, the discomfort of stuffy nose was improved. After taking the medicine for 30 days, the passage of the nose became extremely good, and odors were frequently felt both in the outside air and in the oral cavity. bottom.

For each of 9 healthy female subjects, 8 healthy male subjects, and 1 14-year-old boy showing symptoms of hay fever, the orotic acid prepared in Example 1 was administered for any 5 days when the symptoms of hay fever were considered severe. One tablet of potassium salt-containing laryngeal was dissolved in the oral cavity and ingested. Itching and watery eyes) were evaluated. Table 5 shows the results.

INDUSTRIAL APPLICABILITY The present invention contributes to the field of manufacturing foods (for example, health foods, foods with health claims) and pharmaceuticals for the purpose of alleviating runny nose or stuffy nose.

Claims (7)

A fast-acting ameliorating agent for runny nose or nasal congestion containing orotic acid or a salt thereof as an active ingredient, wherein the dosage of orotic acid or a salt thereof is 100 to 1000 mg/day, and the orotic acid or a salt thereof is , the rapid-acting improving agent for oral mucosa administration, characterized in that it is administered so as to be absorbed into the body through the oral mucosa. 2. The immediate effect improving agent according to claim 1, further comprising carnitine. 3. The immediate effect improving agent according to claim 1 or 2, wherein the orotic acid or a salt thereof is potassium orotate or magnesium orotate. The immediate effect improving agent according to any one of claims 1 to 3, wherein the dose of orotic acid or a salt thereof is 150 to 250 mg/day. 5. The rapid-acting improving agent according to any one of claims 1 to 4, wherein the runny nose or nasal congestion is caused by sinusitis. 5. The rapid-acting improving agent according to any one of claims 1 to 4, wherein the runny nose or nasal congestion is caused by a cold. 5. The rapid-acting improving agent according to any one of claims 1 to 4, wherein the runny nose or nasal congestion is caused by hay fever.