WO2000056344A1

WO2000056344A1 - Artificial saliva

Info

Publication number: WO2000056344A1
Application number: PCT/JP2000/001804
Authority: WO
Inventors: Yasuaki Kakinoki; Hiroyuki Inoue; Satoshi Miyauchi
Original assignee: Seikagaku Corporation
Priority date: 1999-03-24
Filing date: 2000-03-24
Publication date: 2000-09-28
Also published as: AU3327000A

Abstract

An additive characterized by containing hyaluronic acid or its pharmaceutically acceptable salt and being to be added to artificial saliva for ameliorating various symptoms caused by dryness in the oral cavity. The artificial saliva containing this additive exhibits a prolonged effect of imparting an improved non-dry feel to the oral cavity.

Description

Artificial saliva technology

The present invention relates to an additive comprising hyaluronic acid (hereinafter, also referred to as HA) or a pharmaceutically acceptable salt thereof, which is added to artificial saliva for application to a patient with xerostomia. The present invention also relates to artificial saliva containing the additive and being applied to a patient with xerostomia, wherein the non-dryness in the oral cavity is improved. Background art

Hereinafter, a technique that is considered to be closest to the present invention will be described.

Japanese Patent Application Laid-Open No. 61-24510 describes a composition for preventing drying, in which a humectant such as a saccharide and a surfactant are mixed with water. It is disclosed that it is used to prevent the drying of lime. Also specifically described are such compositions comprising a solution containing 0.1, 1 or 3% HA.

However, there is no disclosure or suggestion about the idea of application in the oral cavity of xerostomia patients. In addition, it is described that when only the humectant was applied, a sufficient effect was not obtained, and that even if the effect was obtained, it was extremely temporary.

Japanese Unexamined Patent Application Publication No. 9-5088898 describes a therapeutic composition comprising an aqueous solution of at least one polymer and at least one electrolyte, and a saliva substitute containing the composition. Are also described.

However, there is no description of HA, nor is there any description or suggestion of a remarkable effect observed in the present invention, as shown in the Examples below. European Patent No. 4444 92 describes the use of a pharmaceutical composition containing HA having an average molecular weight of 800,000 to 400,000 as an active ingredient for the treatment and prevention of oral inflammation, oral hygiene, and the like. Have been.

However, the application to the oral cavity of xerostomia patients and the persistence of non-dryness in the oral cavity There is no disclosure or suggestion about the idea of improving.

Japanese Patent Application Laid-Open No. Hei 6-170550 discloses an oral anti-inflammatory agent comprising HA as an active ingredient. An allergic therapeutic agent as an active ingredient is disclosed, and application to the oral cavity is also disclosed.

However, none of these publications disclose or suggest the application to the oral cavity of xerostomia patients or the idea of improving the persistence of non-dryness in the oral cavity. Disclosure of the invention

In recent years, geriatric medical problems have become social problems. Elderly people are susceptible to xerostomia due to the effects of various drugs in addition to the decrease in salivary secretion due to aging. Xerostomia causes eating disorders and may eventually require reliance on tube feedings and infusions. If you lose your diet, you will lose your willingness to live quickly, often causing intellectual disability. The prognosis for life in such a prone state is poor, and it is said that half of the patients die in one year. Improving the feeling of dryness in the mouth of a patient with xerostomia and having a self-sustaining diet would have a significant effect on geriatric care. Psychiatric patients, such as those receiving antidepressants, often have xerostomia due to side effects of the drug.

Some people think that it is better to drink water, but experience has shown that even if a patient with xerostomia drinks water, it will only moisten the moment and is not practical. Even if a healthy person feels comfortable, it may be uncomfortable for a patient with xerostomia, and it is important to evaluate in consideration of the patient's evaluation.

Accordingly, an object of the present invention is to provide an artificial saliva with improved non-dryness in the mouth of a patient with xerostomia.

The present inventors have conducted intensive studies in order to solve the above problems, and as a result, have found that HA or a pharmaceutically acceptable salt thereof can significantly maintain the non-dryness in the oral cavity of xerostomia patients. Furthermore, it has been found that HA or a pharmaceutically acceptable salt thereof having properties such as a specific molecular weight and an intrinsic viscosity can obtain the above-mentioned excellent effects. By utilizing such HA or a pharmaceutically acceptable salt thereof as a component of artificial saliva, xerostomia is significantly prevented and ameliorated, and various accompanying It was also found that the symptoms and condition can be prevented and improved. The present invention has been completed based on these findings.

That is, the present invention relates to an additive comprising hyaluronic acid or a pharmaceutically acceptable salt thereof and being added to artificial saliva for application to a patient with xerostomia (hereinafter referred to as “the additive of the present invention”). Also referred to as ").

The hyaluronic acid or a pharmaceutically acceptable salt thereof used in the additive of the present invention preferably has a weight average molecular weight of 300,000 to 1,200,000 and an intrinsic viscosity of 7 to 20 d 1 Zg. is there. More preferably, the weight average molecular weight is from 500,000 to 1200,000, and the intrinsic viscosity is from 10 to 20 d1 g. Further, the iron content is preferably 20 ppm or less. The present invention also relates to an artificial saliva containing the additive of the present invention, which is applied to a patient with xerostomia, which has an improved non-dryness in the oral cavity (hereinafter, referred to as “artificial saliva of the present invention”). Saliva).

The artificial saliva of the present invention is preferably in the form of a liquid preparation, and has an apparent viscosity of preferably 10 to 600 mPa · s measured at a shear rate of 1 second 1 at 25 ° C.

The artificial saliva of the present invention is preferably blended so that the concentration of the additive of the present invention is 0.01 to 0.6% (w / v).

The artificial saliva of the present invention can be preferably used for the purpose of maintaining a non-dry feeling in the oral cavity.Psychotropic drugs such as antihypertensives, diuretics, tranquilizers, antipsychotics, anxiolytics, and antidepressants, It is also a preferred form of application to patients with xerostomia associated with the administration of drugs such as neuroleptics and anticancer agents.

The present invention also provides a non-drying agent for oral cavity, an agent for improving oral mucosal disorder, an agent for relieving pain in the oral cavity, and various symptoms caused by xerostomia, comprising hyaluronic acid or a pharmaceutically acceptable salt thereof. It also provides a ameliorating and / or prophylactic agent. Preferable purposes of the agent for improving and / or preventing various symptoms caused by xerostomia of the present invention include prevention of excessive intake of water, prevention of enuresis, and prevention of tongue hardening.

As described above, the application of HA to the oral cavity for the purpose of preventing dryness, treating and preventing inflammation, treating allergies, etc. has been disclosed so far, but HA, particularly the specificity revealed by the present invention, has been disclosed. HA, which has properties such as concentration, molecular weight, intrinsic viscosity, etc., has the effect of improving the sustainability of non-dryness in the oral cavity It has never been known to have a sustaining action. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the results of measuring the moisturizing effect of the oral mucosa by the artificial saliva of the present invention. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, embodiments of the present invention will be described.

<1> Additive of the present invention

The origin of the hyaluronic acid or a pharmaceutically acceptable salt thereof used in the additive of the present invention is not particularly limited, and hyaluronic acid isolated and purified from a cockscomb, an umbilical cord, a microorganism producing hyaluronic acid, or the like can be used. In particular, those that are highly purified and substantially do not contain substances that are not allowed to be mixed as pharmaceuticals are preferable.

Examples of pharmaceutically acceptable salts of hyaluronic acid include salts with inorganic bases such as alkali metal salts (sodium salt, lithium salt, potassium salt, etc.), alkaline earth metal salts, ammonium salts, and diethanolamine. Among salts with organic bases such as salts, cyclohexylamine salts and amino acid salts, pharmaceutically acceptable salts can be used. Of these, sodium hyaluronate is preferred.

The weight average molecular weight of hyaluronic acid or a pharmaceutically acceptable salt thereof is not particularly limited, but is preferably about 300,000 to 1,200,000, more preferably about 500,000 to 1,200,000. About 100,000 to 900,000 is particularly preferable.

The hyaluronic acid or a pharmaceutically acceptable salt thereof is preferably 7 to 20 d1Zg, more preferably 10 to 2Od1Zg, and particularly preferably 10 to 16 d1. It has an intrinsic viscosity of Z g.

By using hyaluronic acid or a pharmaceutically acceptable salt thereof having the above-mentioned molecular weight and intrinsic viscosity, a particularly long-lasting effect of preventing dry mouth can be obtained.

The concentration of endotoxin in hyaluronic acid or a pharmaceutically acceptable salt thereof used in the additive of the present invention is 0 in the case of artificial saliva which is a liquid preparation described later. It is preferably at most 3 EUZmL. The endotoxin concentration in the additive of the present invention can be measured by a commonly used method for measuring endotoxin, which is well known to those skilled in the art, but the Limulus test method using a horseshoe crab amebocyte-lysate component is preferred. EU (endotoxin unit) is based on Japanese Industrial Standards for Biochemical Reagents (JIS K8008), US Department of Health and Human Services, Public Health First Service, Food and Drug Administration, Guideline on validation of the Limulus amebocyte lysate test as an end-product endotoxin test for human and animal parenteral drugs, biological products, and medical devices. Measured according to Rockvi le, MD, 1987. Further, the iron content is preferably 2 Oppm or less.

The additive of the present invention can contain optional components in addition to hyaluronic acid or a pharmaceutically acceptable salt thereof. Such an optional ingredient is not particularly limited as long as it is not inappropriate for the use of the additive of the present invention, but is a pharmaceutical carrier, an additive, or a pharmacologically active ingredient that can be added to artificial saliva described below. Is preferred.

The additive of the present invention is prepared in a solid form such as a powder containing the above-mentioned hyaluronic acid or a pharmaceutically acceptable salt thereof, and these components are dissolved or suspended in water, a buffer solution, physiological saline, or the like. It may be prepared in a liquid form.

The amount of the additive of the present invention can be appropriately selected.However, when used as an active ingredient in artificial saliva which is a liquid as described below as hyaluronic acid or a pharmaceutically acceptable salt thereof, The final concentration in the solution is preferably about 0.01 to 1% (w / v), more preferably about 0.01 to 0.6% (w / v), and still more preferably 0.01 to 0.5%. (w / v), particularly preferably about 1 to 0.4% (w / v). When used for artificial saliva which is a solid preparation, about 0.1 to 5% (w / w) in the solid preparation is preferable.

<2> Artificial saliva of the present invention

The artificial saliva of the present invention is an artificial saliva containing the additive of the present invention and being applied to a patient with xerostomia, wherein the non-dryness of the oral cavity is improved.

The artificial saliva of the present invention can be prepared in the form of a liquid preparation, a solid preparation and the like as described below. The content of the additive of the present invention in the artificial saliva of the present invention is determined by the content of the active ingredient, hyaluronic acid. As an acid or a pharmaceutically acceptable salt thereof, the artificial saliva of the present invention, which is a liquid, is preferably about 0.01 to 1% (w / v), more preferably 0.01 to 0.6% (w / v). v), more preferably about 0.01 to 0.5% (w / v), and particularly preferably about 0.1 to 0.4% (w / v). In the artificial saliva of the present invention, which is a solid preparation, the content is preferably about 0.1 to 5% (w / w). Particularly, by using hyaluronic acid or a pharmaceutically acceptable salt thereof having such properties in such an amount as to be used in the above-mentioned additive of the present invention, particularly excellent non-dryness in the oral cavity can be obtained. Is obtained.

When the artificial saliva of the present invention is provided as a liquid preparation, the value obtained by measuring the apparent viscosity of the liquid preparation at a shear rate of 1 sec- ¹ at 25 ° C. is preferably 10 to 6000 mPa's, and more preferably 10 to 3000111? &'3, particularly preferably 10 to 1500111? &' S. By using the artificial saliva of the present invention which is a liquid preparation having such an apparent viscosity, a particularly excellent non-dryness lasting feeling in the oral cavity can be obtained. The composition of the artificial saliva of the present invention is not particularly limited as long as it contains the additive of the present invention.However, the composition is adjusted so that the composition of the liquid electrolyte and the composition of the inorganic electrolyte component are almost the same as normal human saliva. The composition may be a given composition. As the composition of such artificial saliva (solution), the following composition is exemplified and preferable.

Hyaluronic acid or its salt (content: 0.01-1% (w / v))

Sodium chloride (content: 0.05 to 0.1% (w / v))

Potassium chloride (content: 0:! ~ 0.15% (w / v))

Calcium chloride (content: 0.01 to 0.02% (w / v))

Magnesium chloride (content: 0.004 to 0.006% (w / v))

Potassium diphosphate (Content: 0.01 to 0.05% (w / v))

In addition, these inorganic electrolyte components may be blended in their entirety, or may be blended in one or more of them.

The solvent for dissolving these components is preferably water, and particularly preferably pharmaceutically acceptable water such as distilled water for injection and sterilized water.

The artificial saliva of the present invention is physiologically acceptable, has no adverse effect on hyaluronic acid or a pharmaceutically acceptable salt thereof in the artificial saliva of the present invention, and has the above-mentioned properties of the artificial saliva of the present invention. As long as it is maintained, even if other substances are appropriately added Good. Such substances include pharmaceutical carriers, additives, pharmacologically active ingredients, and the like. Pharmaceutical carriers include conventional excipients, and additives include colorants, buffering agents, tonicity agents, preservatives, stabilizers, PH regulators, emulsifiers, solubilizing agents, suspending agents, Dispersants, bases, thickeners, sweeteners, flavoring agents, fragrances, fresheners and the like that are usually used in medicine are exemplified.

For example, examples of the buffer include a phosphate buffer, a Tris buffer, an acetate buffer and the like.

Examples of the pH adjuster include hydrochloric acid, sodium hydroxide, sodium hydrogen phosphate, sodium hydrogen phosphate and the like.

Examples of the tonicity agent include sodium salt sodium, glycerin, glucose, polyethylene glycol, propylene glycol, D-mannitol, fructose, xitol, sodium dihydrogen phosphate, sodium phosphate and the like. .

Examples of the stabilizing agent include tartaric acid, succinic acid, acetic acid, glutamic acid, glycine, malic acid, lactic acid, citric acid and salts thereof (sodium salt, potassium salt, calcium salt, lithium salt, ammonium salt, etc.), iodine -Containing reducing agents (metal iodide compounds such as potassium iodide, sodium iodide, etc.), sulfur-containing reducing agents (metal salts of thiosulfate, such as potassium thiosulfate and sodium thiosulfate, thiocyanate) Potassium and metal thiocyanates such as sodium thiocyanate; thioketones such as thiourea, thiosemicarbazide and thiopental; and sulfides such as L-methionine).

Examples of preservatives include paraoxybenzoic acid ester (paraben), sodium sorbate, sodium benzoate, and chlorhexidine gluconate.

Examples of the sweetener include aspartame, Amatilla, Kanzo, D-sorbitol, D-mannitol, saccharin and the like.

Examples of the flavoring agent include xylitol, ascorbic acid, erythritol, copper porphyrin sodium, green tea powder, kumazasa extract, orange oil, lemon oil, rose oil and the like.

Examples of the fragrance include heart oil, spearmint oil, thymol, hinokitiol, and lavender oil. Examples of the refreshing agent include 1-menthol, camphor, heart oil, and the like. The pharmacologically active components include glycosaminoglycans such as chondroitin sulfate, dermatan sulfate, heparan sulfate, heparin, and keratin sulfate, and herbal medicines (eg, o-gon extract, Bakumondoto, Shiratoraka-ninjin-to, Gorei (San, Hachimi-jio-gan, Hangatsu-koboku-to, Shiryo-to, Sho-saiko-to, Juzen-taiho-to, Ginger, Ginger, Hang-sum, Chimo, Bukuryo, Tenmon-winter, Gomiko, Kakkon, Ginseng, Shikon, etc.) And known anti-inflammatory agents, analgesics, vitamins, antibacterials, growth factors, adhesion factors, antibacterials and the like.

The artificial saliva of the present invention is particularly applied to a patient with xerostomia (including hyposalivation and the same in the present specification), and when administered to such a patient, the non-dryness in the oral cavity is maintained. Is improved, that is, the effect of preventing the feeling of dryness in the oral cavity can be maintained for a long time.

Xerostomia is a condition that indicates abnormal dryness in the oral cavity due to a decrease in the amount of saliva secreted. The causes are many and varied, and temporary xerostomia may be caused by rapid dehydration, high fever, bleeding, stress, etc., and persistent xerostomia may be caused by senile atrophy of salivary glands, face or cervix. Radiation to the head, Sini-Gren's syndrome, Mikul icz disease, salivary gland diseases such as chronic salivary glanditis, diabetes insipidus, diabetes, chronic renal failure, thyroid dysfunction, vitamin B deficiency, anemia, drugs (eg, antihypertensives) , Diuretics, psychotropic drugs, neuroleptics, anticancer drugs, etc.). Xerostomia to which the artificial saliva of the present invention is applied is not particularly limited by these causes, but senile atrophy of salivary glands, irradiation of the head and head, xerostomia associated with Scheigren's syndrome or It is preferably applied to xerostomia associated with drug administration. The drug is not particularly limited as long as it causes xerostomia. Antihypertensives, diuretics, psychotropics (eg, psychotropics, antipsychotics, anxiolytics, antidepressants, etc.) Particularly preferred are neuroleptics or anticancer agents.

The administration form of the artificial saliva of the present invention is not particularly limited as long as it is applied to the oral cavity of a patient. The power preferably used as a liquid preparation is not limited to this, and it can be administered in the form of a solid preparation such as a powder, granules, candy, gummy, jelly, troche and the like. It may be provided in the form of a solid preparation (for example, powder, granules, etc.), and may be made into a liquid preparation by adding water or the like at the time of use. Further, it may be used as an ointment (cream) or a patch, or may be in the form of toothpaste or gum. That is, the artificial saliva of the present invention may be provided not only as pure medicines but also as quasi-drugs, cosmetics, foods, medical devices and the like. For example, when the artificial saliva of the present invention is provided as a quasi-drug or cosmetics, the following composition can be obtained and is preferable.

Sodium hyaluronate, xylitol, 1-menthol, potassium sorbate, sodium benzoate, sodium hydrogen phosphate, sodium dihydrogen phosphate, purified water

When the artificial saliva of the present invention is provided as a cosmetic, for example, any of the following compositions (a) and (b) can be used and is preferable.

(a) Sodium hyaluronate, sodium copper chlorophyllin, kumazasa extract, sodium sorbate, sodium benzoate, sodium monohydrogen phosphate, sodium dihydrogen phosphate, legal dye, purified water

(b) Sodium Hyaluronate, Ozone Extract, Potassium Sorbate, Sodium Benzoate, Sodium Monohydrogen Phosphate, Sodium Dihydrogen Phosphate, Purified Water For liquids, sprays, rinsing agents (mouthwash (mouthwash ), Oral rinse, liquid dentifrice, etc. The same applies hereinafter in the specification.) It can be applied as a preparation for oral application. When the artificial saliva of the present invention is used as a spray, a spray container is filled with the artificial saliva of the present invention. The spray container may be a simple spray container that releases artificial saliva for each stroke, or a pressure-resistant spray container filled with an inflatable gas together with the artificial saliva of the present invention. As the expansive gas, a gas exhibiting acidity in a dissolved state is preferable since it has an effect of maintaining HA stably. As such a gas, a carbon dioxide gas is exemplified and preferable.

When the artificial saliva of the present invention is used as a rinsing agent, for example, a bottle can be filled with the artificial saliva of the present invention. For example, a large-capacity bottle may be filled and the required amount may be fractionated at the time of use, but a single-use unit bottle is preferred because it is convenient and easy to use.

When the artificial saliva of the present invention is used as a preparation for oral application, for example, the spray -Agent: The artificial saliva of the present invention filled in the same container or bottle as the soap-containing agent can be used by attaching it to clean absorbent cotton, gauze, sponge, non-woven fabric, etc. at the time of use, and applying it to the oral cavity. it can. In addition, absorbent cotton, gauze, sponge, non-woven fabric and the like to which the artificial saliva of the present invention is attached in advance may be sealed in a sealable container or package, and provided as a preparation for oral application. In addition, a pattern may be attached to absorbent cotton or the like to make it easier to use.

As used herein, “improvement of the sustainability of the non-dry feeling in the oral cavity” refers to the case where the artificial saliva of the present invention is not applied, or the case where water or conventionally known artificial saliva is used. By applying the artificial saliva of the present invention, the non-dry feeling in the oral cavity means that the period during which the wet feeling is maintained is extended. The artificial saliva of the present invention is characterized in that a long non-drying duration can be obtained, and the duration is about 1 hour to 6 hours, depending on patients and symptoms.

If the patient is extremely severe, there may be no long-lasting non-drying effect at the beginning of application. However, it was confirmed by the examples described later that the non-dry feeling was maintained for a long time when applied continuously for several days.

In addition, the artificial saliva of the present invention also has a protective effect on oral mucosa by HA, and can be particularly preferably applied to various specific uses as described below.

The artificial saliva of the present invention is preferably applied particularly for maintaining the non-dryness in the mouth of a patient with xerostomia. It can maintain a dry feeling for a long time. Accordingly, the present invention also provides a non-drying agent for oral sensation comprising HA or a pharmaceutically acceptable salt thereof.

In addition, the artificial saliva of the present invention containing HA also has a pain relieving action in the oral cavity as shown in Examples described later. The causes of pain in the oral cavity include those associated with dry mouth (eg, tongue pain and oral mucosal pain) and those associated with oral ulcers (such as aphthous stomatitis). Regardless of the type, the artificial saliva of the present invention can be applied to obtain a pain relieving effect. Accordingly, the present invention also provides an oral pain relieving agent comprising HA or a pharmaceutically acceptable salt thereof.

In addition, the artificial saliva of the present invention containing HA can be used for oral mucosal damage as shown in the Examples below. For example, it also has the effect of improving oral ulcers (such as aphthous stomatitis) (the effect of promoting healing). Accordingly, the present invention also provides an oral mucosal disorder improving agent (oral mucosal disorder healing promoting agent, oral mucosal disorder therapeutic agent) comprising HA or a pharmaceutically acceptable salt thereof. Among oral mucosal disorders, it is preferable to use it as an agent for improving oral ulcers.

In this case, when a solution is prepared, the concentration of HA or a pharmaceutically acceptable salt thereof in the solution is preferably 0.2 to 0.4% (w / v).

In addition, the artificial saliva of the present invention containing HA has the effect and effect of making it easier for a patient with xerostomia to wear a denture and improving discomfort and discomfort when the denture is properly mounted, as shown in Examples described later. are doing. Therefore, the present invention provides an auxiliary agent for denture wearing, which comprises HA or a pharmaceutically acceptable salt thereof and is applied to a patient with xerostomia. Such adjuvants make it easier to wear dentures by reducing the pain and discomfort of dentures in patients with xerostomia, and also improve the discomfort and discomfort of continuous dentures by improving the dentures. This has the effect of increasing the suitability of mounting. Therefore, it is preferable to apply this auxiliary for such a purpose. In this case, when a solution is prepared, the concentration of HA or a pharmaceutically acceptable salt thereof in the solution is preferably 0.1 to 0.4% (w / v).

In addition, the artificial saliva of the present invention containing HA has an action and effect of improving the drying of the nasal cavity by administering it to the nasal cavity, as shown in Examples below. Accordingly, the present invention provides a nasal dryness improving agent comprising HA or a pharmaceutically acceptable salt thereof.

Since the artificial saliva of the present invention containing HA has an improved non-dryness in the oral cavity as described above, it can be applied to prevent (improve) various symptoms and conditions caused by xerostomia. it can. Symptoms and conditions associated with xerostomia include, for example, excessive intake of water, nocturnal enuresis due to excessive intake of water, diarrhea associated with excessive intake of water, taste disorder associated with dry mouth, dysphagia, hardening of the tongue, burning sensation , Eating disorders, frequent caries, severe gingivitis, oral infections (such as candidiasis), symptomatic leukoplakia, pronunciation disorders, trauma, frequent occurrence of aphtha and stomatitis, occurrence of decubitus ulcer, gram Examples include pneumonia induction (onset of aspiration pneumonia) due to the residual negative bacilli, and discomfort in the mouth, and these can be administered as an agent for improving and / or preventing these symptoms. Therefore, the present invention relates to HA or a pharmaceutical thereof. Also provided is an agent for ameliorating and / or preventing various symptoms caused by xerostomia, which comprises a salt that is acceptable. The agent for improving and / or preventing various symptoms caused by xerostomia of the present invention is preferably applied particularly for preventing excessive intake of water, preventing enuresis or preventing hardening of the tongue.

In addition, prevention of oral mucosal damage, improvement of dysphagia (symptoms such as difficulty swallowing), improvement of mastication disorders (symptoms such as difficulty in eating, difficulty biting, etc.), and taste disorders (loss of taste, loss of understanding) It is also preferred to be applied for the purpose of improving symptoms such as symptoms that cannot be understood unless the taste is thick, dysphonia (the mouth does not rotate well, making it difficult to speak), and reducing the discomfort in the oral cavity.

The dosage of the artificial saliva of the present invention and each drug should be determined individually according to the dosage form, administration method, administration purpose, specific symptoms of the patient, body weight, age, etc., and is not particularly limited. However, the dose of HA is about 1 to 100 mg per day.

The administration interval of the above-mentioned preparation may be every other day or every day, and is not particularly limited. It can be administered about once a day, or it can be divided into about 2 to 20 times a day.

The artificial saliva of the present invention can be widely applied to mammals as well as humans, but it is particularly preferable to use it for humans.

HA or its pharmaceutically acceptable salt has already been used in pharmaceuticals (eg, joint function improving agents and ophthalmic surgery adjuvants), cosmetics, foods, and the like, and its safety has been confirmed. In addition, high security was confirmed by the examples described later.

[Example]

Hereinafter, examples of the present invention will be specifically described as formulation examples and test examples. However, these do not limit the technical scope of the present invention.

In this example, sodium hyaluronate having an iron content of 4.6 ppm and a weight average molecular weight of 900,000 was used. The intrinsic viscosity of this sodium hyaluronate was measured and found to be 16 OdI / g.

[Formulation example]

(1) Simple spray agent 1 Dissolve sodium hyaluronate in distilled water for injection to a concentration of 0.2% (w / v), 0.4% (w / v) or 0.6% (w / v), and add 50 ml each. Filled in a simple spray container.

(2) Simple spray agent 2

Dissolve sodium hyaluronate in a 3% (w / v) aqueous solution of xylitol to a concentration of 0.2% (w / v) or 0.4% (w / v), and use a simple spray of 5 Oml each. The container was filled.

(3) Simple spray agent 3

Dissolve sodium hyaluronate to a concentration of 0.2% (w / v) or 0.4% (w / v) in an aqueous phosphate buffer solution of the following composition, each containing a simple spray of 5 Om1. The container was filled.

0.9% sodium chloride (w / v)

Sodium dihydrogen phosphate 0.1 mM

Nittrium hydrogen phosphate 1.5 mM

(4) Soap-containing agent 1

Sodium hyaluronate was dissolved in distilled water for injection to a concentration of 0.2% (w / v) and filled in a unit bottle.

(5) Soap-containing agent 2

Sodium hyaluronate was dissolved in a physiological saline solution to a concentration of 0.4% (w / v) and filled in a unit bottle.

(6) Soap-containing agent 3

Sodium hyaluronate and chondroitin sulfate were each dissolved in distilled water for injection to a concentration of 0.2% (w / v) and filled into unit bottles.

(7) Gummy Candy 1

Dissolve sodium hyaluronate at a concentration of 0.5% (w / v), gelatin at a concentration of 10% (w / v), and sorbitol at a concentration of 10% (w / v) in distilled water for injection. The mixture was heated, dispensed into molds of 2 g each, and cooled to produce gummy candy.

(8) Gummy Candy 2

Sodium hyaluronate at a concentration of 0.5% (w / v), gelatin at a concentration of 10% (w / v), Xylitol was dissolved in distilled water for injection so as to have a concentration of 5% (w / v), heated, dispensed into molds in 2 g portions, and cooled to produce gummy candi.

(9) Jelly-type preparation

Dissolve sodium hyaluronate at a concentration of 0.5% (w / v), gelatin at a concentration of 3% (w / v), and xylitol at a concentration of 5% (w / v) in distilled water for injection. The mixture was heated, dispensed into 2 g molds, and cooled to produce a jelly-type preparation.

(10) Lozenges

1 Omg of sodium hyaluronate, 1600 mg of purified sucrose, 20 mg of hydroxypropylcellulose, a small amount of fragrance and coloring agent, lactose was added to adjust the final amount to 2000 mg, and a troche of 2000 mg per tablet was prepared by a conventional method. .

(11) Spray agent

Sodium hyaluronate was dissolved in a solution having the following composition so as to have a concentration of 0.1% (w / v), and 5 Om 1 was filled in a pressure-resistant spray container together with carbon dioxide to produce a spray agent. .

Sodium chloride (0.0844% (w / v))

Potassium chloride (0.120% (w / v))

Calcium chloride (0.0146% (w / v))

Magnesium chloride (0.0052% (w / v))

Dipotassium phosphate (0.0342% (w / v))

(12) Liquid for application

Dissolve sodium hyaluronate in distilled water for injection to a concentration of 0.02% (w / v), 0.05% (w / v) or 0.1% (w / v), and fill each bottle did. Administration can be carried out by immersing a sponge with a handle in this solution and applying it to the oral cavity.

[Test example]

(1) Pharmacological study 1

Using the formulation prepared in Formulation Example (1) (simple spray agent 1 (sodium hyaluronate concentration: 0.2%)), the following four oral patients with xerostomia have 1-2 strokes ( One stroke was administered at about 120 to 130 mg The results are shown in Table 1. Patient Objective Age Gender Subjective symptoms Other symptoms

Subjective symptoms

1 7 2 Male Good

Undecidable

2 6 0s Female Good Good

3 6 0s Female Good Good

Complication of oral ulcer

Pain

4 3 0s Female Good

Pain and dryness immediately after administration

Disappearance, effect lasts about 1 hour. As comparative examples, "water", "commercial artificial saliva (Salibe (registered trademark); manufactured by Teijin Limited; containing carboxymethylcellulose"), "Bakumondo-to" , And "Hakutora Kajinsan-to" were tested in the same manner.

As a result, in both “water” and “commercial artificial saliva”, the feeling of dryness and pain disappeared immediately after administration, but the effect was instantaneous, and the sustainability of the effect as in the above preparation was not observed. I couldn't see it.

Bakumondo-to and Hakutoka-ka-ninjin-to took a long time to develop their effects, and did not show any effects immediately after administration as in the above formulation.

From these results, it was revealed that the artificial saliva of the present invention, when applied to a patient with xerostomia, eliminated and relieved dryness and pain in an extremely short time, and the effect lasted for a long time. . In addition, it was revealed that the artificial saliva of the present invention was also effective for pain due to oral ulcer.

(2) Pharmacological study 2

The same administration as in Pharmacological Pharmacological Test 1 was performed on 12 xerostomia patients, and the duration of non-dryness in the oral cavity and changes in symptoms were observed. For patients with a history of using salivate, we also compared the feeling of use with salivate. Table 2 shows the results. Table 2 Patient number Age Gender Dryness Viscous Effect Duration, Other effects Remarks

5 59 Female 3 3 4 4-6 hours, general condition improvement (taste disorder

Eating due to improvement of harm and dysphagia

Increased intake, weight gain and physical fitness

Has improved. With this, the wheelchair

Necessary, but independent walking is also possible

became. )

6 33 Female 3 3 4 2 to 4 hours, tongue aphtha (ulcer) pain steroid use, pain relief aphtha

7 52 Female 3 3 4 2 to 3 hours, denture pain relief Steroids used

8 68 Female 3 4 4 1-3 hours, very good usability

9 64 Male 3 4 4 Moist feeling in the oral cavity and discomfort

Disappearance, alleviation of dysphagia

10 56 Female 4 4 4 Usability is always better than non-Siedalen syndrome compared to salivate

11 68 Male 4 4 3 3 to 4 hours, conversation enabled, swallowing advanced stomatitis

Alleviation of difficulties

12 79 Male 4 4 4 Severe stomatitis that makes mouth easy to move for 2 to 4 hours

13 68 Female 3 3 4 1 to 4 hours, pain relief for glossodynia

14 70 Male 2 3 4 1-2 hours, pain relief

15 56 Female 3 4 4 2-3 hours, improved tongue and gingival condition

16 11 Male 1 2 3 2-3 hours, pain almost disappeared

In Table 2, the degree of dryness represents the dryness in the oral cavity before administration of the preparation, 4: a very dry feeling, 3: a dry feeling, 2: a little dry feeling, 1: a very dry feeling. No, 0: No dry feeling. Viscosity indicates the evaluation of the viscosity (stickiness) in the oral cavity by the formulation after administration of the formulation. 4: Viscous, 3: Viscous, 2: Slightly viscous, 1: Normal viscosity as the oral cavity Sexual feeling, 0: represents a state of lying without any viscous feeling. The effect indicates the evaluation of the patient's feeling of use, and indicates the evaluation of 4: want to use it by all means, 3: use it if possible, 2: use either, 1: use it if it is possible, 0: do not use it. The duration and other effects showed the duration of oral dryness after administration and changes in other symptoms. All of these evaluations are the patient's own subjective symptoms and evaluations.

The remarks indicate the disease, condition, and drug administered to the patient. As can be seen from the results shown in Table 2, when the artificial saliva of the present invention is administered, the non-dry feeling in the oral cavity is maintained for at least one hour to several hours, and the non-dry feeling can be maintained for a long time. In addition, alleviation of oral pain associated with xerostomia, stomatitis, and aphtha was generally observed. All patients evaluated that they wanted to use the artificial saliva of the present invention, and that they felt much better in use than commercial artificial saliva containing carboxymethylcellulose.

(3) Pharmacological pharmacology test 3

Separately from the pharmacology study 2, 16 patients with xerostomia were treated in the same manner as in the pharmacology study 2 and evaluated similarly. Table 3 shows the results.

Table 3 Patient number Age Gender Dryness viscosity Effect Duration, Other effects Remarks

17 65 Female 4 3 4 2-3 hours, improvement of dysphagia

18 72 Female 4 4 4 2 hours, masticatory disorders improved

19 65 Male 4 4 4 3-4 hours, improved taste disorder

20 68 Female 3 3 3:! ~ 3 hours, reduced pain by aphtha

21 62 Male 3 3 3 2 to 4 hours, denture compatibility is up Applied at HA concentration of 0.2 to 0.4%

22 55 Female 3 4 4 1-3 hours, reduces pain from aphtha

23 42 Male 3 4 3 2 to 4 hours, improving stomatitis symptoms and promoting healing

24 65 Female 3 3 4 1 to 4 hours, Improvement of oral mucosal pain

25 63 Female 4 4 4 2-3 hours, pain relief for tongue pain, improvement of denture ulcer

26 68 Female 4 4 4 1-3 hours, improved taste and dysphagia

27 54 Female 2 3 4 2-3 hours, also effective for nasal dryness Administered to nasal cavity

28 82 Female 4 4 4 3-4 hours, improved dysphagia

29 81 Male 4 4 4 2-4 hours, tongue movement can be pronounced (pronunciation severe xerostomia

Effective for nasal dryness Administered to nasal cavity

30 66 Female 3 3 3 2 to 3 hours, Pain relief for glossodynia Administered at HA concentration of 0.2 to 0.4%

31 70 Female 3 4 4 1-3 hours, pain relief for tongue pain

32 59 Female 3 4 3 About 2 hours, pain relief for glossodynia

As can be seen from the results shown in Table 3, the same favorable results as in Pharmacological Test 2 were obtained. This suggests that the artificial saliva of the present invention is widely useful for xerostomia patients. In addition, it has been found that the artificial saliva of the present invention is also effective in improving mastication disorders.

It was also shown that the administration of the artificial saliva of the present invention to the nasal cavity also improved the drying of the nasal cavity.

(4) Pharmacological pharmacology study 4

Patients with xerostomia (both are psychiatric patients and xerostomia due to administration of a drug) were treated with the formulation (soap 1) prepared in Formulation Example (4). The dose was administered using a mL cup. Since subjective symptoms are difficult to evaluate, the evaluation was based on the doctor's objective findings only. As a result, good results were obtained in each case. Among these patients, more detailed observations were made when administered to a 53-year-old man. The patient was a schizophrenic patient, whose tongue had hardened due to dry mouth. In addition, some patients had night urine almost every night, probably because of excessive drinking of juice due to dry mouth.

When the patient was given three doses at regular intervals (approximately every 3 hours), about 5 mL each time, the tongue stiffness was clearly improved and a non-dry state was observed until the next day. During this time, the patient's fluid intake also decreased and nocturnal urine improved.

From these results, it was shown that the artificial saliva of the present invention was also effective for patients with xerostomia caused by administration of the drug, and the effect could be maintained for about half a day.

In addition, it was revealed that the artificial saliva of the present invention also has an effect of improving the tongue hardening, and can be used for preventing excessive intake of water and preventing enuresis.

(5) Pharmacological test 5

The formulation (formulation for application) prepared in Formulation Example (12) was applied to the mouth of four patients with xerostomia shown in Table 4 by applying with a patterned sponge. Table 4 shows the results. The daily condition before administration, dryness, food residue, adhesion of tongue coating, presence of bad breath, and saliva volume are also shown. Except for the amount of saliva, it was evaluated by observation by a dentist. To measure the amount of saliva, at rest, insert a rollette (dental absorbent cotton wool) into the oral cavity, leave it for 1 minute, and measure the amount of saliva soaked into it in 0.5 g units. I asked by doing.

In Table 4, the meanings of the symbols indicating the condition of the patient before administration are as follows. * Daily condition

〇: There is no dry mouth subjectively, but dry mouth is subjectively recognized.

1: Slight dryness (does not affect daily life.)

2: Moderate dryness (chewing and swallowing are difficult and water is required for food intake)

3: Severe feeling of dryness (Water drinking and awakening during the night, large amounts of water required during meals. Dentures are difficult to wear.)

* Dryness

1: Moist, Soil: Dry, +: Whole

* Food leftovers

1: No, +: Yes

* Adhering tongue moss

One: None, +: — Partial, + +: Two or three or more

* Bad breath

One: None, +: Somewhat yes, + +: Yes

Table 4

As can be seen from the results shown in Table 4, sodium hyaluronate in the artificial saliva of the present invention was effective even at a low concentration of 0.02 to 0.1%. In addition, effects such as a marked decrease in water intake and the possibility of wearing dentures were also observed.

(6) Pharmacological pharmacology study 6

In order to more objectively and quantitatively evaluate the effectiveness of the artificial saliva of the present invention, in particular, the moisturizing effect of the oral f occlusive membrane and the sustained effect of the non-dry state, a hamster (Syrian; SPF; 13 weeks old) was used. The following experiment was conducted.

(6-1) Preparation of dry mouth (dry mouth model) with dryer

Under anesthesia with Nembutal (Dainippon Pharmaceutical), a test tube with a diameter of about 1 O mm was inserted from the 頰 side, and the inside of the oral cavity was turned upside down and exposed. Hot air was blown into the mouth exposed by the dryer for about 20 seconds, and then cool air was blown for 2 minutes and 40 seconds. Thereafter, the oral cavity was kept exposed until the measurement was completed.

(6-2) Test substance

(i) 0.2% sodium hyaluronate (simple spray agent 1)

(i i) Distilled water (control)

(6-3) Administration of test substance

Immediately after the preparation of the dry mouth model, 100 L of the test substance was applied to the oral cavity of the model (7 mice per group) using a microsyringe.

(6-4) Measurement of water loss

The amount of water loss in the exposed oral cavity of the hamster was measured using a water loss system (Moisture loss monitor AS-TW2, manufactured by Asahi Piomed). The measurement was performed immediately after the preparation of the dry mouth model, immediately after administration of the test substance, and at 10 minutes and 20 minutes after administration. The measurement results were obtained as relative values when the average value of the water loss immediately after the preparation of the mouth dry model was set to 1.

The results are shown in Figure 1.

As shown in Fig. 1, in the group to which distilled water was administered (control group), the amount of water transpiration increased immediately after application, but decreased to the same extent at 10 minutes after administration as before administration. In contrast, in the group to which 0.2% sodium hyaluronate was administered, the water transpiration was maintained at about 1 Z 2 immediately after administration even at 10 minutes after administration. From this result, 0.2% hyaluron Sodium acid has a moisturizing effect on the oral mucosa and has been shown to maintain a non-dry state in the oral cavity.

(7) Pharmacological study 7

In order to objectively and quantitatively evaluate the effectiveness of the artificial saliva of the present invention, in particular, the improvement (healing promotion) effect of oral mucosal damage, a hamster (Syrian; SPF; 13 weeks old; male) was used. The following experiment was performed.

(7-1) Preparation of oral mucosal injury (acetic acid-induced oral mucosal injury model)

After anesthetizing the hamster with a mixed solution of ketamine and xylazine, apply a test tube from the outside of the right sack of the nomster, invert the sack to expose the oral mucosal surface, and wash the mucosal surface with saline. Washed with solution. After removing excess saline solution, circular filter paper (1 cm in diameter) was placed on the exposed mucosal surface. A 30% acetic acid solution was dropped on the filter paper, and left as it was for 10 minutes to cause damage to the mucosal surface. At this time, an acetic acid solution was appropriately added dropwise so as to keep the surface of the filter paper always filled with a sufficient acetic acid solution. After standing for 10 minutes, the filter paper was removed and washed thoroughly with a physiological saline solution. (7-2) Test substance

The following (i) to (iii) used those of the simple spray preparation 1 prepared in Preparation Example I).

(i) 0.2% sodium hyaluronate

(ii) 0.4% sodium hyaluronate

(iii) 0.6% sodium hyaluronate

(iv) Phosphate buffered saline (PBS; control substance)

(7-3) Administration of test substance

Each test substance and control substance were administered to the above model once a day for 3 days from the day after the induction of the disorder. The test substances (i) and (ii) were administered to 10 models each, the test substance (iii) was administered to 8 models, and the control substance was administered to 9 models. Administration was performed as follows.

After anesthesia using a mixed solution of ketamine and xylazine, Hamster's bag is turned over to expose the damaged area, and 150 μl of »substance is exposed to the damaged area using a microsyringe. Was administered. After leaving it for 20 minutes, it was returned to the cage without washing. (7-4) Measurement and statistical processing of the area of the affected area

In order to objectively and quantitatively evaluate the degree of healing of oral mucosal damage, the area of the damaged site was measured, and the degree of reduction was evaluated as the degree of healing of mucosal damage. The area of the lesion site was measured the day after the last administration (4 days after the induction).

Specifically, on the day after the final administration, the entire lesion was photographed first, and then the entire lesion was stained with 20% fluorescein and photographed. The area of the lesion was determined based on the results of image analysis of the photographed image before fluorescein staining and the photographed image after fluorescein staining.

In each group, the relative value of the area of disability was calculated by setting the average value of the area of disability on the day after the induction of the disorder as 100%. The results (average value S.D.) were as follows.

Control group 4 6 ± 16%

0.2% administration group 3 8 ± 10%

0.4% group 3 4 8%

0.6% administration group 3 8 9%

From these results, it was found that the groups to which sodium hyaluronate was administered at any concentration had a reduced area of oral mucosal damage as compared to the control group. This indicates that sodium hyaluronate has an effect of improving oral mucosal damage, and particularly an effect of promoting healing of oral mucosal damage.

Statistical analysis by Dunnett's multiple comparison test (nonparametric) showed that the reduction in the area of oral mucosal damage in the 0.4% treatment group was significant (p <0.05) compared to the control group.

In addition, as a result of the above pharmacology studies 1 to 7, no side effects were observed due to the administration of the drug product, indicating that it was extremely safe-industrial applicability

The additive of the present invention is useful as an additive for the artificial saliva of the present invention. In addition, the artificial saliva of the present invention is extremely useful because it can eliminate or alleviate dryness and pain in the oral cavity in a patient with xerostomia in a very short time, and its effect lasts for a long time and is highly safe. . The artificial saliva of the present invention can prevent and improve various symptoms and conditions caused by xerostomia, such as excessive intake of water, nocturnal enuresis due to excessive intake of water, taste disorder, and eating disorder. For example, xerostomia in older people can cause eating disorders and ultimately rely on tube feeding and infusion. Loss of motivation to live quickly leads to loss of motivation, often leading to intellectual disability and bedriddenness--improving dryness in the oral cavity and sustaining non-dryness so that you can eat independently In that case, the effect on the geriatric medical care is great, and it is very useful from the viewpoint of reducing the cost of geriatric medical care.

The artificial saliva of the present invention can also moisturize the oral cavity and protect the oral mucosa. Therefore, the artificial saliva of the present invention can be used for purification of the oral cavity, for example, for prevention and improvement of oral infections and dental caries, and is considered to greatly contribute to oral hygiene of the public.

Further, the non-drying agent for oral cavity, the agent for improving oral mucosal disorder, the agent for relieving pain in the oral cavity, the auxiliary agent for denture wearing, and the agent for improving nasal dryness provided by the present invention are also extremely safe and easy to administer. Which is extremely useful.

Claims

The scope of the claims

1. An additive containing hyaluronic acid or a pharmaceutically acceptable salt thereof, which is added to artificial saliva for improving various symptoms caused by dry mouth.

2. An additive containing hyaluronic acid or a pharmaceutically acceptable salt thereof, which is added to artificial saliva for application to a patient with xerostomia.

3. The additive according to claim 1, wherein the weight-average molecular weight of hyaluronic acid or a pharmaceutically acceptable salt thereof is from 300,000 to 1.2 million.

4. The additive according to any one of claims 1 to 3, wherein the intrinsic viscosity of hyaluronic acid or a pharmaceutically acceptable salt thereof is 7 to 20 d1.

5. The additive _{s according} to any one of claims 1 to 4, wherein the iron content of hyaluronic acid or a pharmaceutically acceptable salt thereof is 20 ppm or less.

6. Improved non-drying in the oral cavity, characterized in that it contains the additive according to any one of claims 1 to 5, and is applied to improve various symptoms caused by dryness in the oral cavity. Artificial saliva that shows lasting feeling.

7. The artificial saliva according to claim 6, which is applied to a patient with xerostomia.

8. The artificial saliva according to claim 6, which is in a liquid form.

9. 25 ° apparent viscosity measured at a shear rate of 1 sec ¹ at C is 10~600 Om Pa · s, artificial saliva according to claim 8.

10. The concentration of hyaluronic acid or a pharmaceutically acceptable salt thereof in artificial saliva is formulated to be 0.01 to 0.6% (w / v), Claims. The artificial saliva according to 8 or 9.

11. The artificial saliva-sodium chloride according to claim 10, further comprising at least one or more of the following components in the following content (content: 0.05 to 0.1% (w / v))

Potassium chloride (content: 0.1 to 0.15% (w / v))

Calcium chloride (content: 0.01 to 0.02% (w / v))

Magnesium chloride (content: 0.004 to 0.006% (w / v)) Phosphorus diphosphate (Content: 0.01 to 0.05% (w / v))

12. The artificial saliva according to any one of claims 8 to 11, wherein the artificial saliva is filled in a spray container or a bottle.

13. The artificial saliva according to any one of claims 8 to 12, wherein the artificial saliva is filled in a pressure-resistant container together with an inflatable gas that is acidic in a dissolved state.

14. The artificial saliva according to claim 13, wherein the gas is carbon dioxide.

15. The artificial saliva according to any one of claims 6 to 14, which is applied for maintaining a non-dry feeling in the oral cavity.

16. The artificial saliva according to any one of claims 6 to 15, which is applied to a patient with xerostomia associated with drug administration.

17. The human saliva according to claim 16, wherein the drug is an antihypertensive, a diuretic, a tranquilizer, an antipsychotic, an anxiolytic, an antidepressant, a neuroleptic, or an anticancer agent. .

18. An oral non-drying sensate comprising hyaluronic acid or a pharmaceutically acceptable salt thereof.

19. Improvement of oral mucosal injury, including hyaluronic acid or pharmaceutically acceptable salts thereof

20. The oral mucosal disorder modification according to claim 19, wherein the oral mucosal disorder is an oral ulcer.

21. An oral pain relieving agent comprising hyaluronic acid or a pharmaceutically acceptable salt thereof.

22. A denture mounting aid, comprising hyaluronic acid or a pharmaceutically acceptable salt thereof, which is applied to xerostomia patients.

23. A nasal dryness improving agent comprising hyaluronic acid or a pharmaceutically acceptable salt thereof.

24. Improvement and / or prevention of symptoms caused by xerostomia, including hyaluronic acid or a pharmaceutically acceptable salt thereof-

25. Prevent excessive intake of water, prevent enuresis, prevent tongue hardening, prevent oral mucosal disorders, improve dysphagia, improve mastication disorders, improve taste disorders, improve pronunciation disorders, and oral discomfort Applied for one or more purposes selected from the group consisting of: The agent for improving or preventing various symptoms caused by xerostomia according to claim 2, characterized in that:

26. A method for sustaining a non-dry feeling in the oral cavity, which comprises administering an effective amount of hyaluronic acid or a pharmaceutically acceptable salt thereof to the oral cavity.

27. Use of hyaluronic acid or a pharmaceutically acceptable salt thereof for the production of a non-drying agent in the oral cavity.