JP2015096473A - Saliva secretion promoter and oral composition comprising the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an amino acid-containing formulation having excellent body fluid secretion promotion action, particularly saliva secretion promoting action, for oral application.SOLUTION: A local mucosa application body fluid secretion promoter composition comprises at least one selected from L-methionine, L-theanine, L-aspartic acid or a salt thereof, and lysine or a salt thereof.

Description

  The present invention relates to a body fluid secretion promoter composition applied to a local mucosa, which contains L-methionine, L-theanine, sodium L-aspartate or lysine hydrochloride.

  Saliva is secreted from the three major salivary glands (the parotid gland, the submandibular gland, the sublingual gland) in the oral cavity and several small salivary glands, and the daily secretion amount is 1 to 1.5 L on average. Salivary functions include oral self-cleaning, oral moisturizing, taste media, digestive, antibacterial, excretory, and buffering. Many cases have been introduced that make daily life difficult.

  There are various causes for the decrease in salivary secretion, mainly including Sjogren's syndrome, diabetes, liver cirrhosis, renal diseases and other internal diseases, decreased secretion function due to aging, irradiation in cancer treatment and side effects of various drugs, etc. It is done.

  Xerostomia caused by a decrease in the amount of saliva secreted causes various unpleasant symptoms such as dry mouth, tongue pain, discomfort in the throat, swallowing disorders, and taste disorders, resulting in a marked decrease in QOL in daily life. In addition, if the condition of xerostomia continues for a long time, the effects on oral problems such as caries, periodontal disease, bad breath and systemic symptoms such as infection cannot be ignored.

  Conventionally, for treatment of xerostomia, gargles, artificial saliva, and the like that are expected to have a moisturizing action in the oral cavity have been used.

  In medical practice, drugs such as cevimeline hydrochloride and pilocarpine hydrochloride may be used as an agent for improving dry mouth symptoms in patients with Sjogren's syndrome (see Non-Patent Document 1).

  Xerostomia is associated with a decrease in the amount of saliva secreted from the salivary glands in the oral cavity. Therefore, a drug that promotes saliva secretion by acting locally is desired rather than a drug that has a systemic effect. In the present invention, an attempt has been made to improve the salivary secretion effect by applying the above-mentioned drug to the oral cavity as an oral rinse preparation, but the current state of the art has not yet reached a general therapeutic method (Non-Patent Documents 2 to 3). reference).

  L-methionine is an important sulfur-containing amino acid, is involved in methyl transfer and supply of SH groups, and has been recognized as an antidote for drug addiction (for example, see Non-Patent Document 4).

  L-theanine is a kind of amino acid that is abundant in tea and is a glutamic acid derivative. Ingestion of theanine has been recognized to improve the generation of α waves, which are indexes of relaxation, suppression of stress, refreshing feeling when waking up, feeling of deep sleep, and feeling of recovery from fatigue (for example, see Non-Patent Document 5).

  L-aspartic acid is an excitatory neurotransmitter in the central nervous system of amino acids, and is closely related to ammonia metabolism and the urea cycle, and has effects such as treatment of waste products in the body, promotion of liver function, and recovery from fatigue. is there. Further, it is said that when applied to the skin by metabolic activation, it has an effect of giving nutrition to the skin (see, for example, Non-Patent Document 6).

  Lysine is an essential amino acid, and deficiency symptoms such as growth failure, weight loss, loss of appetite, loss of nitrogen balance, decreased blood protein, tooth growth failure, nausea, hypersensitivity, etc. (See Patent Document 7).

So far, salivary secretion is promoted by ingestion of amino acids, and it has been described that amino acids having such functions include tryptophan, lysine, arginine and γ-aminobutyric acid. Neither disclosed nor cited documents are disclosed (see Patent Document 1). On the other hand, there is an opposite report that GABA (γ-aminobutyric acid) suppresses salivary secretion via the GABA _A receptor (see Non-Patent Document 8). It is also known that salivary secretion is induced by the taste stimulation of sodium glutamate (see, for example, Non-Patent Document 9).

JP 2007-63228 A

Dry Mouth Clinical, 2007, 128-135, Bio-Dental Publishing Pharmaceutical Journal, 40 (5), 175-179, 2004 Japanese Journal of Oral Surgery, 55, 273 pages, 2009 JAPIC Medical Drug Collection 2013, Maruzen, 2012 Japanese Journal of Agricultural Chemistry, Vol. 72 (2), 19-23, 1998 New Cosmetic Handbook, Nikko Chemicals et al., 401, 2006 List of OTC medicinal properties (group), Shinsha Shinsha, 2002 Autonomic nerve, Vol. 31 (2), 276-281, 1994. Japanese Journal of Taste and Smell, Vol. 18 (3), 355-356, 2011

  The subject of this invention is providing the composition which has the humor secretion promotion effect excellent in the intraoral application. More specifically, it is an object to provide an amino acid-containing saliva secretion promoter composition that is excellent in the saliva secretion promoting action.

  As a result of intensive studies to solve such problems, the present inventors have found that, for example, when applied to the oral cavity which is a local mucosa, a specific amino acid exhibits an excellent salivary secretion promoting action. The present invention has been completed. That is, it was found that L-methionine, L-theanine, L-sodium aspartate, and lysine hydrochloride exhibited excellent fluid secretion promoting action, particularly salivary secretion promoting action.

That is, the present invention provides the following (1) to (7).
(1) A body fluid secretion promoter composition for topical mucosa application, comprising at least one selected from L-methionine, L-theanine, and L-aspartic acid or a salt thereof.
(2) The composition according to (1), further comprising lysine or a salt thereof.
(3) The composition according to (1) or (2), wherein the topical mucosal application is for intraoral use, eye drops or vaginal use.
(4) The composition according to any one of (1) to (3), wherein L-aspartic acid or a salt thereof is sodium aspartate.
(5) The composition according to (2), wherein lysine or a salt thereof is lysine hydrochloride.
(6) The composition according to any one of (1) to (5), which is used for improving dry mouth, dry eye or driver jainer.
(7) The composition according to any one of 1 to 5, which is a saliva secretion promoter.

  The body fluid (particularly saliva) secretion promoting agent applied to the topical mucosa according to the present invention exhibits an excellent body fluid (particularly saliva) secretion promoting action. For example, it can be provided as a composition for improving dry mucosal symptoms in dry mice (dry mouth), dry eyes (dry eyes) or driver gina (vaginosis).

The results of total saliva secretion for 30 minutes after administration of the L-methionine administration solution, DL-tryptophan administration solution, L-proline administration solution, and control administration solution (n = 4) are shown. The results of total salivary secretion for 30 minutes after administration of the L-theanine administration solution, DL-tryptophan administration solution, L-proline administration solution, and control administration solution (n = 4) are shown. The results of total salivary secretion for 30 minutes after administration of the L-aspartate sodium dosing solution, DL-tryptophan administration solution, L-proline administration solution, and control administration solution are shown (n = 4). The results of the total salivary secretion amount (n = 4) for 30 minutes after administration of the lysine hydrochloride (lysine hydrochloride) administration solution, DL-tryptophan administration solution, L-proline administration solution, and control administration solution are shown.

  The dry mouse in the present invention means xerostomia, causing various oral mucosal symptoms due to insufficient salivation, and dry eye means xerophthalmia, and various ocular mucosal symptoms due to insufficient lacrimation It is well known that driver Jain means vaginal dryness and causes symptoms such as sexual pain due to insufficient secretion of mucosa in the vagina.

L-methionine, L-aspartic acid, lysine (also referred to as lysine) hydrochloride, lysine acetate and L-proline used in the present invention are listed in the 16th revised Japanese Pharmacopoeia.
L-aspartic acid, sodium L-aspartate, calcium L-aspartate and magnesium L-aspartate used in the present invention are listed in the Japanese Pharmacopoeia Standards for Pharmaceuticals 2002. L-theanine is also included in the oral composition and is readily available.

  The amount of L-methionine or L-theanine and L-aspartic acid or a salt thereof, and lysine or a salt thereof when the topical mucosa-applied body fluid secretion promoter composition of the present invention is a solid agent is not particularly limited. 1 to 100 mg, preferably 10 to 60 mg per adult, 1 to several times a day. In addition, the amount of L-methionine or L-theanine and L-aspartic acid or a salt thereof, and lysine or a salt thereof in the case of a liquid preparation is not particularly limited, but one adult several times a day It is 0.01 to 10% per turn, preferably 0.1 to 5%.

  The topical mucosa-applied body fluid secretion promoter composition of the present invention is used as a pharmaceutical, a quasi-drug, a cosmetic and the like.

  The application form of the composition of the present invention is not particularly limited, but it is preferably applied in the oral cavity, eyes or vagina.

  The dosage form of the composition of the present invention is not particularly limited as long as it is usually used. For example, oral tablets, troches, sublingual tablets, buccal tablets, adhesive tablets, gum tablets, sprays, gargle tablets, Vaginal suppositories, ointments (including eye ointments and vaginal ointments), creams, gels, liquids (including eye drops), toothpastes (eg, liquid, cream, powder, solid, smelted), etc. Is mentioned.

  A wetting agent, a stabilizer, a surfactant, a pH adjuster, a solubilizer, a thickener, a sweetener, a corrigent, a fragrance, and the like can be appropriately added to the composition of the present invention.

  The wetting agent is not particularly limited as long as it is commercially available as a raw material for pharmaceuticals, foods and cosmetics. For example, polyhydric alcohol, more specifically sorbit, glycerin, concentrated glycerin, ethylene glycol, propylene glycol, 1,3-butylene. Glycol, propanediol (1,3-propanediol), polyethylene glycol, polypropylene glycol, xylite, malt, lactit, trehalose, sodium hyaluronate, hydrolyzed collagen, etc. are mentioned, one of these alone or a combination of two or more Can be blended.

  The amount of the wetting agent is usually in the range of 0.1 to 60% by mass, preferably 0.1 to 55% by mass, more preferably 1 to 40% with respect to the total mass of the composition of the present invention. The range is mass%, and the balance contains purified water.

  When the composition of the present invention is used for the oral cavity, the pH is preferably in the range of 4.5 to 8.0. Examples of the pH adjuster that can be used for the body fluid (particularly saliva) secretion promoter of the present invention include phosphoric acid, sodium monohydrogen phosphate, sodium dihydrogen phosphate, potassium monohydrogen phosphate, potassium dihydrogen phosphate, Citric acid, malic acid, pyrophosphoric acid, tartaric acid, acetic acid or salts thereof, sodium hydroxide and the like can be mentioned. These 1 type, or 2 or more types of combinations can be selected suitably, and can be mix | blended as needed.

  As the corrigents, preservatives, fragrances, coloring agents, solubilizers, surfactants and the like that can be used in the composition of the present invention, they can be appropriately selected from those that can be used for pharmaceuticals and the like.

  Examples of the corrigent include, for example, saccharin, sodium saccharin, disodium glycyrrhizinate, trisodium glycyrrhizinate, sucrose, glucose, fructose, lactose, honey, aspartame, stevia, sucralose, xylitol, inositol, D-sorbitol, D-mannitol, Examples include raffinose, lactulose, lactitol, erythritol, reduced palatinose, palatinose, palatinit, acesulfame K, maltose, maltosyl trehalose or maltitol. These 1 type, or 2 or more types of combinations can be selected suitably, and can be mix | blended.

  Examples of the preservative include parabens (paraoxybenzoic acid esters) such as methylparaben, ethylparaben, isopropylparaben, propylparaben, butylparaben, isobutylparaben and benzylparaben, alcohols such as phenoxyethanol and ethanol, or sorbic acid and benzoic acid. Examples thereof include acids, dehydroacetic acid, propionic acid, and salts thereof. These 1 type, or 2 or more types of combinations can be selected suitably, and can be mix | blended.

  Examples of the fragrance include l-menthol, peppermint, spearmint or fruit fragrance, mint oil and the like. The perfume also has the advantage of stimulating salivation. These 1 type, or 2 or more types of combinations can be selected suitably, and can be mix | blended.

  You may add a solubilizer in order to accelerate | stimulate melt | dissolution of the said additive and medicinal component in the water which is the main base of the composition of this invention. Examples of such a solubilizer include polyhydric alcohols such as propylene glycol, dipropylene glycol, butylene glycol, and polyethylene glycol.

  In addition, in the case of dentifrice and ointment, an abrasive, a foaming agent, and a thickener are appropriately used.

  The composition of the present invention can further contain medicinal ingredients such as a moisturizer, antibacterial agent, anti-inflammatory agent, fluoride, vitamin agent, and herbal extract. These medicinal ingredients are not particularly limited as long as they can be used for pharmaceuticals and the like.

  Examples Examples and preparations are shown below, and the present invention will be described in more detail. However, the scope of the present invention is not limited to these examples.

(Example 1) Salivary secretion promoting effect test with L-methionine, L-theanine, L-sodium aspartate and lysine hydrochloride (hereinafter sometimes referred to as lysine hydrochloride)

(1) Test substance
L-methionine is manufactured by Junsei Kagaku Co., Ltd., L-theanine is manufactured by LKT Laboratories Inc., sodium L-aspartate is manufactured by Wako Pure Chemical, lysine hydrochloride is manufactured by Sigma-Aldrich, DL-tryptophan is manufactured by Wako Pure Chemical, L- Proline was manufactured by Peptide Institute.

(2) Animals used
Slc: Wistar male rats [Japan SLC Co., Ltd.] 6 weeks old were purchased and quarantined / acclimated.

(3) Test method Rats that have completed the quarantine / acclimation period (8 days) are anesthetized with urethane and α-chloralose administered intraperitoneally, and a tracheal cannula is placed to secure the airway. To prevent, the esophagus was ligated with sutures.
Next, 100 μL of a test substance administration solution prepared by adjusting L-methionine to 160 mg / mL using a medium (4% sodium carboxymethylcellulose aqueous solution) was administered into the oral cavity with a micropipette.
Similarly, with respect to L-theanine, L-sodium aspartate, lysine hydrochloride, DL-tryptophan and L-proline, 100 μL of a test substance administration solution prepared to 160 mg / mL in a medium was administered into the oral cavity.
As a control, 100 μL of the medium was administered into the oral cavity.
10 minutes after administration of the medium or test substance administration liquid, wipe the oral medium or test substance administration liquid with a dry cotton ball, drip physiological saline solution into the oral cavity, and then dry the water with the dry cotton ball. Immediately after wiping, a cotton ball having a tare weight was put in the oral cavity, the cotton ball was replaced every 10 minutes, and the saliva secretion amount was measured by the weight and subtraction after the replacement. The measurement was carried out until 30 minutes later.

(4) Test results
Total of 30 minutes after administration of L-methionine administration solution, L-theanine administration solution, L-aspartate sodium administration solution, lysine hydrochloride administration solution, DL-tryptophan administration solution, L-proline administration solution and control administration solution (vehicle) The measurement results of salivary secretion (all n = 4) are shown in Tables 1 to 6 and FIGS.
From the figure and table, the L-methionine administration solution and the lysine hydrochloride administration solution showed a significant salivary secretion promoting effect compared to the control. Similarly, the L-theanine administration solution and the L-sodium aspartate administration solution showed an excellent salivary secretion promoting effect as compared with the control.
On the other hand, even with the same amino acid, the DL-tryptophan or L-proline administration group described in Patent Document 1 did not show a significant salivary secretion promoting effect as compared to the control group.

(Formulation Example 1)-(Formulation Example 4) Toothpaste Taking the ingredients and amounts shown in Table 7, a toothpaste is produced according to a conventional method.

(Formulation Example 5)-(Formulation Example 8) Toothpaste Take the ingredients and amounts shown in Table 8 and prepare a toothpaste according to a conventional method.

(Formulation Example 9)-(Formulation Example 12) Liquid Dentifrice The ingredients and amounts shown in Table 9 are taken, and a liquid dentifrice is produced according to a conventional method.

(Formulation Example 13)-(Formulation Example 16) Mouthwash The ingredients and amounts shown in Table 10 are taken to produce a mouthwash according to a conventional method.

(Formulation Example 17)-(Formulation Example 20) Oral Ointment The ingredients and amounts shown in Table 11 are taken, and an oral ointment is produced according to a conventional method.

(Formulation Example 21)-(Formulation Example 24) Gum Agent The above-mentioned components and amounts shown in Table 12 are taken, and a gum agent is produced according to the section of the Japanese Pharmacopoeia General Rules “Gum Agent”.

(Formulation Example 25)-(Formulation Example 28) Lozenge The ingredients and amounts shown in Table 13 are used to produce a lozenge in accordance with the section “General Lozenge” in Japanese Pharmacopoeia.

(Formulation example 29)-(Formulation example 32) Oral spray The ingredients and amounts shown in Table 14 are used to produce an oral spray according to the section “General Oral Spray”.

(Formulation Example 33)-(Formulation Example 36) Oral Tablets The ingredients and amounts shown in Table 15 are taken, and oral tablets are produced according to the section “General Oral Tablets”.

(Preparation Example 37)-(Formulation Example 40) Sublingual Tablets The ingredients and amounts shown in Table 16 are used to produce tablets for oral use according to the section of the Japanese Pharmacopoeia General Rules “Sublingual Tablets”.

(Formulation Example 41)-(Formulation Example 44) Buccal Tablets Ingredients and amounts shown in Table 17 are used to produce tablets for oral use in accordance with the section of the Japanese Pharmacopoeia General Rules “Buccal Tablets”.

(Formulation Example 45)-(Formulation Example 48) Adhesive Tablets The ingredients and amounts shown in Table 18 are used to produce tablets for the oral cavity according to the section of the Japanese Pharmacopoeia General Rules “Adhesive Tablets”.

(Formulation Example 49)-(Formulation Example 52) Eye Drops Taking the components and amounts shown in Table 19, eye drops are produced according to the section of the Japanese Pharmacopoeia “General Eye Drops”.

(Formulation Example 53)-(Formulation Example 56) Vaginal Suppository Taking the ingredients and amounts shown in Table 20, a vaginal suppository is produced in accordance with the section “General Vaccine Suppository”.

  It can be used as a new salivary secretion promoting composition containing L-methionine, L-theanine, sodium L-aspartate or lysine hydrochloride.

Claims (7)

  A body fluid secretion promoter composition for topical mucosa application, comprising at least one selected from L-methionine, L-theanine, and L-aspartic acid or a salt thereof.   Furthermore, the composition of Claim 1 containing a lysine or its salt.   The composition according to claim 1 or 2, wherein the topical mucosal application is for intraoral use, eye drops or vaginal use.   The composition according to any one of claims 1 to 3, wherein L-aspartic acid or a salt thereof is sodium aspartate.   The composition according to claim 2, wherein the lysine or a salt thereof is lysine hydrochloride.   The composition according to any one of claims 1 to 5, which is used for improving dry mouth, dry eye or driver jainer.   The composition according to any one of claims 1 to 5, which is a salivary secretion promoter.