Pharmaceutical composition for enhancing salivation

Abstract

The present disclosure provides a pharmaceutical composition which comprises a vasodilator, which is for enhancing salivation, and which is for local administration to salivary glands. The pharmaceutical composition can enhance salivation by being administered to a salivary gland, and can be used for improving, preventing or treating xerostomia.

Description

Pharmaceutical composition for enhancing saliva secretion

[0001] The present invention relates to a pharmaceutical composition for topical administration to the salivary glands to enhance saliva secretion, which contains a vasodilator.

[0002] Xerostomia is a condition in which saliva production decreases due to various causes such as drug side effects, stress, and other factors. Adults typically produce about 0.5 to 1.5 liters of saliva per day, and it is said that symptoms of xerostomia appear when saliva production decreases by about 50%. While xerostomia does not directly threaten life, it significantly reduces quality of life (QOL) by causing difficulties with eating, changes in taste, and speech. In Japan, there are estimated to be approximately 8 million patients and around 30 million potential patients, but effective treatment methods have not yet been fully established.

[0003] Salivary glands are divided into major salivary glands (parotid, submandibular, and sublingual glands) and minor oral glands, with the majority of saliva being secreted from the major salivary glands. Salivary glands are innervated by the parasympathetic nervous system, and M is present in the acinar cells of the salivary glands. ３ When acetylcholine binds to muscarinic receptors, phospholipase C is activated within the cell, producing inositol triphosphate. This inositol triphosphate stimulates the release of calcium ions from the endoplasmic reticulum, increasing the intracellular calcium ion concentration. This increase in calcium ion concentration opens ion channels such as chloride ion channels, creating an osmotic gradient and causing water to move toward the lumen. This water movement involves transcellular transport, which passes through the cell via the membrane protein aquaporin 5, and paracellular transport, which passes through the spaces between acinar cells. As a result, saliva is secreted.

[0004] The muscarinic receptor agonists pilocarpine and cevimerin, used as oral medications for the treatment of xerostomia, are M2 cells of acinar cells. ３It is thought that these drugs promote saliva secretion by acting on muscarinic receptors and accelerating intracellular inositol phospholipid turnover in a concentration-dependent manner. However, these muscarinic receptor agonists often do not provide sufficient improvement in saliva secretion, and the high incidence of side effects such as excessive sweating, abdominal pain, and diarrhea leads to low rates of continued medication use. Although transdermal saliva secretion promoters containing muscarinic receptor agonists such as pilocarpine and cevimeline (Patent Documents 1 and 2) and pharmaceutical compositions for promoting saliva secretion applied to or patched onto the oral mucosa (Patent Document 3) have been reported with the aim of avoiding side effects and maintaining drug efficacy for extended periods, further treatments for xerostomia are needed.

[0005] The present inventors' research group has conducted research focusing on the relationship between saliva secretion and aquaporin 5, and has reported that the contribution of aquaporin 5-dependent water transport changes depending on the intensity of acetylcholine stimulation and blood flow (Non-Patent Literature 1).

[0006] Japanese Patent Publication No. 2016-210701, Japanese Patent Publication No. 2016-210702, Japanese Patent Publication No. 2017-066126

[0007] MST Tahmina AKTER et al., Biomedical Research, 2023;44(2):51-63. doi: 10.2220 / biomedres.44.51.

[0008] This invention provides a means for treating xerostomia based on a novel mechanism of action.

[0009] The inventors have discovered that saliva secretion can be enhanced by locally administering a vasodilator to the salivary glands.

[0010] This disclosure provides: Item 1. A pharmaceutical composition for topical administration to the salivary glands for enhancing salivary secretion, comprising a vasodilator. Item 2. The pharmaceutical composition according to Item 1, wherein the salivary secretion is acetylcholine-induced salivary secretion. Item 3. The pharmaceutical composition according to Item 1 or 2, wherein the vasodilator does not have M3 muscarinic receptor agonist activity. Item 4. The pharmaceutical composition according to claim 1 or 2, wherein the vasodilator is selected from the group consisting of calcium channel blockers, angiotensin II receptor antagonists, cholinesterase inhibitors, α1-adrenergic receptor blockers, nitrates, 5-HT2 serotonin receptor blockers, prostaglandin E1 preparations, TRP receptor agonists, ATP-sensitive K channel activators, β2-adrenergic receptor agonists, angiotensin-converting enzyme inhibitors, phosphodiesterase inhibitors, adenylyl cyclase direct activators, cyclooxygenase inhibitors, thromboxane A2 synthase inhibitors, thromboxane A2 receptor blockers, ET1 endothelin receptor blockers, H1 histamine receptor agonists, and histaminidase inhibitors. Claim 5. The pharmaceutical composition according to claim 1 or 2, wherein the vasodilator is selected from the group consisting of calcium channel blockers, angiotensin II receptor antagonists, cholinesterase inhibitors, α1-adrenergic receptor blockers, nitrates, 5-HT2 serotonin receptor blockers, prostaglandin E1 preparations, TRP receptor agonists, and ATP-sensitive K channel activators. Claim 6. The pharmaceutical composition according to claim 1 or 2, wherein the vasodilator is a calcium channel blocker, and the calcium channel blocker is selected from the group consisting of nifedipine, nilvadipine, amlodipine, nicardipine, benidipine, barnidipine, nitrendipine, nisoldipine, azelnidipine, manidipine, efonidipine, cilnidipine, aranidipine, felodipine, nimodipine, crebidipine, lasidipine, relcanidipine, diltiazem, and verapamil. Claim 7. The pharmaceutical composition according to claim 1 or 2, wherein the vasodilator is an angiotensin II receptor antagonist, and the angiotensin II receptor antagonist is selected from the group consisting of irbesartan, losartan, candesartan, valsartan, telmisartan, olmesartan, and azilsartan.Item 8. The pharmaceutical composition according to Item 1 or 2, wherein the vasodilator is a cholinesterase inhibitor, and the cholinesterase inhibitor is selected from the group consisting of physostigmine, neostigmine, distigmine, pyridostigmine, rivastigmine, donepezil, galantamine, itopride, acotiamide, ambenonium, and edrophonium. Item 9. The pharmaceutical composition according to Item 1 or 2, wherein the vasodilator is an α1-adrenergic receptor blocker, and the α1-adrenergic receptor blocker is selected from the group consisting of prazosin, doxazosin mesil, urapidil, nicergoline, ifenprodil, tamsulosin, terazosin, silodosin, olanzapine, bunazosin, and naphtopidil. Item 10. A pharmaceutical composition according to claim 1 or 2, wherein the vasodilator is a nitrate, and the nitrate is selected from the group consisting of nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, nicorandil, and amyl nitrite. Claim 11. A pharmaceutical composition according to claim 1 or 2, wherein the vasodilator is a 5-HT2 serotonin receptor blocker, and the 5-HT2 serotonin receptor blocker is selected from the group consisting of ketanserin, salpogralate, and ritanserin. Claim 12. A pharmaceutical composition according to claim 1 or 2, wherein the vasodilator is a prostaglandin E1 preparation, and the prostaglandin E1 preparation is selected from the group consisting of alprostadil, limaprost, and misoprostol. Claim 13. A pharmaceutical composition according to claim 1 or 2, wherein the vasodilator is a TRP receptor agonist, and the TRP receptor agonist is selected from the group consisting of l-menthol, geraniol, and eucalyptol. Claim 14. A pharmaceutical composition according to claim 1 or 2, wherein the vasodilator is an ATP-sensitive K channel activator, and the ATP-sensitive K channel activator is selected from the group consisting of minoxidil, nicorandil, and diazoxide. Claim 15. A pharmaceutical composition according to any one of claims 1 to 14, administered transdermally to the skin on the surface of the major salivary glands. Claim 16. A pharmaceutical composition according to any one of claims 1 to 14, administered transmucosally into the oral cavity.Item 17. A pharmaceutical composition according to any one of Items 1 to 16, which is in a dosage form selected from the group consisting of external solid preparations, external liquid preparations, spray preparations, ointment preparations, cream preparations, gel preparations, patch preparations, nanoneedle injection preparations, tablet preparations, troche preparations, paste preparations, gel preparations, buccal tablets, orally disintegrating tablets (OD tablets), and oral film preparations. Item 18. A pharmaceutical composition for improving, preventing or treating xerostomia, which contains a vasodilator. Item 19. A pharmaceutical composition according to any one of Items 1 to 17 for improving xerostomia. Item 20. A pharmaceutical composition according to any one of Items 1 to 19, which is used in combination with a parasympathetic stimulant. Item 21. A pharmaceutical composition according to any one of Items 1 to 20, which is administered to a subject who has been administered a parasympathetic stimulant or to whom administration is scheduled.

[0011] The present disclosure also provides the following. Item 1A. A pharmaceutical composition for local administration to the salivary gland for enhancing M3 muscarinic receptor agonist-induced salivary secretion, which contains a vasodilator. Item 2A. The pharmaceutical composition according to Item 1A, wherein the vasodilator has no muscarinic receptor activating ability. Item 3A. The vasodilator is a calcium antagonist, an angiotensin II receptor antagonist, a cholinesterase inhibitor, an α ３ adrenergic receptor blocker, a nitrate, a 5-HT １ serotonin receptor blocker, a prostaglandin E1 preparation, a TRP receptor agonist, an ATP-sensitive K channel activator, a β ２ adrenergic receptor agonist, an angiotensin-converting enzyme inhibitor, a phosphodiesterase inhibitor, an adenylate cyclase direct activator, a cyclooxygenase inhibitor, a thromboxane A ２ synthetase inhibitor, a thromboxane A ２ receptor blocker, an ET ２ endothelin receptor blocker, an H １ histamine receptor agonist, and a histamine degrading enzyme inhibitor, and is selected from the group consisting of the pharmaceutical composition according to Item 1A or 2A. Item 4A. The vasodilator is a calcium antagonist, an angiotensin II receptor antagonist, a cholinesterase inhibitor, an α １ adrenergic receptor blocker, a nitrate, a 5-HT １ serotonin receptor blocker, and is selected from the group consisting of the pharmaceutical composition according to Item 1A or 2A. ２A pharmaceutical composition according to claim 1A or 2A, selected from the group consisting of a serotonin receptor blocker, a prostaglandin E1 preparation, a TRP receptor agonist, and an ATP-sensitive K channel activator. Claim 5A. A pharmaceutical composition according to claim 1A or 2A, wherein the vasodilator is a calcium channel blocker, and the calcium channel blocker is selected from the group consisting of nifedipine, nilvadipine, amlodipine, nicardipine, benidipine, barnidipine, nitrendipine, nisoldipine, azelnidipine, manidipine, efonidipine, cilnidipine, aranidipine, felodipine, nimodipine, crebidipine, lasidipine, relcanidipine, diltiazem, and verapamil. Claim 6A. A pharmaceutical composition according to item 1A or 2A, wherein the vasodilator is an angiotensin II receptor antagonist, and the angiotensin II receptor antagonist is selected from the group consisting of irbesartan, losartan, candesartan, valsartan, telmisartan, olmesartan, and azilsartan. Item 7A. A pharmaceutical composition according to item 1A or 2A, wherein the vasodilator is a cholinesterase inhibitor, and the cholinesterase inhibitor is selected from the group consisting of physostigmine, neostigmine, distigmine, pyridostigmine, rivastigmine, donepezil, galantamine, itopride, acotiamide, ambenonium, and edrophonium. Item 8A. A vasodilator is α １ It is an adrenergic receptor blocker, and α １ A pharmaceutical composition according to claim 1A or 2A, wherein the adrenergic receptor blocker is selected from the group consisting of prazosin, doxazosin mesil, urapidil, nicergoline, ifenprodil, tamsulosin, terazosin, silodosin, olanzapine, bunazosin, and naphtopidil. Claim 9A. A pharmaceutical composition according to claim 1A or 2A, wherein the vasodilator is a nitrate, and the nitrate is selected from the group consisting of nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, nicorandil, and amyl nitrite. Claim 10A. The vasodilator is 5-HT ２ It is a serotonin receptor blocker, and 5HT ２The pharmaceutical composition according to item 1A or 2A, wherein the serotonin receptor antagonist is selected from the group consisting of ketanserin, sarpogrelate, and ritanserin. Item 11A. The pharmaceutical composition according to item 1A or 2A, wherein the vasodilator is a prostaglandin E1 preparation, and the prostaglandin E1 preparation is selected from the group consisting of alprostadil, limaprost, and misoprostol. Item 12A. The pharmaceutical composition according to item 1A or 2A, wherein the vasodilator is a TRP receptor agonist, and the TRP receptor agonist is selected from the group consisting of l-menthol, geraniol, and eucalyptol. Item 13A The pharmaceutical composition according to item 1A or 2A, wherein the vasodilator is an ATP-sensitive K channel activator, and the ATP-sensitive K channel activator is selected from the group consisting of minoxidil, nicorandil, and diazoxide. Item 14A. The pharmaceutical composition according to any one of items 1A to 13A, which is administered transdermally to the skin on the surface of the major salivary gland. Item 15A. The pharmaceutical composition according to any one of items 1A to 13A, which is administered transmucosally into the oral cavity. Item 16A. The pharmaceutical composition according to any one of items 1A to 15A, which is in a dosage form selected from the group consisting of topical solid preparations, topical liquid preparations, sprays, ointments, creams, gels, patches, nanoneedle injections, tablets, troches, pastes, gels, buccal tablets, orally disintegrating tablets (OD tablets), and oral film preparations. Item 17A. The pharmaceutical composition according to any one of items 1A to 16A for improving xerostomia. Item 18A. The pharmaceutical composition according to any one of items 1A to 17A, which is used in combination with a parasympathomimetic. Item 19A. The pharmaceutical composition according to any one of items 1A to 18A, which is administered to a subject who has been administered or is scheduled to be administered a parasympathomimetic.

[0012] According to the present invention, there is provided a pharmaceutical composition capable of enhancing salivary secretion with less risk of side effects, thereby enabling improvement of xerostomia.

[0013] This graph shows the amount of saliva secreted in rats when intermittent intravenous administration of acetylcholine is combined with transdermal administration of nifedipine into the submandibular gland. This graph shows the amount of saliva secreted in rats when intermittent intravenous administration of acetylcholine is combined with transdermal administration of irbesartan into the submandibular gland. This graph shows the amount of saliva secreted in rats when intermittent intravenous administration of acetylcholine is combined with transdermal administration of physostigmine into the submandibular gland. This graph shows the amount of saliva secreted in rats when intermittent intravenous administration of acetylcholine is combined with transdermal administration of nilvadipine into the submandibular gland. This graph shows the amount of saliva secreted in rats when intermittent intravenous administration of acetylcholine is combined with transdermal administration of diltiazem into the submandibular gland. This graph shows the amount of saliva secreted in rats when intermittent intravenous administration of acetylcholine is combined with transdermal administration of isosorbide dinitrate into the submandibular gland. This graph shows the amount of saliva secreted in rats when intermittent intravenous administration of acetylcholine is combined with transdermal administration of nitroglycerin into the submandibular gland. This graph shows the amount of saliva secreted in rats receiving intermittent intravenous administration of acetylcholine and transdermal administration of prazosin into the submandibular gland. This graph shows the amount of saliva secreted in rats receiving intermittent intravenous administration of acetylcholine and transdermal administration of ketanserin into the submandibular gland. This graph shows the amount of saliva secreted in rats receiving intermittent intravenous administration of acetylcholine and transdermal administration of control white petrolatum into the submandibular gland. This graph shows the amount of saliva secreted in acetylcholine-administered rats in the absence of each vasodilator (A in the figure) and with transdermal administration of a vasodilator or control white petrolatum (B in the figure, or B1 and B2 in order of increasing dose if there are two doses of vasodilator). This corresponds to a summary of the results in Figures 1 to 10. This graph shows the amount of saliva secreted in rats receiving intermittent intravenous administration of acetylcholine and transdermal administration of alprostadil into the submandibular gland. This graph shows the amount of saliva secreted in rats receiving intermittent intravenous administration of acetylcholine and transdermal administration of limaprost into the submandibular gland. This graph shows the amount of saliva secreted in rats when intermittent intravenous administration of acetylcholine was combined with transdermal administration of misoprostol into the submandibular gland. This graph shows the amount of saliva secreted in rats when intermittent intravenous administration of acetylcholine was combined with transdermal administration of donepezil into the submandibular gland.This graph shows the amount of saliva secreted in rats combined with intermittent intravenous administration of acetylcholine and transdermal administration of rivastigmine into the submandibular gland. This graph shows the amount of saliva secreted in rats combined with intermittent intravenous administration of acetylcholine and transdermal administration of galantamine into the submandibular gland. This graph shows the amount of saliva secreted in rats combined with intermittent intravenous administration of acetylcholine and transdermal administration of valsartan into the submandibular gland. This graph shows the amount of saliva secreted in rats combined with intermittent intravenous administration of acetylcholine and transdermal administration of candesartan into the submandibular gland. This graph shows the amount of saliva secreted in rats combined with intermittent intravenous administration of acetylcholine and transdermal administration of losartan into the submandibular gland. This graph shows the amount of saliva secreted in rats combined with intermittent intravenous administration of acetylcholine and transdermal administration of peppermint oil into the submandibular gland. This graph shows the amount of saliva secreted in rats combined with intermittent intravenous administration of acetylcholine and transdermal administration of minoxidil into the submandibular gland. This graph shows the amount of saliva secreted in rats administered intravenously with acetylcholine, in the absence of each vasodilator (A in the figure) and with transdermal administration of a vasodilator or control white petrolatum (B in the figure, or B1 and B2 in order of increasing dose if two doses of vasodilator are used). This corresponds to a summary of the results in Figures 12-22. This graph shows the amount of saliva secreted in rats administered intravenously with acetylcholine (also referred to as ACh in the following figures) under transdermal administration of 0.001-10 mM nifedipine, as a ratio to the amount of saliva secreted in the absence of nifedipine. This graph shows the amount of saliva secreted in rats when the time interval between nifedipine administration and acetylcholine administration is varied. This graph shows the amount of saliva secreted in rats when intravenous administration of acetylcholine was repeated under transdermal administration of nifedipine. This graph shows the blood pressure of rats administered nifedipine transdermally into the submandibular gland or nicardipine intraperitoneally. The graphs show the changes in submandibular gland blood flow upon administration of acetylcholine in rats that received transdermal administration of control (a) or nifedipine (b) into the submandibular gland, and graph (c) shows the cumulative change from resting blood flow.

[0014] The following description may be based on representative embodiments or specific examples, but the present invention is not limited to such embodiments or specific examples. In this specification, a numerical range represented by "~" or "-" means a range including the numerical values at both ends thereof as the upper limit value and the lower limit value, unless otherwise specified. The upper limit value and the lower limit value of each numerical range exemplified in this specification can be arbitrarily combined.

[0015] In one aspect, the present disclosure provides a pharmaceutical composition for local administration to the salivary gland for enhancing salivary secretion, which contains a vasodilator.

[0016] The pharmaceutical composition of this aspect contains at least one vasodilator. In the present disclosure, the vasodilator refers to a drug having the ability to dilate blood vessels through mechanisms such as relaxation of vascular smooth muscle and inhibition of contraction of vascular smooth muscle. The vasodilator in the present disclosure does not have to have the ability to activate the M ３ muscarinic receptor (also referred to as M ３ muscarinic receptor activating ability in the present disclosure). That is, a drug having the ability to dilate blood vessels and M ３ muscarinic receptor activating ability can be excluded from the vasodilators in the present disclosure. Examples of drugs that can be excluded from the vasodilators in the present disclosure include muscarinic receptor agonists such as acetylcholine, bethanechol, carbachol, cevimeline, and pilocarpine.

[0017] The vasodilator in the present disclosure includes, for example, calcium antagonists, angiotensin II receptor antagonists, cholinesterase inhibitors, α １ adrenergic receptor blockers, nitrates, 5-HT ２ serotonin receptor blockers, prostaglandin E1 preparations, TRP receptor agonists, ATP-sensitive K channel activators, β ２ adrenergic receptor agonists, angiotensin-converting enzyme inhibitors, phosphodiesterase inhibitors, adenylate cyclase direct activators, cyclooxygenase inhibitors, thromboxane A ２ synthetase inhibitors, thromboxane A ２ receptor blockers, ET １ endothelin receptor blockers, H１ The vasodilator can be selected from the group consisting of histamine receptor agonists and histamine-degrading enzyme inhibitors. The vasodilator in this disclosure is preferably a calcium channel blocker, angiotensin II receptor antagonist, cholinesterase inhibitor, or α １ Adrenergic receptor blockers, nitrates, 5-HT ２ The following can be selected: serotonin receptor blockers, prostaglandin E1 preparations, TRP receptor agonists, and ATP-sensitive K channel activators.

[0018] Calcium channel blockers (also called Ca channel blockers or calcium blockers) are drugs that target the membrane voltage-dependent Ca ２＋ L-type Ca classified as a channel ２＋ Acts on the channel, Ca ２＋ These are drugs that suppress the intracellular influx of calcium. Examples of calcium channel blockers include dihydropyridine compounds such as nifedipine, nilvadipine, amlodipine, nicardipine, benidipine, barnidipine, nitrendipine, nisoldipine, azelnidipine, manidipine, efonidipine, cilnidipine, aranidipine, felodipine, nimodipine, crebidipine, lacidipine, and relcanidipine; benzothiazepine compounds such as diltiazem; and phenylalkylamine compounds such as verapamil.

[0019] Angiotensin II receptor antagonists are drugs that target angiotensin II type 1 receptors (AT) among the angiotensin II receptor subtypes. １ These are drugs that antagonize the receptor and block its activity. Examples of angiotensin II receptor antagonists include irbesartan, losartan, candesartan, valsartan, telmisartan, olmesartan, and azilsartan.

[0020] Cholinesterase inhibitors are drugs that indirectly activate muscarinic receptors by inhibiting cholinesterase, thereby suppressing the breakdown of acetylcholine and increasing the concentration of acetylcholine in the synaptic cleft. Examples of cholinesterase inhibitors include physostigmine, neostigmine, distigmine, pyridostigmine, rivastigmine, donepezil, galantamine, itopride, acotiamide, ambenonium, and edrophonium.

[0021] α １ Adrenergic receptor blockers affect the alpha of vascular smooth muscle. １ It is a drug that antagonizes the receptor and blocks its activity. １ Examples of adrenergic receptor blockers include prazosin, doxazosin mesil, urapidil, nicergoline, ifenprodil, tamsulosin, terazosin, silodosin, olanzapine, bunazosin, and naphtopidil.

[0022] Nitrate drugs generate nitric oxide (NO) in cells, activating guanylate cyclase and increasing cyclic GMP production, thereby increasing intracellular Ca ２＋ These are drugs that reduce concentration. Examples of nitrates include nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, nicorandil, and amyl nitrite.

[0023] 5-HT ２ Serotonin receptor blockers are a subtype of serotonin receptors, specifically 5-HT ２ This drug antagonizes serotonin receptors and blocks their activity. (5-HT) ２ Examples of serotonin receptor blockers include ketanserin, salpogralate, and ritanserin.

[0024] Prostaglandin E1 preparations are drugs that act on prostaglandin E receptors (EP receptors) and increase cAMP production by activating adenylyl cyclase. Examples of prostaglandin E1 preparations include alprostadil, limaprost, and misoprostol.

[0025] TRP receptor agonists are drugs that activate TRP receptors, which are ion channels located on the cell membranes of sensory nerve cells. Examples of TRP receptor agonists include l-menthol, geraniol, and eucalyptol. Preferably, TRP receptor agonists are drugs that activate TRPM8 receptors or TRPA1 receptors.

[0026] ATP-sensitive K channel activators work by opening ATP-sensitive K channels present in the cell membrane of vascular smooth muscle, thereby promoting K ＋ These are drugs that promote extracellular efflux of potassium, thereby causing cellular hyperpolarization. Examples of ATP-sensitive potassium channel activators include minoxidil, nicorandil, and diazoxide.

[0027] β ２ Adrenergic receptor agonists affect the β of vascular smooth muscle. ２ It is a drug that activates receptors. ２ Examples of adrenergic receptor agonists include isoprenaline, salbutamol, tulobuterol, procaterol, terbutaline, salmeterol, formoterol, indacaterol, and vilanterol.

[0028] Angiotensin-converting enzyme inhibitors (ANGIOTS) are drugs that inhibit the enzyme angiotensin-converting enzyme and suppress the production of angiotensin II. Examples of ANGIOTS inhibitors include captopril, enalapril, imidapril, lisinopril, perindopril, and ramipril.

[0029] Phosphodiesterase inhibitors are drugs that increase the concentrations of cAMP and cGMP by inhibiting phosphodiesterase, an enzyme that breaks down cAMP and cGMP in cells. Examples of phosphodiesterase inhibitors include caffeine, theophylline, milrinone, cilostazol, sildenafil, tadalafil, vardenafil, and ventoxifylline.

[0030] Adenylyl cyclase direct activators are drugs that directly stimulate adenylyl cyclase, an enzyme that produces cAMP from ATP, thereby increasing intracellular cAMP production. An example of adenylyl cyclase direct activator is colforsin daloperitone.

[0031] Cyclooxygenase inhibitors inhibit cyclooxygenase, an enzyme that converts arachidonic acid to prostaglandin H2, thereby inhibiting thromboxane A2, a vasoconstrictive mediator. ２ These are drugs that suppress the production of prostaglandin F2α. Examples of cyclooxygenase inhibitors include nonsteroidal anti-inflammatory drugs such as aspirin, indomethacin, ibuprofen, flufenamic acid, phenylbutazone, and piroxicam.

[0032] Thromboxane A ２ Synthase inhibitors include thromboxane A ２ By inhibiting the synthesis enzyme, thromboxane A ２ This is a drug that suppresses the production of thromboxane A. ２ Examples of synthase inhibitors include ozagrel and trapidil.

[0033] Thromboxane A ２ Receptor blockers include thromboxane A ２ This is a drug that antagonizes receptors and blocks their activity. (Example: Thromboxane A) ２ Examples of receptor blockers include lamotropan and seratrodast.

[0034] ET １ Endothelin receptor blockers are drugs that antagonize and block the activity of endothelin receptors to which endothelin-1 (ET-1) binds. １ Examples of endothelin receptor blockers include bosentan, ambrisentan, macitentan, and clazosentan.

[0035] H １ Histamine receptor agonists are H １ It is a drug that activates histamine receptors.１ Examples of histamine receptor agonists include histamine, 2-methylhistamine, and histaprodifen.

[0036] Histamine inhibitors are drugs that inhibit histamine-degrading enzymes such as histamine-N-methyltransferase, thereby suppressing the breakdown of histamine and indirectly activating histamine receptors. An example of a histamine inhibitor is methoprine.

[0037] Vasodilators may be in the form of free compounds or pharmaceutically acceptable salts, such as acid-added salts or base-added salts, as long as they have a vasodilatory effect. Examples of acid-added salts include inorganic salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, and phosphate, and organic salts such as citrate, oxalate, acetate, formate, propionate, benzoate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, and p-toluenesulfonate. Examples of base-added salts include inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, and ammonium salt, and organic base salts such as triethylammonium salt, triethanolammonium salt, pyridinium salt, and diisopropylammonium salt. Furthermore, amino acid salts such as basic or acidic amino acids such as arginine, aspartic acid, and glutamic acid are also included.

[0038] Vasodilators may be in the form of free compounds or solvates, as long as they have a vasodilatory effect. Examples of solvents in solvates include water, methanol, ethanol, isopropanol, butanols (including n-butanol), acetic acid, tetrahydrofuran, acetone, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, acetamide, ethylene glycol, propylene glycol, butylene glycols (including 1,3-butylene glycol), and dimethoxyethane.

[0039] The pharmaceutical composition of this embodiment contains an effective amount of a vasodilator to enhance saliva secretion. The effective amount can be appropriately determined depending on the type of vasodilator, the method of use, the age, weight, severity of the condition, and other factors. When the pharmaceutical composition is administered to a human, the effective amount of the vasodilator may be, for example, 0.1 to 20 mg / day, preferably 0.2 to 10 mg / day, more preferably 1 to 2 mg / dose as needed, up to three times a day, if the vasodilator is nifedipine.

[0040] The salivary gland may be a major salivary gland or a minor oral gland. The major salivary gland may be any of the parotid gland, submandibular gland, or sublingual gland. Preferably, the salivary gland is a major salivary gland, and more preferably, a submandibular gland. The vasodilators in this disclosure can enhance salivary secretion, preferably from the major salivary glands, and more preferably from the submandibular gland.

[0041] The vasodilators in this disclosure can enhance salivary secretion, for example, acetylcholine-induced salivary secretion, and more particularly acetylcholine-induced physiological salivary secretion. Accordingly, in one aspect, this disclosure provides a pharmaceutical composition for topical administration to the salivary glands, comprising a vasodilator, for enhancing acetylcholine-induced salivary secretion, and more particularly acetylcholine-induced physiological salivary secretion.

[0042] Acetylcholine-induced salivary secretion refers to the reaction of acetylcholine to the M cells of the salivary gland acinar cells. ３ This refers to salivary secretion induced by stimulating muscarinic receptors. The pharmaceutical composition of this embodiment is similar to known salivary secretion promoters such as pilocarpine and cevimeline. ３ This invention is characterized by enhancing acetylcholine-induced salivary secretion rather than directly stimulating muscarinic receptors to forcibly promote salivary secretion. The pharmaceutical composition of this embodiment enhances salivary secretion in the presence of acetylcholine, and does not need to have the ability to induce salivary secretion itself, nor does it need to induce salivary secretion in the absence of acetylcholine.

[0043] Acetylcholine-induced physiological salivation refers to salivation as a physiological response induced by acetylcholine released from the parasympathetic nervous system during rest or in response to taste stimuli. The rate of acetylcholine-induced physiological salivation is approximately 0.1–5 mL / min in humans and approximately 2–100 μL / min in rats. In rats, acetylcholine-induced physiological salivation can be induced by intravenous administration of acetylcholine at a rate of 30 nmol / min to 300 nmol / min.

[0044] The vasodilators in this disclosure can enhance salivary secretion, and can also enhance M3 muscarinic receptor agonist-induced salivary secretion other than acetylcholine. Accordingly, in one aspect, this disclosure provides a topical pharmaceutical composition containing a vasodilator for enhancing M3 muscarinic receptor agonist-induced salivary secretion. M3 muscarinic receptor agonist-induced salivary secretion refers to M ３ Muscarinic receptor agonists affect salivary gland acinar cells. ３ This refers to salivary secretion induced by stimulation of muscarinic receptors. A pharmaceutical composition for enhancing M3 muscarinic receptor agonist-induced salivary secretion is M ３ It enhances salivary secretion in the presence of a muscarinic receptor agonist, and does not necessarily have the ability to induce salivary secretion itself. ３ It is not necessary to induce salivary secretion in the absence of muscarinic receptor agonists. ３ Muscarinic receptor agonists are M ３ This refers to drugs that bind to muscarinic receptors and activate intracellular signaling pathways. ３ Examples of muscarinic receptor agonists include, for example, endogenous ligands such as acetylcholine, choline esters such as betanethyl and carbachol; acetylcholine analogs such as cevimeline; and cholinergic alkaloids such as pilocarpine.

[0045] Furthermore, in one embodiment, this disclosure provides a topical pharmaceutical composition containing a vasodilator for enhancing saliva secretion when used in combination with a parasympathetic stimulant. The pharmaceutical composition of this embodiment, when combined with a parasympathetic stimulant, contains an effective amount of M to induce saliva secretion. ３ Saliva secretion can be enhanced even in subjects lacking muscarinic receptor agonists. The pharmaceutical composition of this embodiment can be used in subjects who have been administered or are scheduled to be administered a parasympathetic stimulant and for whom enhanced saliva secretion is desired, for example, in patients with xerostomia. The pharmaceutical composition of this embodiment may also contain a vasodilator and a parasympathetic stimulant. Examples of parasympathetic stimulants include choline esters such as acetylcholine, bethanechol, and carbachol; acetylcholine analogs such as cevimeline; cholinergic alkaloids such as pilocarpine; and reversible cholinesterase inhibitors such as physostigmine and ambenonium.

[0046] The pharmaceutical compositions described herein can enhance saliva secretion and improve the symptoms of xerostomia by being administered locally to subjects who desire increased saliva secretion, for example, to the salivary glands, particularly the major salivary glands, of patients with xerostomia. Examples of local administration include transdermal administration, transmucosal administration, intraoral injection, and retrograde infusion. Preferably, local administration may be transdermal. The subjects may be humans or non-human animals, and non-human animals may include mammals such as rodents including mice, rats, hamsters, and guinea pigs, primates including chimpanzees and rhesus monkeys, livestock including pigs, cattle, goats, horses, and sheep, and companion animals including dogs and cats. The pharmaceutical compositions are preferably administered to humans.

[0047] The pharmaceutical compositions described herein can be formulated into dosage forms suitable for local administration to the salivary glands and used. Examples of dosage forms of the pharmaceutical compositions include topical solid preparations, topical liquid preparations (including liniments and lotions), sprays (including aerosols and pump sprays), ointments, creams, gels, transdermal patches (including poultices, tapes, patches, and films), nanoneedle injections, tablets (sublingual tablets), lozenges, pastes, gels, buccal tablets, orally disintegrating tablets (OD tablets), and oral film preparations, injections, and infusions.

[0048] Transdermal administration can be performed by applying the formulated pharmaceutical composition to the skin on the surface of the major salivary glands. For example, in the case of administration to the submandibular and parotid glands, it can be applied to the skin from the lower jaw and near the mandibular angle of the mandible down to the neck, and in the case of administration to the parotid gland, it can be applied to the skin from below the sideburns down to around the earlobe. Preferred dosage forms of the pharmaceutical composition for transdermal administration may be topical solutions, sprays, ointments, creams, gels, patches, and nanoneedle injections.

[0049] When the pharmaceutical composition is administered transdermally, the concentration of the vasodilator in the pharmaceutical composition may be 0.1 to 500 mM, preferably 0.1 to 100 mM, and more preferably 1 to 50 mM. If the vasodilator is nifedipine, physostigmine, donepezil, rivastigmine, or galantamine, the concentration of the vasodilator in the pharmaceutical composition when the pharmaceutical composition is administered transdermally may be 0.1 to 100 mM, preferably 0.1 to 10 mM, and more preferably 0.5 to 2 mM. If the vasodilator is irbesartan, nilvadipine, valsartan, candesartan, or losartan, the concentration of the vasodilator in the pharmaceutical composition when the pharmaceutical composition is administered transdermally may be 0.5 to 500 mM, preferably 0.5 to 50 mM, and more preferably 0.25 to 10 mM. When the vasodilator is diltiazem, the concentration of the vasodilator in the pharmaceutical composition when administered transdermally may be 1 to 1000 mM, preferably 1 to 100 mM, and more preferably 5 to 20 mM. When the vasodilator is isosorbide dinitrate, the concentration of the vasodilator in the pharmaceutical composition when administered transdermally may be 2 to 2000 mM, preferably 2 to 200 mM, and more preferably 10 to 40 mM. When the vasodilator is prazosin or ketanserin, the concentration of the vasodilator in the pharmaceutical composition when administered transdermally may be 5 to 5000 mM, preferably 5 to 500 mM, and more preferably 25 to 100 mM. When the vasodilator is alprostadil, the concentration of the vasodilator in the pharmaceutical composition when administered transdermally may be 0.0003 to 0.3% (w / w), preferably 0.0003 to 0.03% (w / w), and more preferably 0.0015 to 0.006% (w / w). When the vasodilator is limaprost or misoprostol, the concentration of the vasodilator in the pharmaceutical composition when administered transdermally may be 0.00005 to 0.05% (w / w), preferably 0.00005 to 0.005% (w / w), and more preferably 0.00025 to 0.001% (w / w). When the vasodilator is minoxidil, the concentration of the vasodilator in the pharmaceutical composition when administered transdermally may be 0.5 to 50% (w / w), preferably 2.5 to 10% (w / w).When the vasodilator is nitroglycerin, the concentration of the vasodilator in the pharmaceutical composition when administered transdermally may be 0.065 to 65% (w / w), preferably 0.065 to 6.5% (w / w), and more preferably 0.325 to 1.3% (w / w). When the vasodilator is l-menthol, the concentration of the vasodilator in the pharmaceutical composition when administered transdermally may be 5 to 99% (w / w), preferably 25 to 90% (w / w), and more preferably 40 to 70% (w / w).

[0050] Transmucosal administration can be performed by applying the formulated pharmaceutical composition to the oral mucosa, for example, the surface of the oral mucosa on the inside of the cheek, or sublingually. Preferred dosage forms of pharmaceutical compositions for transmucosal administration may include sprays, ointments, patches, nanoneedle injections, sublingual tablets, lozenges, pastes, gels, buccal tablets, orally disintegrating tablets (OD tablets), and oral film formulations.

[0051] Intraoral injection can be performed by injecting a pharmaceutical composition formulated into an injectable agent near the major salivary glands. Retrograde injection can be performed by injecting a pharmaceutical composition formulated into an injectable agent into the opening of the duct of the major salivary glands.

[0052] The pharmaceutical compositions in this disclosure include vasodilators, M ３ In addition to active ingredients such as muscarinic receptor agonists and parasympathetic stimulants, the product may contain pharmaceutically acceptable excipients and additives. Examples of these include bases, oils, surfactants, thickeners, resin components, wetting agents, antioxidants, buffers, and solvents. Pharmaceutically acceptable components are well known to those skilled in the art, and can be appropriately selected and used within the scope of normal practical ability by those skilled in the art, depending on factors such as the type of vasodilator, dosage, and dosage form.

[0053] This disclosure further provides a method for enhancing saliva secretion and a method for improving, preventing or treating xerostomia, comprising administering an effective amount of the above-described pharmaceutical composition to a subject for whom enhanced saliva secretion is desired, for example, to the salivary glands of a patient having xerostomia. In addition, the present invention provides the use of the above-described vasodilators in the manufacture of pharmaceutical compositions for enhancing saliva secretion or improving, preventing or treating xerostomia; and the use of the above-described vasodilators for enhancing saliva secretion or improving, preventing or treating xerostomia, particularly topical use.

[0054] The present invention will be described in more detail by the following examples, but the present invention is not limited thereto.

[0055] [Materials and Methods] Animal rats (Wistar / ST, 11-14 weeks old) were housed in a constant temperature and humidity chamber with a 12-hour light-dark cycle (light period 08.00-20.00 hours, temperature 24±1°C, relative humidity 55%±5%). The rats were fed a normal diet (CREA Japan Co., Ltd., Tokyo, Japan) and given free access to water. The drugs acetylcholine chloride was purchased from Enzo Life Sciences, nifedipine and physostigmine sulfate from Wako Pure Chemical Industries, Ltd., irbesartan, nilvadipine, prazosin hydrochloride, losartan potassium, candesartan cilexetil, valsartan, rivastigmine, donepezil, galantamine, minoxidil, and ketanserine from Tokyo Chemical Industries, Ltd. (TCI), diltiazem hydrochloride from Fujifilm Wako Pure Chemical Industries, Ltd., isosorbide dinitrate from MedChemExpress, alprostadil from Ono Pharmaceutical Co., Ltd., limaprost alfadex from Sawai Pharmaceutical Co., Ltd., misoprostol from Pfizer Inc., and peppermint oil (main component l-menthol, l-menthol concentration approximately 50-65% (w / w)) from Kitami Peppermint Trading Co., Ltd. Nitroglycerin was purchased from Toa Eiyo Co., Ltd. in the form of an aerosol product (Myokol) containing 0.3 mg of nitroglycerin per spray. Formulated nifedipine, irbesartan, physostigmine, nilvadipine, isosorbide dinitrate, prazosin, ketanserin, rivastigmine, donepezil, galantamine, candesartan, valsartan, and losartan were used as ointments by mixing their respective powders with white petrolatum (Kenei Pharmaceutical Co., Ltd.) to a concentration of 1, 5, 10, 20, or 50 mM. Limaprost, misoprostol, and minoxidil were used as ointments by mixing their respective powders with white petrolatum (Kenei Pharmaceutical Co., Ltd.) to a concentration of 0.0005, 0.003, 1, or 5% (w / w). Diltiazem was used in the form of 2 ml of a 10 mM aqueous solution soaked into a cotton ball. Peppermint oil was used in the form of 1 ml of undiluted solution soaked into a cotton ball. Evaluation of saliva secretion A depilatory agent was applied from the mandible to the throat of urethane-anesthetized Wistar / ST rats to expose the skin on the surface of the submandibular gland. An acetylcholine solution, prepared by dissolving 10 mM acetylcholine in physiological saline, was placed in a syringe and attached to a continuous infusion pump, to which a catheter was connected.Rats were fixed supine on a heating pad, and a catheter was inserted into the femoral vein of the right hind limb. The catheter was connected to a syringe set up on a continuous infusion pump. The experiment was conducted in cycles with and without administration of acetylcholine solution as described below. In this experiment, the administration rate of acetylcholine solution was set to 6 μl / min, resulting in an acetylcholine dose of 60 nmol / min. 0-10 min: No administration 10-40 min: Acetylcholine solution (1st dose) 40-80 min: No administration 80-110 min: Acetylcholine solution (2nd dose) 110-130 min: No administration 50 minutes after the start of the experiment, the drug was administered transdermally by applying 1 g of ointment containing the drug or white petrolatum (control) to the skin on the surface of the submandibular gland, or by contacting cotton wool containing 2 ml of diltiazem aqueous solution or 1 ml of peppermint oil. Transdermal administration of nitroglycerin was performed by spraying nitroglycerin spray once onto the skin surface of the submandibular gland 70 minutes after the start of the test. During the test, saliva secretion was measured by inserting a pre-weighed cotton ball into the oral cavity under the tongue to collect saliva every 10 minutes and weighing it. Salivary gland blood flow evaluation: The submandibular gland was exposed by incising the neck of rats that were not administered the drug (control) or rats that received transdermal administration of the drug. Acetylcholine solution was administered to Wistar / ST rats in the same manner as described in the salivary secretion evaluation test, and the submandibular gland blood flow was evaluated every second using a 2D laser blood flow imaging device OMEGAZONE OZ-2 (Omega Wave Co., Ltd.). Statistical analysis: The results of the tests using nifedipine, irbesartan, physostigmine, alprostadil, and peppermint oil are expressed as the mean ± standard error of the mean (SEM) of the individual measured values. The results of studies using nilvadipine, diltiazem, isosorbide dinitrate, nitroglycerin, prazosin, ketanserin, limaprost, misoprostol, donepezil, rivastigmine, galantamine, valsartan, candesartan, losartan, and minoxidil are expressed as the mean of three measurements per individual. For statistical significance testing, Student's t-test was used for two-group comparisons, and for three or more groups, one-way analysis of variance (ANOVA) and Tukey's multiple comparison test were used, with a p-value < 0.05 considered statistically significant.

[0056] [Example 1. Evaluation of salivary secretion enhancement by vasodilators] Various vasodilators (nifedipine, irbesartan, physostigmine, nilvadipine, diltiazem, isosorbide dinitrate, nitroglycerin, prazosin, ketanserin, alprostadil, limaprost, misoprostol, donepezil, rivastigmine, galantamine, valsartan, candesartan, losartan, peppermint oil, minoxidil) were administered transdermally to the submandibular gland of rats, and the enhancement of salivary secretion induced by acetylcholine was evaluated. Figures 1-10 and 12-22 show the time course of salivary secretion when each vasodilator or control white petrolatum is administered, while Figures 11 and 23 show salivary secretion when acetylcholine is administered, both in the absence of a vasodilator (A in the figure) and with transdermal administration of a vasodilator or control white petrolatum (B in the figure, or B1 and B2 in order of increasing dose if two doses of the vasodilator are used). All vasodilators enhanced salivary secretion when acetylcholine was administered.

[0057] [Example 2. Detailed Analysis of Salivary Secretion Enhancement by Nifedipine] Ointments containing nifedipine at different concentrations from 0.001 to 10 mM mixed with petrolatum were administered transdermally, and the enhancement of salivary secretion induced by acetylcholine was evaluated. Figure 24 shows the ratio of salivary secretion in the presence of nifedipine to salivary secretion in the absence of nifedipine. Transdermal administration of nifedipine enhanced salivary secretion in a dose-dependent manner when acetylcholine was administered.

[0058] Furthermore, using an ointment containing 1 mM nifedipine, the timing of the onset of nifedipine's effect was evaluated by setting the time interval from ointment application to acetylcholine administration to 0, 15, or 30 minutes. Figure 25 shows the amount of saliva secreted during the 30 minutes of acetylcholine administration. It was shown that the enhancement of saliva secretion by nifedipine was exerted 30 minutes after ointment application.

[0059] Next, after applying an ointment containing 1 mM nifedipine, acetylcholine administration was repeated for 5 cycles to evaluate the persistence of the nifedipine effect. The time course of saliva secretion is shown in Figure 26. The saliva-enhancing effect of nifedipine was maintained for about 3 hours after application, and then gradually decreased.

[0060] To check for side effects, an ointment containing 1 mM nifedipine was applied to the submandibular gland of rats, and blood pressure was non-invasively measured using the tail cuff method 30 minutes later. For comparison, 2 mg / kg of nicardipine was administered intraperitoneally, and blood pressure was similarly measured 30 minutes later. The application of the nifedipine-containing ointment did not affect resting blood pressure (Figure 27), and no systemic effects were observed.

[0061] To evaluate the effect of transdermal administration of nifedipine on salivary gland blood flow, an ointment containing 1 mM nifedipine was applied to the submandibular gland of rats, and acetylcholine was administered for 10 minutes 30 minutes later to evaluate changes in submandibular gland blood flow. In rats that did not receive the nifedipine ointment (control), administration of acetylcholine caused blood flow oscillations, where blood flow increased and then decreased and increased repeatedly (Figure 28a). In contrast, application of the nifedipine ointment suppressed blood flow oscillations during acetylcholine administration and maintained a high blood flow state (Figures 28b, c). This suggests that the increase in salivary gland blood flow due to transdermal administration of a vasodilator enhanced salivary secretion induced by acetylcholine.

Claims

1. A pharmaceutical composition for topical administration to the salivary glands, containing a vasodilator, for enhancing saliva secretion.

2. The pharmaceutical composition according to claim 1, wherein the salivary secretion is acetylcholine-induced salivary secretion.

3. Vasodilators, M ３ A pharmaceutical composition according to claim 1 or 2, which does not have muscarinic receptor agonist activity.

4. Vasodilators include calcium channel blockers, angiotensin II receptor blockers, cholinesterase inhibitors, and α １ Adrenergic receptor blockers, nitrates, 5-HT ２ Serotonin receptor blockers, prostaglandin E1 preparations, TRP receptor agonists, ATP-sensitive K channel activators, β ２ Adrenergic receptor agonists, angiotensin-converting enzyme inhibitors, phosphodiesterase inhibitors, adenylyl cyclase direct activators, cyclooxygenase inhibitors, thromboxane A ２ Synthase inhibitors, thromboxane A ２ Receptor blockers, ET １ Endothelin receptor blockers, H １ A pharmaceutical composition according to claim 1 or 2, selected from the group consisting of a histamine receptor agonist and a histamine-degrading enzyme inhibitor.

5. The vasodilator is selected from the group consisting of a calcium antagonist, an angiotensin II receptor antagonist, a cholinesterase inhibitor, an α １ adrenergic receptor blocker, a nitrate, 5-HT ２ serotonin receptor blocker, a prostaglandin E1 preparation, a TRP receptor agonist, and an ATP-sensitive K channel activator, and the pharmaceutical composition according to claim 1 or 2.

6. The pharmaceutical composition according to claim 1 or 2, wherein the vasodilator is a calcium channel blocker, and the calcium channel blocker is selected from the group consisting of nifedipine, nilvadipine, amlodipine, nicardipine, benidipine, barnidipine, nitrendipine, nisoldipine, azelnidipine, manidipine, efonidipine, cilnidipine, aranidipine, felodipine, nimodipine, clebidipine, lasidipine, relcanidipine, diltiazem, and verapamil.

7. The pharmaceutical composition according to claim 1 or 2, wherein the vasodilator is an angiotensin II receptor antagonist, and the angiotensin II receptor antagonist is selected from the group consisting of irbesartan, losartan, candesartan, valsartan, telmisartan, olmesartan, and azilsartan.

8. The pharmaceutical composition according to claim 1 or 2, wherein the vasodilator is a cholinesterase inhibitor, and the cholinesterase inhibitor is selected from the group consisting of physostigmine, neostigmine, distigmine, pyridostigmine, rivastigmine, donepezil, galantamine, itopride, acotiamide, ambenonium, and edrophonium.

9. Vasodilators are alpha １ It is an adrenergic receptor blocker, and α １ The pharmaceutical composition according to claim 1 or 2, wherein the adrenergic receptor blocker is selected from the group consisting of prazosin, doxazosin mesil, urapidil, nicergoline, ifenprodil, tamsulosin, terazosin, silodosin, olanzapine, bunazosin, and naphtopidil.

10. The pharmaceutical composition according to claim 1 or 2, wherein the vasodilator is a nitrate, and the nitrate is selected from the group consisting of nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, nicorandil, and amyl nitrite.

11. Vasodilators 5-HT ２ It is a serotonin receptor blocker, and 5HT ２ The pharmaceutical composition according to claim 1 or 2, wherein the serotonin receptor blocker is selected from the group consisting of ketanserin, salpogralate, and ritanserin.

12. The pharmaceutical composition according to claim 1 or 2, wherein the vasodilator is a prostaglandin E1 preparation, and the prostaglandin E1 preparation is selected from the group consisting of alprostadil, limaprost, and misoprostol.

13. The pharmaceutical composition according to claim 1 or 2, wherein the vasodilator is a TRP receptor agonist, and the TRP receptor agonist is selected from the group consisting of l-menthol, geraniol, and eucalyptol.

14. The pharmaceutical composition according to claim 1 or 2, wherein the vasodilator is an ATP-sensitive K channel activator, and the ATP-sensitive K channel activator is selected from the group consisting of minoxidil, nicorandil, and diazoxide.

15. The pharmaceutical composition according to claim 1 or 2, which is administered transdermally to the skin on the surface of the major salivary glands.

16. The pharmaceutical composition according to claim 1 or 2, which is administered transmucosally into the oral cavity.

17. The pharmaceutical composition according to claim 1 or 2, wherein the dosage form is selected from the group consisting of external solid preparations, external liquid preparations, spray preparations, ointments, creams, gels, patches, nanoneedle injections, tablets, lozenges, pastes, gels, buccal tablets, orally disintegrating tablets, and oral film preparations.

18. A pharmaceutical composition containing a vasodilator for the improvement, prevention, or treatment of dry mouth.

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