JP6566707B2 - Salivary secretion promoter for transdermal salivary gland administration - Google Patents

Description

  The present invention relates to a salivary secretion promoter. More specifically, the present invention relates to a salivary secretion promoter for transdermal salivary gland administration that absorbs an active ingredient from the skin surface and delivers it to the major salivary gland.

  Saliva is mainly secreted from salivary glands such as the parotid gland, submandibular gland and sublingual gland, and daily saliva secretion is reported to be about 500-600 milliliters in adults. Saliva is known to act as a digestive fluid, as well as protect and cleanse by preventing dryness of the oral mucosa, bactericidal action of microorganisms entering the oral cavity, prevention of caries, and facilitating food intake. Yes. In addition to the major salivary glands (parotid gland, submandibular gland, sublingual gland), there are small salivary glands everywhere under the oral mucosa.

  In general, it is considered that saliva secretion is reduced when saliva secretion in resting 10 minutes is 1 mL or less, and subjective symptoms of xerostomia are said to occur when saliva secretion decreases to about 50%. ing. Symptoms such as discomfort due to dry mouth, mastication disorders, and taste abnormalities occur in the short-term onset, and caries, periodontal disease, tongue coating, bad breath, stomatitis, glossodynia, etc. Cause severe symptoms such as dysphagia and dysarthria, causing a decrease in QOL. It is also known that Sjogren's syndrome is associated with xerostomia, and one of the diagnostic criteria is a decrease in salivary secretion (10 mL or less for gum test for 10 minutes or 2 g or less for saxon test for 2 minutes), and salivary gland scintigraphy The findings of functional decline are established.

Conventionally, for xerostomia, oral medicines containing muscarinic receptor agonists such as pilocarpine hydrochloride and cevimeline hydrochloride as active ingredients have been marketed.
Non-Patent Documents 1 and 2 report that pilocarpine has a salivary secretion promoting action when taken internally.
Patent Document 1 and Non-Patent Documents 3 and 4 report that cevimeline has a salivary secretion promoting action when taken internally.

Japanese Patent No. 2668383

Kazuhiro Maruyama et al., “Pharmacological characteristics and clinical trial results of pilocarpine hydrochloride, a drug for improving xerostomia”, Japanese Pharmacological Journal, 127, 399-407, 2006. Jun Sakurai et al., "Long-term administration study of pilocarpine hydrochloride for oral dryness in Sjogren's syndrome" pharmacology and treatment, vol.35, supplement 2007. Yoichi Ichikawa et al., `` Double-blind comparison study between SNI-2011 and placebo for dry mouth symptoms in Sjogren's syndrome '' diagnosis and new drug, 38 (4), 349-368 (2001). Iga Y et al., `` SNI-2011 induces saliva and tear secretions in rat and mice; The role of muscarinic acethylcholine receptors. '', Jpn. J. Pharmacol., 78, 373-380 (1998).

However, if these active ingredients are taken as internal medicines to be effective, they must be taken into the body from the digestive tract after internal use and then circulated in the blood before being delivered to the salivary glands. The blood concentration rises to the range where the side effect appears because the blood concentration and tissue concentration rapidly rise and then fall, and the range of effective blood concentration and effective tissue concentration that achieves the desired effect There was a problem that the time to stay in was shortened.
For this reason, it has been difficult to avoid the occurrence of side effects in the therapy using the internal medicine, and the duration of the effect has been short, and it was necessary to increase the frequency of taking.

  As a result of intensive studies aimed at achieving the salivary gland tissue concentration to an effective tissue concentration while suppressing the blood concentration of the active ingredient to less than the concentration at which side effects occur over a long period of time, a specific solubilizer The present inventors have found that such a problem can be solved by transdermally administering the active ingredient dissolved in the skin from the surface skin of the major salivary gland, thereby completing the present invention.

That is, the present invention
[1] A salivary secretion promoter for transdermal salivary gland administration containing a muscarinic receptor agonist;
[2] The saliva secretion promoter for transdermal salivary gland administration according to the above [1], wherein the compounding amount of the muscarinic receptor agonist is 0.1 to 50% by weight with respect to the total weight of the saliva secretion promoter;
[3] The salivary secretion promoter for transdermal salivary gland administration according to [1] or [2] above, which contains 1,3-butylene glycol as a solubilizer;
[4] Saliva for transdermal salivary gland administration according to any one of the above [1] to [3], wherein the muscarinic receptor agonist is selected from pilocarpine, cevimeline and pharmaceutically acceptable salts thereof. Secretagogues;
[5] In any one of the above [1] to [4], which is a dosage form selected from the group consisting of a liniment, a lotion, an external aerosol, a pump spray, an ointment, a cream and a gel The salivary secretion promoter for transdermal salivary gland administration as described;
[6] The salivary secretion promoter for transdermal salivary gland administration according to any one of [1] to [4] above, which is a dosage form selected from the group consisting of a tape and a poultice;
[7] A percutaneous absorption-type salivary gland topical preparation for improving xerostomia containing a muscarinic receptor agonist;
[8] Use of a muscarinic receptor agonist for producing a percutaneous absorption type salivary gland topical preparation for improving dry mouth symptoms;
[9] The salivary secretion promoter for transdermal salivary gland administration according to any one of the above [1] to [6], characterized in that saliva secretion is sustained for a long time compared to oral administration;
[10] The promotion of salivary secretion for transdermal salivary gland administration according to any one of [1] to [6] above, wherein sweating and / or gastrointestinal disorders are suppressed as compared with oral administration Agent;
[11] The salivary secretion promoter for transdermal salivary gland administration according to any one of [1] to [6] above, which is characterized by sustained release action of a muscarinic receptor agonist;
[12] The salivary secretion promoter for transdermal salivary gland administration according to any one of [1] to [6], which is applied once a day.

  According to the present invention, the side effect is suppressed, the effect lasts for a long time, thereby preventing the occurrence of xerostomia and secondary diseases and symptoms derived therefrom, or the administration frequency can be reduced. Can be treated.

It is a graph which shows the time-dependent change of the rat saliva secretion amount by various pilocarpine formulation administration routes.

In a first aspect, the present invention provides a salivary secretion promoter for transdermal salivary gland administration.
The salivary secretion promoter of the present invention contains a muscarinic receptor agonist and 1,3-butylene glycol.

  Muscarinic receptor agonists are drugs that act on metabolically regulated muscarinic receptors belonging to the acetylcholine receptor, and selectively act on drugs that act non-selectively on M1-M5 receptor subtypes. The drug is present. Muscarinic receptors (M3) are expressed in cells of the major salivary glands, and saliva is secreted through these receptors.

The muscarinic receptor agonist used for the salivary secretion promoter of the present invention is a component capable of activating the muscarinic receptor by acting non-selectively or selectively on the M1-M5 receptor subtype, Examples thereof include pilocarpine acting on the M3 receptor receptor, cevimeline, acetylcholine, carbachol, betanecol, methacholine, aceclidine, talsaclidine, arecoline, and pharmaceutically acceptable salts thereof. Examples of the pharmaceutically acceptable salt include salts of inorganic acids or organic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid and tartaric acid; alkali metal salts such as sodium and potassium; alkaline earth metal salts such as calcium An organic ammonium salt such as ammonia, triethylamine or pyridine. Of these, pilocarpine or cevimeline is preferable, and pilocarpine hydrochloride or cevimeline hydrochloride is most preferable. The content of the muscarinic receptor agonist is 0.1 to 50% by weight, preferably 1 to 40% by weight, more preferably 3 to 40% by weight, based on the weight of the salivary secretion promoter.
When the saliva secretion promoter of the present invention is applied as a coating agent such as an ointment, cream, or gel, the content of the muscarinic receptor agonist is 0.1 to 40% by weight based on the weight of the saliva secretion promoter. , Preferably 1 to 30% by weight, more preferably 3 to 20% by weight. When applied as a patch such as a tape or a poultice, the content of the muscarinic receptor agonist is 1 to 50% by weight, preferably 10 to 40% by weight, more preferably based on the weight of the salivary secretion promoter. Is 20-40% by weight.

  In addition, 1,3-butylene glycol used as a solubilizer in the salivary secretion promoter of the present invention dissolves or disperses the above-described muscarinic receptor agonist and other components and is applied to the skin surface. A medium capable of stimulating the major salivary gland for a long time, for example, 1,3-butylene glycol. On the other hand, if ethanol, glycerin and 1,3-propanediol are added in an amount larger than the amount of 1,3-butylene glycol, it is preferable because it may inhibit the percutaneous absorption promoting effect of 1,3-butylene glycol. Absent. The total amount of ethanol, glycerin and 1,3-propanediol in the preparation to be applied to the human body is preferably smaller than the blended amount of 1,3-butylene glycol, more preferably less than half. Most preferably, it is 1/10 or less.

Further, the solubilizer used in the salivary secretion promoter of the present invention is a long-term permeability of a muscarinic receptor agonist in a permeability test using a stationary Franz cell in addition to the above 1,3-butylene glycol. It can be a solubilizer in which (persistence) is recognized. Preferably, Merct Millipore Strat-M ^TM attached to a stationary Franz cell kept at 37 ° C. can be used as a solubilizing agent that allows a muscarinic receptor agonist to permeate at a constant rate for 24 hours.
Stationary Franz cells and Strat-M ^™ are devices that have been established for use in in vitro evaluation of drug transdermal absorbability (Biopharm. Drug Disps. 33: pp. 218-228 (2012), Pharmazie , 66: pp.849-852 (2011)).

  The salivary secretion promoter of the present invention is characterized by being transdermally administered from the skin on the surface of the major salivary gland. Specifically, there are three major salivary glands: the submandibular gland near the throat behind the jaw, the sublingual gland near the base of the tongue, and the parotid gland near the earlobe from the bottom of the side of the side To do. As an effective method of administering drugs to the great salivary gland, when applied to the submandibular gland and sublingual gland, the skin from the lower jaw and near the lower jaw angle of the mandible to the neck, and when applied to the parotid gland The salivary secretion promoter for transdermal salivary gland administration of the present invention is applied or applied to the skin from near the bottom of the skin to the periphery of the earlobe. In particular, it is more preferable to apply to the skin near the submandibular gland and the sublingual gland because it has a higher possibility of acting more effectively in the case of Sjogren's syndrome or salivary gland tumors than in other sites.

  The saliva secretion-promoting agent of the present invention can be made into dosage forms for transdermal administration such as liniment, lotion, external aerosol, pump spray, ointment, cream and gel. Moreover, the saliva secretion promoter of this invention can be made into dosage forms for transdermal administration, such as a tape agent and a poultice.

  Tapes and poultices, which are pasted and used, have the advantage of sustaining the effect over a long period of time compared to other dosage forms in terms of drug penetration, but the surface skin of the major salivary glands, especially the parotid gland and When it is applied to the skin near the submandibular gland, the adhesive sticks easily into other people's eyes, so it is inconvenient in situations where people are concerned about it, such as when going out. On the other hand, coating agents such as ointments, creams, and gels have the advantage that they can be applied inconspicuously when going out, although the retention after application is poor when applied. By having both dosage forms, it becomes possible to select different preparations according to lifestyle, for example, at bedtime and when going out.

  In addition, the salivary secretion promoter of the present invention is a base, base matrix, oil, ordinarily used for pharmaceuticals or quasi-drugs, as long as the effects of the present invention are not impaired, according to the above-mentioned dosage form. Arbitrary components such as a surfactant, a thickener, a resin component, and a wetting agent can be contained.

  Examples of bases include petrolatum, paraffin, silicone, plastibase, hydrophilic petrolatum, purified lanolin, hydrolyzed lanolin, carboxyvinyl polymer, polyacrylic acid, methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide, polyacrylamide, sodium alginate, gelatin , Gum arabic, gum tragacanth, guar gum, xanthan gum, isopropyl myristate, isopropyl palmitate, lactic acid, lauric acid, oleic acid, linoleic acid, linolenic acid, squalene, squalane, styrene isoprene styrene block copolymer, styrene butadiene block copolymer , Polyisobutylene, raw rubber, polyisoprene, polybutene and the like.

  Examples of oils include cetyl alcohol, isostearyl alcohol, isostearic acid, oleic acid, glycerin, sorbitol, ethylene glycol, propylene glycol, polyethylene glycol, myristyl myristate, hexyl laurate, decyl oleate, isopropyl myristate, Glyceryl monostearate, capric acid, lauric acid, myristic acid, palmitic acid, linoleic acid, stearic acid, lauryl lactate, oleyl oleate, diisopropyl adipate, diisopropyl sebacate, glyceryl monocaprylate, ethylene glycol almond oil monoisooctanoate , Olive oil, camellia oil, persic oil, mint oil, soybean oil, sesame oil, sink oil, cottonseed oil, corn oil, safflower oil, coconut oil, -Potash oil, castor oil, hydrogenated castor oil, soybean lecithin, squalene, dl or l-menthol, l-menton, limonene, pinene, piperitone, terpinene, terpinolene, terpinol, carveol, dl-camphor, N-methyl-2-pyrrolidone And liquid paraffin.

  As examples of the surfactant, an anionic surfactant, a cationic surfactant, a nonionic surfactant, and an amphoteric surfactant can be used. For example, anionic surfactants such as fatty acid salts, alkyl sulfates, polyoxyethylene alkyl ether sulfates, alkyl sulfosuccinates, alkyl ether carboxylates; stearyl trimethyl ammonium chloride, oleyl trimethyl ammonium chloride, cetyl trimethyl ammonium chloride, Cationic surfactants such as distearyldimethylammonium chloride; polyoxyethylene hydrogenated castor oil, polyoxyethylene fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, sorbitan fatty acid ester, propylene glycol fatty acid ester, glycerin fatty acid Nonionic surfactants such as esters; monoalkyldimethylaminoacetic acid betaine, monofatty acid amidopropyldimethylamino Betaine acetate, N- fatty acyl -N- carboxymethyl -N- hydroxyethyl ethylenediamine salt, dimethyl alkyl glycine, the zwitterionic surfactant such as lecithin and the like.

  Examples of thickeners or resin components include sodium polyacrylate, ethylene-acrylic acid copolymer, vinyl pyrrolidone polymer, vinyl alcohol-vinyl pyrrolidone copolymer, acrylamide polymer, acrylic acid methacrylic acid copolymer. Copolymer, polyoxyethylene-polyoxypropylene copolymer, polyacrylamide, carboxyvinyl polymer, polyvinyl alcohol, cellulose ether, cationized guar gum, pullulan, gelatin, xanthan gum, carrageenan, guar gum, gum arabic, karaya gum, tragacanth gum, gellan gum, cellulose , Crystalline cellulose, alginic acid, dextran and the like. When an aqueous polymer compound such as polyacrylic acid or sodium polyacrylate is used, activated alumina, synthetic aluminum silicate, aluminum hydroxide, or the like can be used as an aluminum compound that can undergo a crosslinking reaction. The fat-soluble polymer compounds include natural rubber, isoprene rubber, polyisobutylene rubber, styrene butadiene rubber, styrene isoprene styrene block copolymer, styrene butadiene styrene block copolymer, (meth) acrylic acid ester copolymer, silicone. Resins, rosin, polybutene, lanolin, petrolatum, plastibase, beeswax, solid paraffin and the like can be used.

  Examples of wetting agents include aliphatic alcohols such as starch acrylate, polyethylene glycol, sorbitol, maltitol, methanol, and isopropyl alcohol; aliphatic polyhydric alcohols such as octanediol, ethylene glycol, polyethylene glycol, and D-sorbitol. Araliphatic alcohols such as benzyl alcohol; trimethylglycine and the like.

  Examples of antioxidants include ascorbic acid, erythorbic acid, ascorbic palmitate, sodium bisulfite, sodium edetate, tetrasodium edetate, dry sodium sulfite, citric acid, sodium citrate, tocopherol acetate, dl-α- Tocopherol, potassium dichloroisocyanurate, dibutylhydroxytoluene, butylhydroxyanisole, soy lecithin, sodium pyrosulfite, benzotriazole, pentaerythryl-tetrakis [3- (3,5-di-t-butyl-4-hydroxyphenyl) Propionate], propyl gallate, 2-mercaptobenzimidazole and the like.

The saliva secretion-promoting agent of the present invention can be formulated into a dosage form suitable for transdermal administration using a well-known technique.
The salivary secretion promoter of the present invention is a salivary secretion promoter for transdermal salivary gland administration that is applied to the skin surface in the vicinity of the large salivary gland such as the parotid gland, submandibular gland or sublingual gland. The muscarinic receptor agonist in the salivary secretion promoter of the present invention can achieve an effective tissue concentration in the major salivary gland while suppressing the blood concentration of the muscarinic receptor agonist by directly stimulating the major salivary gland. Therefore, the salivary secretion promoter of the present invention can be effective locally and for a long time in the large salivary gland while suppressing the occurrence of side effects such as hyperhidrosis and gastrointestinal disorders, and can increase the amount of saliva secreted.

  The saliva secretion promoter of the present invention is applied to the skin of a predetermined body part once a day. The conventional type of salivary secretion-promoting agent to be taken has partly circulated in the blood to stimulate the salivary gland to promote saliva secretion. However, the salivary secretion-promoting agent of the present invention substantially passes through the blood. The salivary secretion promoter applied can effectively stimulate the large salivary gland because it reaches the large salivary gland locally without any problems, and its efficacy is durable.

Test example 1
Screening of solubilizers Using a stationary Franz cell (diffusion area approximately 0.636 cm ² ) equipped with a human skin model membrane (trade name Strat-M, Merck Millipore), muscarinic receptor agonists with various solubilizers In vitro skin permeability test was performed. A receiver solution (saline) was filled in a receiver phase (capacity: about 15 mL) of Franz cell kept at 37 ° C. Place human skin model membrane in Franz cell joint and add muscarinic receptor agonist, pilocarpine hydrochloride (1% (w / w), 200μL) prepared with various solubilizing agents to the donor phase in the center Then, the inside of the Franz cell was kept at 37 ° C., and the test was started. A certain amount of receiver solution was sampled over time, and the same amount of receiver solution (saline) was replenished. The amount of pilocarpine contained in the collected receiver solution was analyzed by high performance liquid chromatography (instrument name: Alliance HPLC system (Waters), column: Chromolith Performance RP-18e (Merck Millipore), temperature: 25 ° C, elution: phosphate buffer (pH = 3) / Methanol = 980/20, detection condition: 214 nm). The permeation results after 24 hours are shown in Table 1 below.

*2回測定の平均値

* Average of two measurements

  As shown in Table 1, among the solubilizers, 1,3-butylene glycol permeated pilocarpine, but it was shown that purified water, ethanol, and concentrated glycerin could not permeate.

Test example 2
Divalent alcohol permeability test In vitro skin permeability tests of muscarinic receptor agonists with various solubilizers were conducted in the same manner as in Test Example 1 except that the following dihydric alcohols were used as solubilizers. The results transmitted after 24 hours are shown in Table 2 below.

  As shown in Table 2, among the dihydric alcohols having similar alkyl chain lengths, 1,3-butylene glycol, 1,2-hexylene glycol and dipropylene glycol have pilocarpine model membrane permeability, It was found that 3-propanediol hardly penetrates.

  Japanese Patent No. 4308255 describes an ophthalmic transdermal absorption preparation for promoting tear secretion, which contains a muscarinic receptor agonist as an active ingredient. In this patented invention, isopropyl myristate is described as an absorption promoter for muscarinic receptor agonists. Therefore, the skin permeability of pilocarpine by the solubilizing agent that showed skin permeability in the present invention and isopropyl myristate was compared by an in vitro skin permeability test. The results are shown in Table 3 below.

  As shown in Table 3, it was shown that 1,3-butylene glycol used as a solubilizer in the present invention has higher pilocarpine skin permeability compared to isopropyl myristate in Japanese Patent No. 4308255.

Test example 3
Time-course permeability test with solubilizing agent Using the same human skin model membrane and Franz cell as in Test Example 1, time-lapse in vitro skin permeability test of pilocarpine hydrochloride and cevimeline hydrochloride with 1,3-butylene glycol went. The results are shown in Table 4 and Table 5 below.

  As shown in Tables 4 and 5, 1,3-butylene glycol was shown to permeate pilocarpine and cevimeline for a long time up to 24 hours after the start of the test. In addition, pilocarpine was shown to gradually permeate compared to cevimeline.

From these results, it was shown that 1,3-butylene glycol can deliver a muscarinic receptor agonist to the great salivary gland for a long time after application.
Therefore, a salivary secretion enhancer for transdermal salivary gland administration using 1,3-butylene glycol as a solubilizer provides a drug with reduced side effects, effective effects over a long period of time, and reduced administration frequency. It was shown that.

Test example 4
Permeability test using rat skin Test except that rat skin (SD male rat, 7 weeks old, dorsal skin) is used instead of human skin model membrane, and the preparation prepared according to the following method is applied according to the following formulation The skin permeability test of pilocarpine with 1,3-butylene glycol was conducted in the same manner as in Example 1. The results are also shown in Table 6 below.

  As shown in Table 6, 1,3-butylene glycol was shown to penetrate pilocarpine even in rat skin.

Test Example 5
Rat salivation promotion test The rat neck was shaved with a clipper and disinfected with alcohol. Apply the pilocarpine preparation (ointment) prepared in Test Example 4 to the skin of the parotid gland, submandibular gland and sublingual gland of a shaved rat, and the amount of saliva secreted at 1, 2, 4 and 6 hours after application It was measured. The saliva secretion was measured by removing the saliva in the rat mouth immediately with a cotton ball immediately before the measurement, and then adding the cotton ball to the mouth and taking it out 5 minutes later. As comparative examples, the amount of secretory saliva was measured when the same amount of placebo preparation was transdermally administered from the vicinity of the major salivary gland, when the same amount of pilocarpine preparation was transdermally administered from the back skin, and when administered intravenously. The results are shown in FIG.

As shown in Figure 1, when transdermal salivary gland was administered from the skin surface near the major salivary gland, it was shown to promote saliva secretion over a long period of time, unlike transdermal and intravenous administration from the back. .
The ratio of the pilocarpine blood concentration to the major salivary gland concentration in rats subjected to the experiment of Test Example 5 is shown in Table 7 with 1 being 5 minutes after intravenous administration.

As shown in Table 7, when compared to 5 minutes after intravenous administration and 4 hours after percutaneous salivary gland administration, the salivary gland tissue concentration relative to blood concentration is approximately It was shown to be 3 times higher.
Therefore, a salivary secretion promoter for transdermal salivary gland administration using 1,3-butylene glycol as a solubilizing agent directly stimulates the large salivary gland, thereby suppressing the blood concentration of the muscarinic receptor agonist and reducing the blood salivary gland. It was suggested that an effective tissue concentration in can be achieved.

  The salivary secretion promoter of the present invention was prepared by a known production method according to the following formulation example.

  The salivary secretion promoters of Examples 1 to 16 are applied to the skin surface in the vicinity of the major salivary glands such as the parotid gland, submandibular gland or sublingual gland, thereby controlling the blood concentration of the muscarinic receptor agonist. An effective tissue concentration in the major salivary gland could be achieved while suppressing. As a result, the salivary secretion promoters of Examples 1 to 16 are effective on the large salivary gland locally and over a long time while suppressing the occurrence of side effects such as hyperhidrosis and gastrointestinal disorders, and increase the amount of saliva secreted. I was able to.

Claims (10)

  A salivary secretion promoter for transdermal salivary gland administration, comprising a muscarinic receptor agonist selected from pilocarpine, cevimeline and pharmaceutically acceptable salts thereof and 1,3-butylene glycol as a solubilizer.   The salivary secretion promoter for transdermal salivary gland administration according to claim 1, wherein the compounding amount of the muscarinic receptor agonist is 0.1 to 50% by weight based on the total weight of the salivary secretion promoter.   3. Saliva secretion for transdermal salivary gland administration according to claim 1 or 2, wherein the dosage form is selected from the group consisting of a liniment, a lotion, an external aerosol, a pump spray, an ointment, a cream and a gel. Accelerator.   The salivary secretion promoter for transdermal salivary gland administration according to claim 1 or 2, which is a dosage form selected from the group consisting of a tape and a poultice.   A transdermal salivary gland for improving dry mouth, comprising a muscarinic receptor agonist selected from pilocarpine, cevimeline and pharmaceutically acceptable salts thereof and 1,3-butylene glycol as a solubilizer Topical formulation.   As a muscarinic receptor agonist and solubilizer selected from pilocarpine, cevimeline and pharmaceutically acceptable salts thereof for producing a percutaneous absorption type salivary gland topical preparation for improving dry mouth symptoms 1, Use with 3-butylene glycol.   The salivary secretion promoter for transdermal salivary gland administration according to any one of claims 1 to 4, characterized in that saliva secretion is sustained for a longer time than in the case of oral administration.   5. The salivary secretion promoter for transdermal salivary gland administration according to any one of claims 1 to 4, wherein sweating and / or gastrointestinal disorders are suppressed as compared to oral administration.   The salivary secretion promoter for transdermal salivary gland administration according to any one of claims 1 to 4, characterized by a sustained release action of a muscarinic receptor agonist.   The salivary secretion promoter for transdermal salivary gland administration according to any one of claims 1 to 4, which is applied once a day.

Images