JP4804420B2 - Artificial saliva - Google Patents

Description

  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 dry mouth patients. The present invention also relates to artificial saliva with improved non-drying susceptibility in the oral cavity, characterized in that it contains the additive and is applied to xerostomia patients.

Hereinafter, a technique considered to be closest to the present invention will be described.
Patent Document 1 describes a composition for preventing dryness in which a humectant such as a saccharide and a surfactant are blended in water, and the composition is used to prevent drying of the oral cavity and the like. Is disclosed. 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 applying to the oral cavity of xerostomia patients. Further, there is a description that a sufficient effect cannot be obtained when only the humectant is applied, and that even if an effect is obtained, it is extremely temporary.

  Patent Document 2 describes a therapeutic composition comprising an aqueous solution of at least one polymer and at least one electrolyte, and also describes a saliva substitute containing the composition.

However, there is no description about HA, and there is no description or suggestion about a remarkable effect recognized in the present invention, as shown in Examples described later.
Patent Document 3 describes the use of a pharmaceutical composition containing HA having an average molecular weight of 800,000 to 4,000,000 as an active ingredient for treatment and prevention of oral inflammation, oral hygiene and the like.

However, there is no disclosure or suggestion about the idea of applying to the oral cavity of xerostomia patients and improving the non-drying susceptibility in the oral cavity.
Patent Document 4 discloses an oral anti-inflammatory agent containing HA as an active ingredient, and Patent Document 5 discloses an allergy therapeutic agent containing HA as an active ingredient, and also discloses application to the oral cavity. Has been.

  However, none of these discloses or suggests the idea of applying to the oral cavity of patients with xerostomia or improving the persistence of the non-dry feeling in the oral cavity.

JP 61-24510 A Special table hei 9-508898 European Patent No. 444492 JP-A-6-107550 JP-A-5-320055

  In recent years, geriatric medical problems have become social issues. Elderly people are prone to xerostomia due to the influence of various drugs in addition to the decrease in saliva secretion due to aging. When xerostomia occurs, eating disorders may eventually occur and you may eventually have to rely on tube feeding or infusion. Also, if you can't eat, your willingness to live is lost rapidly, often causing intellectual disability. In such a state, the prognosis is poor, and it is said that half of the patients die in one year. If the dryness in the oral cavity of a patient with xerostomia is improved and the person can eat independently, the improvement effect on geriatric medicine will be extremely large.

In addition, psychiatric patients who are administered antidepressants often have xerostomia due to side effects of the drug.
Although there is a view that it is only necessary to drink water, experience has shown that even if a patient with xerostomia drinks water, the moment is only moistened, which is not practical. Even if a healthy person feels comfortable, it may be uncomfortable for xerostomia patients, and it is also important to evaluate in consideration of patient evaluation.

  Accordingly, an object of the present invention is to provide artificial saliva with improved non-drying susceptibility in the oral cavity of xerostomia patients.

  As a result of intensive studies to solve the above problems, the present inventors have found that HA or a pharmaceutically acceptable salt thereof significantly maintains a non-dry feeling in the oral cavity of xerostomia patients, Furthermore, it has been found that the above-mentioned effects can be obtained particularly excellently by HA having specific molecular weight, intrinsic viscosity and other properties or a pharmaceutically acceptable salt thereof. And by using such HA or a pharmaceutically acceptable salt thereof as a component of artificial saliva, it is possible to remarkably prevent and improve xerostomia and to prevent and improve various symptoms and conditions associated therewith. I found it. The present invention has been completed based on these findings.

  That is, the present invention includes an additive (hereinafter referred to as “the additive of the present invention”) containing hyaluronic acid or a pharmaceutically acceptable salt thereof and added to artificial saliva for application to a dry mouth patient. (Also called).

  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 dl / g. More preferably, the weight average molecular weight is 500,000 to 1,200,000, and the intrinsic viscosity is 10 to 20 dl / g. The iron content is preferably 20 ppm or less.

  The present invention also includes an artificial saliva (hereinafter referred to as “the present invention artificial saliva”), which contains the additive of the present invention and is applied to a patient with xerostomia and has improved durability of a non-dry feeling in the oral cavity. ").

The artificial saliva of the present invention is preferably in the form of a solution, and the apparent viscosity measured at 25 ° C. with a shear rate of 1 sec ⁻¹ is preferably 10 to 6000 mPa · s.
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, and also includes psychotropic drugs such as antihypertensives, diuretics, tranquilizers, antipsychotics, anxiolytics, antidepressants, It is also a preferred mode of use to apply to xerostomia patients associated with administration of drugs such as neuroleptics and anticancer agents.

  In addition, the present invention provides hyaluronic acid or a pharmaceutically acceptable salt thereof, an oral non-drying susceptibility agent, an oral mucosal disorder ameliorating agent, an oral pain relieving agent, various symptoms caused by xerostomia. An improvement and / or prevention agent is also provided. Examples of preferable application purposes of the agent for improving various symptoms caused by xerostomia and / or a preventive agent of the present invention include prevention of excessive intake of water, prevention of nocturnal enuresis, prevention of tongue hardening, and the like.

  As described above, HA has been disclosed in the oral cavity for the purpose of preventing dryness, treating and preventing inflammation, treating allergies, and the like. It has not been known so far that HA having characteristics such as concentration, molecular weight, and intrinsic viscosity has an effect of improving the persistence of the non-dry feeling in the oral cavity, that is, the action of maintaining the non-dry feeling for a long time by its administration. It is.

  Embodiments of the present invention will be described below.

<1> Additive of the present invention The origin of hyaluronic acid or a pharmaceutically acceptable salt thereof used in the additive of the present invention is not particularly limited, and hyaluronic acid separated and purified from chicken crowns, umbilical cords, microorganisms producing hyaluronic acid, etc. An acid can be used. In particular, those purified to a high purity and substantially free from substances that are not allowed to be mixed as pharmaceuticals are preferred.

  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, or diethanolamine salts, Among salts with organic bases such as cyclohexylamine salts and amino acid salts, pharmaceutically acceptable salts can be used. Of these, sodium hyaluronate is preferable.

  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, and particularly preferably about 500,000 to 900,000. .

  The hyaluronic acid or a pharmaceutically acceptable salt thereof preferably has an intrinsic viscosity of 7 to 20 dl / g, more preferably 10 to 20 dl / g, and particularly preferably 10 to 16 dl / g.

  By using hyaluronic acid having a molecular weight and an intrinsic viscosity as described above or a pharmaceutically acceptable salt thereof, an effect of preventing dry mouth particularly excellent in sustainability can be obtained.

  Note that the endotoxin concentration in hyaluronic acid or a pharmaceutically acceptable salt thereof used in the additive of the present invention is preferably 0.3 EU / mL or less when artificial saliva, which is a liquid agent described later, is used. The endotoxin concentration in the additive of the present invention can be measured using a conventional endotoxin measurement method well known to those skilled in the art, but the Limulus test method using a horseshoe crab, amebosite lysate component is preferred. EU (endotoxin unit) is defined by Japanese Industrial Standard Biochemical Reagents (JIS K8008), US Department of Health and Human Services, Public Health 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, Rockville, MD, 1987. The iron content is preferably 20 ppm or less.

  The additive of the present invention can contain optional components in addition to hyaluronic acid or a pharmaceutically acceptable salt thereof. Such optional components are not particularly limited unless they are unsuitable for the use of the additive of the present invention, but may be a pharmaceutical carrier, additive, or pharmacologically active component that can be added to the artificial saliva described below. preferable.

  The additive of the present invention is prepared in a solid form such as a powder containing the above hyaluronic acid or a pharmaceutically acceptable salt thereof, but those components are dissolved or suspended in water, buffer solution, physiological saline or the like. You may prepare in the form of a liquid agent.

  The amount of the additive of the present invention can be appropriately selected, but when used as an active ingredient hyaluronic acid or a pharmaceutically acceptable salt thereof in an artificial saliva as a liquid as described later, The final concentration 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%. It is about (w / v), and particularly preferably about 0.1 to 0.4% (w / v). When used for artificial saliva, which is a solid agent, about 0.1 to 5% (w / w) in the solid agent is preferable.

<2> The artificial saliva of the present invention The artificial saliva of the present invention is an artificial saliva with improved non-drying susceptibility in the oral cavity, characterized by containing the additive of the present invention and being applied to xerostomia patients. is there.

  The artificial saliva of the present invention can be prepared in the form of a liquid agent, a solid agent, etc. as described later, but the content of the additive of the present invention in the artificial saliva of the present invention is the active ingredient hyaluronic acid or its pharmaceutically As the acceptable salt, the artificial saliva of the present invention which is a liquid is preferably about 0.01 to 1% (w / v), more preferably about 0.01 to 0.6% (w / v), Preferably it is 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 agent, about 0.1 to 5% (w / w) is preferable. In particular, the use of hyaluronic acid or a pharmaceutically acceptable salt thereof having such characteristics as those used in the additive of the present invention in such an amount provides a particularly excellent non-dry feeling in the oral cavity. It is done.

When the artificial saliva of the present invention is provided as a liquid agent, the value when the apparent viscosity of the liquid agent is measured at a shear rate of 1 second ^-1 at 25 ° C is preferably 10 to 6000 mPa · s, more preferably 10 to 10 mPa · s. 3000 mPa · s, particularly preferably 10 to 1500 mPa · s. By using the artificial saliva of the present invention which is a liquid agent having such an apparent viscosity, a particularly excellent non-dry feeling in the oral cavity can be obtained.

  In addition, the component composition of the artificial saliva of the present invention is not particularly limited as long as it contains the additive of the present invention, but it is adjusted so that it is in the form of a liquid and the inorganic electrolyte component composition is substantially the same as that of normal human saliva. The composition may be different. Examples of the composition of such artificial saliva (solution) include the following compositions and are preferred.

Hyaluronic acid or its salt (content: 0.01-1% (w / v))
Sodium chloride (content: 0.05-0.1% (w / v))
Potassium chloride (content: 0.1-0.15% (w / v))
Calcium chloride (content: 0.01-0.02% (w / v))
Magnesium chloride (content: 0.004-0.006% (w / v))
Dipotassium phosphate (content: 0.01-0.05% (w / v))

In addition, these inorganic electrolyte components may mix | blend all and may mix | blend 1 or 2 or more in combination.
As a solvent for dissolving these components, water is preferable, and pharmaceutically acceptable water such as distilled water for injection and sterilized water is particularly preferable.

  The artificial saliva of the present invention is physiologically acceptable, does not adversely affect hyaluronic acid or a pharmaceutically acceptable salt thereof in the artificial saliva of the present invention, and maintains the above-described properties of the artificial saliva of the present invention. As long as it does, you may add another substance suitably. Examples of such substances include pharmaceutical carriers, additives, pharmacologically active ingredients, and the like. As pharmaceutical carriers, conventional excipients and additives include colorants, buffers, isotonic agents, preservatives, stabilizers, pH adjusters, emulsifiers, solubilizers, suspending agents, dispersions Examples of agents, bases, thickeners, sweeteners, flavoring agents, fragrances, refreshing agents, etc. that are usually used in medicine.

For example, examples of the buffer include phosphate buffer, Tris buffer, and acetate buffer.
Examples of the pH adjuster include hydrochloric acid, sodium hydroxide, sodium monohydrogen phosphate, sodium dihydrogen phosphate and the like.

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

  Stabilizers include tartaric acid, succinic acid, acetic acid, glutamic acid, glycine, malic acid, lactic acid, citric acid or their salts (sodium salt, potassium salt, calcium salt, lithium salt, ammonium salt, etc.), iodine-containing reduction Agents (metal iodides such as potassium iodide and sodium iodide), sulfur-containing reducing agents (metal thiosulfates such as potassium thiosulfate and sodium thiosulfate, potassium thiocyanate, and sodium thiocyanate) Metal thiocyanate, thioketones such as thiourea, thiosemicarbazide and thiopental, and sulfides such as L-methionine).

Examples of the preservative include paraoxybenzoic acid ester (paraben), potassium sorbate, sodium benzoate, chlorhexidine gluconate and the like.
Examples of sweeteners include aspartame, amateur, licorice, D-sorbitol, D-mannitol, saccharin and the like.

Examples of the corrigent include xylitol, ascorbic acid, erythritol, copper chlorophyllin sodium, green tea powder, kumazasa extract, orange oil, lemon oil, rose oil and the like.
Examples of the flavor include peppermint oil, spearmint oil, thymol, hinokitiol, lavender oil and the like.

Examples of the refreshing agent include 1-menthol, camphor, mint oil and the like.
As pharmacologically active ingredients, glycosaminoglycans such as chondroitin sulfate, dermatan sulfate, heparan sulfate, heparin, keratan sulfate, etc. Jihuangmaru, semi-summer Koboku-yu, Shion-yu, Sho-saiko-to, Juzen-dai-yu, dry-boiled, ginger, half-summer, mother-in-law, mochi, Tenmon-winter, gomiko, kudzu, carrot, purple root, etc.), known anti Inflammatory agents, analgesics, vitamin agents, antibacterial agents, growth factors, adhesion factors, antibacterial agents and the like can be mentioned.

  The artificial saliva of the present invention is particularly applied to patients with xerostomia (including hyposalivation; the same applies in this specification), and when administered to such patients, the non-drying sensation in the oral cavity is sustained. It is improved, that is, the effect of preventing dryness in the oral cavity can be maintained for a long time.

  Xerostomia is a symptom of abnormal dryness in the oral cavity due to a decrease in salivary secretion or the like. There are various causes, and temporary xerostomia may occur due to rapid dehydration, high fever, bleeding, stress, etc., and persistent xerostomia is senile atrophy of salivary glands, face and neck Irradiation, Sjogren's syndrome, Mikulicz disease, salivary gland diseases such as chronic salivary glanditis, diabetes insipidus, diabetes, chronic renal failure, thyroid dysfunction, vitamin B group deficiency, anemia, drugs (eg antihypertensives, diuresis) Drugs, psychotropic drugs, neuroleptics, anticancer drugs, etc.). Xerostomia to which the artificial saliva of the present invention is applied is not particularly limited depending on these causes, but senile atrophy of salivary glands, irradiation of the face and neck and head, xerostomia associated with Sjogren's syndrome, or drug administration It is preferable to be applied to xerostomia associated with. The drug is not particularly limited as long as it is a drug causing xerostomia, such as an antihypertensive, a diuretic, a psychotropic drug (eg, tranquilizer, antipsychotic, anxiolytic, antidepressant, etc.), Neuroleptics or anticancer agents are particularly preferred.

  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 the patient. It is preferably used as a liquid agent, but is not limited thereto, and can be administered in solid dosage forms such as powders, granules, candy, gummi, jelly, lozenges and the like. Alternatively, it may be provided in the form of a solid agent (eg, powder, granule, etc.), and water or the like may be added at the time of use to form a liquid agent.

  Moreover, it may be used as an ointment (cream) or a patch, and may be in the form of a toothpaste or chewing gum. That is, the artificial saliva of the present invention may be provided not only as a pure drug, but also as a quasi-drug, cosmetic, food, medical device or the like.

  For example, when the artificial saliva of the present invention is provided as a quasi-drug or cosmetic, the composition can be as follows and is preferred.

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

  In addition, 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 it is preferable.

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

(b) Sodium hyaluronate, Ogon extract, potassium sorbate, sodium benzoate, sodium monohydrogen phosphate, sodium dihydrogen phosphate, purified water

  In the case of a liquid preparation, it can be applied as a spray, a mouthwash (including an oral cleaning agent (mouth wash), oral rinse, liquid dentifrice, etc. The same applies hereinafter), a preparation for intraoral application, and the like. it can. When the artificial saliva of the present invention is used as a spray agent, the artificial saliva of the present invention is filled in a spray container. The spray container may be a simple spray container from which artificial saliva is discharged every 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 that shows acidity in a dissolved state is preferable because it has an effect of stably holding HA. As such a gas, carbon dioxide is exemplified and preferable.

  When the artificial saliva of the present invention is used as a gargle, 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 a necessary amount may be collected at the time of use, but a single-use unit bottle is preferable because it is convenient and easy to use.

  Further, when the artificial saliva of the present invention is used as a preparation for intraoral application, for example, the artificial saliva filled in the same container or bottle as the above-mentioned spray or gargle can be used for clean absorbent cotton, gauze, sponge. It can be used by adhering it to a nonwoven fabric or the like and applying it to the oral cavity. In addition, absorbent cotton, gauze, sponge, non-woven fabric, etc., to which the artificial saliva of the present invention is previously attached may be enclosed in a sealable container or packaging, and provided as a preparation for intraoral application. Moreover, you may make it easy to use by giving a pattern to absorbent cotton.

  In the present specification, “improving the persistence of the non-drying sensation in the oral cavity” means that the present invention is compared with the case where the artificial saliva is not applied or the case where water or a conventionally known artificial saliva is used. By applying the artificial saliva, it means that the period during which the non-drying or moist feeling in the oral cavity is maintained is extended. The artificial saliva of the present invention is characterized in that a long duration of non-drying feeling can be obtained, and the time is about 1 to 6 hours although it varies depending on patients and symptoms.

  In addition, when a patient's symptom is very severe, the sustained effect of a long-time non-drying feeling may not be seen at the beginning of application. However, when applied continuously for several days, it was confirmed by the examples described later that the feeling of non-drying lasts for a long time.

  The artificial saliva of the present invention also has an effect of protecting the 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 the maintenance of a non-dry feeling in the oral cavity of xerostomia patients, but generally, non-oral A feeling of dryness can be maintained for a long time. Therefore, the present invention also provides a non-dryness-sustaining agent in the oral cavity 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 below. Causes of intraoral pain include those associated with dry mouth (for example, glossodynia and oral mucosal pain) and those associated with oral ulcers (such as aphthous stomatitis). Regardless, pain relief can be obtained by applying the artificial saliva of the present invention. 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 also has an improving action (healing promoting action) for oral mucosal disorders, for example, oral ulcers (aphthous stomatitis etc.) as shown in Examples below. Therefore, the present invention also provides an oral mucosal disorder ameliorating agent (oral mucosal disorder healing promoter, oral mucosal disorder therapeutic agent) comprising HA or a pharmaceutically acceptable salt thereof. Among oral mucosal disorders, it is preferably used as an agent for improving oral ulcers.

In this case, when the solution is used, 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 action and effect of facilitating the wearing of a denture of a patient with xerostomia and improving the unpleasantness and discomfort at the time of continuous wearing of the denture, as shown in Examples below. Have. Accordingly, the present invention provides a denture wearing aid for application to xerostomia patients comprising HA or a pharmaceutically acceptable salt thereof. Such adjuvants ease the wearing of dentures by reducing the pain and discomfort when wearing dentures in patients with xerostomia, and further improve the discomfort and discomfort during continuous wearing of dentures. It has the effect of increasing compatibility. Therefore, it is preferable to apply this adjuvant for such purposes. In this case, when the solution is used, 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 the action and effect of improving the drying of the nasal cavity by being administered to the nasal cavity as shown in the examples described later. Therefore, 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 the improved persistence of non-dryness in the oral cavity as described above, it can be applied to prevent (improve) various symptoms and conditions caused by dry mouth. it can. Symptoms and conditions associated with xerostomia include, for example, excessive intake of water, nocturnal enuresis associated with excessive intake of water, diarrhea associated with excessive intake of water, taste disorders associated with dry mouth, dysphagia, hardening of the tongue, burning sensation , Eating disorders, frequent tooth decay, severe gingivitis, oral infections (candidiasis, etc.), symptomatic leukoplakia, pronunciation disorders, trauma, frequent after and stomatitis, occurrence of ulcerative ulcers, Examples include pneumonia induction (onset of aspiration pneumonia) due to residual gram-negative bacilli and oral discomfort, and can be administered as a therapeutic and / or prophylactic agent for these symptoms. Therefore, the present invention also provides an agent for treating and / or preventing various symptoms caused by xerostomia comprising HA or a pharmaceutically acceptable salt thereof. The agent for treating and / or preventing various symptoms caused by xerostomia of the present invention is preferably applied particularly for preventing excessive intake of water, preventing nocturnal enuresis or preventing hardening of the tongue.

  In addition, prevention of oral mucosal disorder, improvement of dysphagia (symptoms such as difficulty swallowing), improvement of mastication disorders (symptoms such as poor chewing and difficulty in biting), taste disorders (no taste, no understanding, no deep taste) It is also preferred to be applied to improve symptoms such as not knowing), to improve pronunciation problems (because the mouth does not turn well, so it is difficult to talk), to improve discomfort in the oral cavity.

  The dosage of the artificial saliva and each drug of the present invention is a matter to be determined individually according to the dosage form, administration method, administration purpose, specific symptoms of patient, body weight, age, etc., and is not particularly limited. However, the dose of HA is about 10 mg to 1000 mg per day.

  Moreover, the administration interval of the said formulation may be every other day or every day, and is not specifically limited. Administration can be performed once a day, or can be divided into 2 to 20 times a day.

The artificial saliva of the present invention can be widely applied not only to humans but also to mammals, but is particularly preferably used for humans.
Note that HA or a pharmaceutically acceptable salt thereof has already been used in pharmaceutical products (for example, joint function improving agents and ophthalmic surgery aids), cosmetics, foods, and the like, and its safety has been confirmed. Also, high safety was confirmed by the examples described later.

Examples of the present invention will be specifically described below 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 16.0 dl / g.

[Formulation example]
(1) Simple spray 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). Filled mold spray container.

(2) Simple spray 2
Dissolve sodium hyaluronate in 3% (w / v) xylitol aqueous solution to a concentration of 0.2% (w / v) or 0.4% (w / v), and fill each 50ml simple spray container did.

(3) Simple spray 3
Sodium hyaluronate is dissolved in a phosphate buffer solution with the following composition to a concentration of 0.2% (w / v) or 0.4% (w / v), and each is filled into a 50 ml simple spray container. did.

Sodium chloride 0.9% (w / v)
Sodium dihydrogen phosphate 0.1 mM

Disodium hydrogen phosphate 1.5 mM
(4) Gargle 1
Sodium hyaluronate was dissolved in distilled water for injection to a concentration of 0.2% (w / v) and filled into unit bottles.

(5) Gargle 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) Gargle 3
Sodium hyaluronate and sodium chondroitin sulfate were dissolved in distilled water for injection so as to have a concentration of 0.2% (w / v), respectively, and filled into unit bottles.

(7) Gummy Candy 1
Dissolve sodium hyaluronate in 0.5% (w / v), gelatin in 10% (w / v), and sorbitol in 10% (w / v) in distilled water for injection and warm. Then, 2 g each was dispensed into a mold and cooled to produce a gummy candy.

(8) Gummy Candy 2
Dissolve sodium hyaluronate in 0.5% (w / v), gelatin in 10% (w / v) and xylitol in 5% (w / v) in distilled water for injection and warm. Then, 2 g each was dispensed into a mold and cooled to produce a gummy candy.

(9) Jelly type preparation Distillation for injection so that sodium hyaluronate concentration is 0.5% (w / v), gelatin concentration is 3% (w / v), and xylitol concentration is 5% (w / v). Dissolved in water and heated, dispensed 2 g into a mold and cooled to produce a jelly type preparation.

(10) Lozenges Sodium hyaluronate 10 mg, refined white sugar 1600 mg, hydroxypropylcellulose 20 mg, flavoring and coloring agents are added in a small amount, and lactose is added to finally adjust to 2000 mg. Manufactured.

(11) Spray agent Sodium hyaluronate is dissolved in a solution having the following composition so as to have a concentration of 0.1% (w / v). Manufactured.

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 agent for application Sodium hyaluronate is added to distilled water for injection to a concentration of 0.02% (w / v), 0.05% (w / v) or 0.1% (w / v). Each was dissolved and filled into bottles. Administration can be performed by immersing a sponge with a handle in this solution and then applying it to the oral cavity.

[Test example]
(1) Pharmacological test 1
Using the formulation prepared in Formulation Example (1) (simple spray 1 (sodium hyaluronate concentration 0.2%)), 1 to 2 strokes (1 stroke) in the oral cavity of the following 4 xerostomia patients About 120-130 μL). The results are shown in Table 1.

  As comparative examples, “water”, “commercial artificial saliva (Salibate (registered trademark); manufactured by Teijin Limited; containing carboxymethyl cellulose)”, “Bakumon Fuyuto”, and “Shiratora Kajinjinto” are used. The same test was conducted.

As a result, both “water” and “commercial artificial saliva” showed a feeling of dryness and disappearance of pain immediately after administration, but the effects were instantaneous, and the persistence of the effect as in the above preparation was not observed. I couldn't.
In addition, “Bakumon Fuyuto” and “Shiratorakajinjinto” took time to develop the effect, and no effect was observed immediately after administration as in the above preparation.

  From these results, it was revealed that the artificial saliva of the present invention disappears and relieves dryness and pain in a very short time when applied to a patient with xerostomia, and the effect lasts for a long time. The artificial saliva of the present invention was also found to have an effect on pain due to oral ulcers.

(2) Pharmacological test 2
Twelve patients with xerostomia were administered in the same manner as in Pharmacological Test 1, and the duration of non-drying in the oral cavity, changes in symptoms, etc. were observed. For patients with a history of using salivates, we compared the feeling of use with that of salivates. The results are shown in Table 2.

  In Table 2, the degree of dryness represents the dryness in the oral cavity before administration of the preparation. 4: There is a very strong dry feeling. 3: There is a dry feeling. 2: There is a little dry feeling. None, 0: represents a state where there is no dry feeling. Viscosity represents an evaluation of the viscosity (stickiness) in the oral cavity by the preparation after administration of the preparation, 4: there is a strong stickiness, 3: there is a sticky feeling, 2: there is a little sticky feeling, 1: normal stickiness as an oral cavity It is sexual feeling, 0: it represents a state without any feeling of viscosity. The effect represents an evaluation of the patient's feeling of use. 4: It is desired to use it. 3: It is desired to use it. 2: It may be used. 1: It is not necessary to use it. 0: It is not used. For duration and other effects, the duration of non-dryness in the oral cavity after administration, and changes in other symptoms were shown. All of these evaluations are the patient's own subjective symptoms and evaluations.

In the remarks, the disease, condition and drug being administered to the patient are shown.
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 1 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, after and the like was generally observed. All patients wished to use the artificial saliva of the present invention and evaluated that the feeling of use was much better than commercially available artificial saliva containing carboxymethylcellulose.

(3) Pharmacological test 3
Independently from the pharmacological test 2, 16 patients with xerostomia were administered in the same manner as in the pharmacological test 2 and evaluated in the same manner. The results are shown in Table 3.

  As can be seen from the results shown in Table 3, the same good results as in the pharmacological test 2 were obtained. This suggests that the artificial saliva of the present invention is widely useful for xerostomia patients. It was also found that the artificial saliva of the present invention is effective in improving masticatory disorders.

  It has also been shown that administration of the artificial saliva of the present invention to the nasal cavity improves nasal dryness.

(4) Pharmacological test 4
5 mL in the oral cavity of 7 xerostomia patients (both psychiatric patients and xerostomia caused by administration of drugs) using the formulation (gargle 1) prepared in Formulation Example (4) Were administered using a cup of. Since subjective symptoms are difficult to evaluate, evaluation was performed only by the doctor's objective findings. As a result, good results were obtained.

Of these patients, a more detailed observation was made of the administration to a 53 year old male.
This patient was a schizophrenic patient and his tongue was cured by dry mouth. The patient also had night urine almost every night, probably because he drank much juice due to dry mouth.

When this patient was administered about 5 mL at a fixed interval (about every 3 hours) three times, the cured state of the tongue was clearly improved, and the non-dry state was observed until the next day. During this time, the patient's water intake decreased and night urine improved.
From these results, it was shown that the artificial saliva of the present invention is also effective for xerostomia patients caused by drug administration, and the effect can last about half a day.

  Further, it has been clarified that the artificial saliva of the present invention has an improving effect on the hardening of the tongue, further prevents excessive intake of water, and can be used to prevent nocturnal enuresis.

(5) Medicinal pharmacology test 5
Using the preparation (preparation for application) prepared in Preparation Example (12), administration was carried out by applying a sponge with a handle to the oral cavity of four xerostomia patients shown in Table 4. The results are shown in Table 4. In addition, the daily state before administration, dryness, food residue, adhesion of tongue coating, presence or absence of bad breath, and the amount of saliva are also shown. Except for the amount of saliva, it was evaluated by dentist observation. The amount of saliva was determined by inserting a roll watte (dental cylindrical absorbent cotton) into the oral cavity at rest, allowing it to stand for 1 minute, and measuring the amount of saliva soaked in 0.5 g units.

In Table 4, the meanings of symbols indicating the patient's condition and the like before administration are as follows.
* Daily state ○: There is no subjective dry mouth feeling, but objective dry mouth symptoms are observed.
1: Mild dryness (no problem in daily life)
2: Moderate dryness (has difficulty in chewing and swallowing, and requires water for food intake)
3: Severe dry feeling (drinking and awakening during the night, a large amount of water is required during meals, and dentures are difficult to wear.)

* Dryness-: Wet, ±: Dry, +: Whole * Food residue-: None, +: Existence

* Adherence of tongue coating-: No, +: Partially present, ++: 2/3 or higher * Existence of bad breath-: No, +: Somewhat present, ++: Present

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

(6) Pharmacological test 6
In order to more objectively and quantitatively evaluate the effectiveness of the artificial saliva of the present invention, particularly the oral mucosa moisturizing effect and the non-drying effect, using hamster (Syrian: SPF; 13 weeks old), The experiment was conducted.

(6-1) Preparation of dry mouth (dry mouth model) using a dryer Under anesthesia with Nembutal (Dainippon Pharmaceutical Co., Ltd.), a test tube having a diameter of about 10 mm was inserted from the buccal side and the oral cavity was turned over and exposed. Hot air was applied to the oral cavity exposed with a dryer for about 20 seconds, and then cold air was applied for 2 minutes and 40 seconds. Thereafter, the oral cavity was left exposed until the measurement was completed.

(6-2) Test substance
(i) 0.2%
Sodium hyaluronate (simple spray 1)
(ii) Distilled water (control)

(6-3) Administration of test substance Immediately after preparation of the dry mouth model, 100 μL of the test substance was applied to the oral cavity of the model (7 per group) using a microsyringe.

(6-4) Measurement of moisture transpiration and statistical treatment The amount of moisture transpiration in the exposed oral cavity of the hamster was measured with a moisture transpiration system (moisture transpiration monitor AS-TW2, manufactured by Asahi Biomed). The measurement was performed immediately after preparation of the dry mouth model, immediately after administration of the test substance, and at 10 and 20 minutes after administration. Moreover, the measurement result was calculated | required as a relative value when the average value of the water | moisture-content transpiration immediately after preparation of a mouth dry model was set to 1.
The results are shown in FIG.

  As shown in FIG. 1, in the group administered with distilled water (control group), although the amount of water transpiration increased immediately after application, it decreased to the same extent as before administration 10 minutes after administration. In contrast, in the group administered with 0.2% sodium hyaluronate, the amount of water transpiration was maintained at about ½ immediately after administration even 10 minutes after administration. From these results, it was shown that 0.2% sodium hyaluronate has a moisturizing effect on the oral mucosa and maintains the non-dry state in the oral cavity.

(7) Pharmacological test 7
In order to objectively and quantitatively evaluate the effectiveness of the artificial saliva of the present invention, especially the improvement (healing promotion) effect of oral mucosal damage, using hamster (Syrian system; SPF; 13 weeks old; male), the following The experiment was conducted.

(7-1) Preparation of Oral Mucosal Disorder (Acetic Acid-Induced Oral Mucosal Disorder Model) After anesthetizing a hamster using a mixed solution of ketamine and xylazine, apply a test tube from the outside of the hamster's right cheek bag and invert the cheek bag Then, the oral mucosa surface was exposed, and the mucosa surface was washed with a physiological saline solution. After removing excess physiological saline solution, circular filter paper (1 cm in diameter) was placed on the exposed mucosal surface. A 30% acetic acid solution was dropped onto the filter paper and left for 10 minutes to cause mucosal surface damage. At this time, an additional acetic acid solution was appropriately added dropwise so that the surface of the filter paper was always filled with sufficient acetic acid solution. After standing for 10 minutes, the filter paper was removed and washed thoroughly with physiological saline solution.

(7-2) Test Substances The following (i) to (iii) used the simple spray 1 prepared in Formulation Example (1).
(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 onset of injury. The test substances (i) and (ii) were administered to 10 models, 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, the hamster cheek pouch was inverted to expose the damaged site in the same manner as in the model preparation, and 150 μl of the test substance was administered to the damaged site using a microsyringe. 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 damaged site In order to objectively and quantitatively evaluate the degree of healing of the oral mucosal disorder, the area of the damaged site was measured, and the degree of reduction was determined for Rated as a degree. The area of the lesion site was measured on the day after the last administration (4 days after the induction).

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

In each group, the relative value of the damaged area was determined by setting the average value of the damaged area on the next day after the occurrence of the disorder as 100%. The results (mean value ± SD) were as follows.
Control group 46 ± 16%
0.2% administration group 38 ± 10%
0.4% administration group 34 ± 8%
0.6% administration group 38 ± 9%

  From these results, the oral mucosa damaged area decreased in the group administered with any concentration of sodium hyaluronate compared to the control group. From this, it was shown that sodium hyaluronate has an action to improve oral mucosal damage, particularly an action to promote healing of oral mucosal damage.

In addition, as a result of statistical analysis by Dunnett's multiple comparison test (non-parametric), the reduction of the oral mucosal lesion area in the 0.4% administration group was significant (p <0.05) compared to the control group.
In addition, as a result of the above-described pharmacological tests 1 to 7, no side effects due to the administration of the preparation were observed, indicating that the safety was extremely high.

  The additive of the present invention is useful as an additive for the artificial saliva of the present invention. The artificial saliva of the present invention is extremely useful because it eliminates and relieves the dryness and pain in the oral cavity in a patient with xerostomia in a very short time, and the effect lasts for a long time and is highly safe.

  The artificial saliva of the present invention prevents and improves various symptoms and conditions resulting from xerostomia, such as excessive intake of water, nocturnal enuresis associated with excessive intake of water, taste disorders, and eating disorders. For example, when xerostomia occurs in the elderly, eating disorders may occur, and eventually there is a need to rely on tube feeding or infusion. If you can't eat, your willingness to live is quickly lost, often resulting in intellectual disability and bedriddenness. If it becomes possible to eat independently by improving the dry feeling in the oral cavity and sustaining the non-dry feeling, the improvement effect on the medical care for the elderly will be great, and it will be very useful from the viewpoint of suppressing medical expenses for the elderly.

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, prevention and improvement of oral infections and dental caries, and is considered to contribute greatly to the oral hygiene of the people.
Furthermore, the oral non-drying sensation agent, oral mucosal disorder improving agent, oral pain relieving agent, denture wearing aid, and nasal dryness improving agent provided by the present invention are also extremely safe and easy to administer. It is extremely useful.

It is a figure which shows the result of having measured the oral mucosa moisturizing effect by the artificial saliva of this invention.

Claims (4)

  A dysphagia-improving agent comprising a solution containing 0.1 to 0.4% (w / v) hyaluronic acid having a weight average molecular weight of 900,000 or a pharmaceutically acceptable salt thereof.   The improving agent according to claim 1, comprising a solution containing 0.2% (w / v) of hyaluronic acid having a weight average molecular weight of 900,000 or a pharmaceutically acceptable salt thereof. Characterized in that it is packed in a spray container or bottle, improving agent according to claim 1 or 2. The improving agent according to claim 3 , wherein the pressure vessel is filled together with carbon dioxide gas.

Images