JP2002255852A - Spray preparation for stomatitis - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a spray preparation for stomatitis considerably excellent in stomatitis prophylactic/therapeutic effect compared to gargle and highly useful from a medical standpoint because of solving the problems involved in conventional gargles including wasteful use, instability, poor hygiene, inconvenience, etc., namely that conventionally, a gargle has been much consumed in a day during therapy, therefore each time it is consumed, a new batch of the gargle had to be prepared for a long time, thus being highly cumbersome. SOLUTION: This spray preparation for stomatitis is obtained by packing a spray vessel with a liquid composition comprising (A) a radical scavenger, (B) a thickening agent, (C) a dispersant and (D) a solubilizing agent for the component A.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a stomatitis spray, and more particularly to the prevention and / or prevention of stomatitis which frequently occurs with chemotherapy and radiotherapy as a treatment for cancer.
Or a spray for stomatitis useful for treatment.

[0002]

2. Description of the Related Art It is well known that oral mucosal disorders such as stomatitis are caused by administration of anticancer drugs or radiotherapy as a treatment for cancer. The hallmark of the disorder is that it causes ulceration and the associated intense pain. As a result, the quality of life (QOL) of the patient is sometimes reduced because the patient sometimes has difficulty in eating due to mastication disorders and dysphagia.
Can be extremely exacerbated, while making oral administration of the drug difficult in pharmacotherapy for the treatment of cancer, leading to reduced compliance. First, the occurrence of oral mucosal disorders such as stomatitis is thought to cause primary stomatitis because mucosal tissue is destroyed by free radicals generated by the administration of anticancer drugs and radiation irradiation, and subsequent inflammation is induced (Semi Oncol., 19, 478, 19
1992). The mechanism of secondary stomatitis that subsequently develops is that the administration of anticancer drugs reduces white blood cell count and saliva volume,
Alternatively, it is thought that the physiological turnover that inhibits the growth of microorganisms on the mucosal surface is inhibited, and as a result, the oral cavity becomes easily infected (NCI Monoger., Vol. 9, 61). Pp. 1990).

[0003] Conventional treatment methods for the above stomatitis disorders, especially aphthous stomatitis, include azulene ointment, dexamethasone steroid ointment, orally inserted tablets (Oto-Clinic, 74, 1915, 1981) and bilayers. Tablet patch (Basic and Clinical, 16, 4599, 1982)
), But stomatitis induced by anticancer drugs or radiation therapy usually spreads not only on mucous membranes but also on the gingiva etc.
The use of the above drugs could not always give a satisfactory therapeutic effect. Therefore, cooling the affected area and protecting the mucous membrane by including an ice ball of an aqueous solution of sodium alginate in the oral cavity should be performed.
The 120th Annual Meeting Abstracts, 31 [PE] 12-12), and gargles with oral rinses containing a fungicide for povidone-iodine tend to be widely used.

In recent years, as a method for preventing or treating the stomatitis, a method using allopurinol, which is conventionally known as a gout remedy, as a gargle has been proposed (Canc).
er, 65, 1879-1882, 1990, Cancer and Chemotherapy, 16, 3449-3451, 1990.
Allopurinol, carboxymethylcellulose (CMC) or a water-soluble salt thereof and an allopurinol suspending agent comprising water (JP-A-3-106817) and a suspension prepared by mixing allopurinol in water in the presence of sodium polyacrylate. Attempts have been made to use the solution as a mouthwash. In addition, as an alternative to allopurinol, gargle of the proteolytic enzyme inhibitor camostat mesylate (Abstract Collection of the 120th Annual Meeting of the Pharmaceutical Society of Japan, 31 [PE] 12-03) Attempts have been made to use still gargle (Nikkaichiyaku Jyaku, Vol. 34, pp. 39-42, 1998).

[0005]

However, among the cancer therapies by chemotherapy and radiotherapy, the above-mentioned gargle solution has not been satisfactory in its preventive effect.
In addition, chemotherapy, in the cancer therapy by radiation therapy, when gargle with the above-mentioned mouthwash, especially in the mouthwash suspended in sodium carboxymethylcellulose, may cause nausea due to unpleasant taste and the like Therefore, it was necessary to examine and examine the taste.

[0006] Since the treatment period of chemotherapy and radiation therapy is generally performed at intervals of 2 to 4 weeks (1 course), the above-mentioned gargle is used 3 to 5 times a day at the same time as the start of treatment. Since gargle is performed daily using 30 to 50 mL of gargle at a time, the gargle is used for about 1.5 to 5.
A large amount of 0 L had to be prepared, and a lot of time and labor was spent during preparation. In addition, since a large amount is prepared at one time and left for a long period of time, practical problems such as precipitation, segregation, and separation of a medicinal ingredient and a dispersant have occurred. Moreover, in the case of a mouthwash, 30 to 50 mL is consumed in the mouth at a time, and after gargle, an excess liquid medicine is to be thrown away, which is wasteful economically.

[0007] On the other hand, the gargle prepared about 1.5 to 5.0 L at a time for the treatment of cancer such as chemotherapy or radiation therapy is stored and stored in a polyethylene container or the like as it is. It is necessary to hold at least three or more polyethylene containers of the gargle for one treatment, and for the patient, the act of gargle in the treatment induces nausea and gargle. Each time the operator has to move to a predetermined place where a facility such as a washroom is located, it is cumbersome and burdensome. Thus, the mental and physical burdens associated with the treatment have been further increased.

Further, since 30 to 50 mL of the medicinal solution is subdivided 3 to 5 times a day from the container containing the gargle, the gargle adhering to the mouth of the container after subdividing is wiped off. There is also concern about the effects on the stability and hygiene of the medicinal component due to the attachment of dirt and the like.

Therefore, an object of the present invention is to provide a highly effective preventive and / or therapeutic treatment for stomatitis, a long-term storage stability,
Another object of the present invention is to provide a preventive / treatment agent for stomatitis, which has good hygiene and feeling of taking, and can be taken for a long time.

[0010]

Therefore, the present inventor has used a radical scavenger as a medicinal ingredient, filled a liquid composition obtained by combining a thickener, a dispersant and a dissolving agent into a spray container, and filled the composition with a radical scavenger. If it is a spray, a sufficient amount of medicinal ingredients can be attached to the oral mucosa,
Further, they have found that a preparation having no unpleasant taste and excellent in stability and usability of a medicinal ingredient can be obtained, thereby completing the present invention.

That is, the present invention provides (A) a radical scavenger, (B) a thickener, (C) a dispersant, and (D)
An object of the present invention is to provide a spray for stomatitis obtained by filling a liquid composition containing the dissolving agent of the component (A) into a spray container.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION The medicinal ingredient (A) used in the present invention is not particularly limited as long as it acts as a radical scavenger.
A component selected from a peptic ulcer therapeutic agent and a protease inhibitor is preferred. Here, as the therapeutic agent for peptic ulcer, rebamipide and / or enprostil are preferable. As the protease inhibitor, camostat mesylate and / or gabexate mesylate are preferred. These radical scavengers may be used alone or in combination of two or more. It is desirable that the radical scavenger is contained in the liquid composition of the spray of the present invention in accordance with the optimal dose of each component.

In the present invention, in addition to the above-mentioned medicinal components, various medicinal components can be blended, for example, (E) an anti-inflammatory analgesic, a local anesthetic and / or a mucosal repair agent can be blended. Examples of the anti-inflammatory analgesic include non-steroidal anti-inflammatory drugs such as aspirin, salicylic acid, mefenamic acid, diclofenac sodium, ibuprofen, and among them, aspirin and / or salicylic acid are preferable. Local anesthetics include dibucaine, procaine, lidocaine and salts thereof. As mucosal repair agents, fibrinolytic enzyme agents such as fibrinolidine deoxyribonuclease, streptokinase streptodornase and / or
Or sodium azulene sulfonate. These components can also be used alone or in combination of two or more, and it is desirable to include them in the liquid composition according to the optimal dose of each component.

As the thickener (B) used in the present invention, thickening polysaccharides and / or gelatins having gelling ability are considered from the viewpoint of improving the efficiency of adhering a sufficient amount of a medicinal ingredient to the oral mucosa. Preferably, especially for thickening polysaccharides,
One or more selected from kappa-type carrageenan, iota-type carrageenan, lambda-type carrageenan, pectin, locust bean gum, guar gum, tamarind gum, xanthan gum, juran gum, tara gum and gum arabic are preferred. Gelatin has a molecular weight of 200
~ 20,000 purified gelatin, especially 3000-4
000 purified gelatin is preferred. The content of these (B) thickeners in the liquid composition is to ensure a suitable viscosity, to obtain good adhesion to mucosal tissues, and to prevent gel formation and a decrease in jettability due to gelation. From the viewpoint of
-1.0% by weight, particularly preferably 0.3-0.5% by weight.

As the dispersant (C) used in the present invention, a dispersant containing no water-soluble salt such as a sodium salt, for example, poly (ethylene oxide), particularly an average molecular weight of 100,000, is preferred from the viewpoint of an effect of improving unpleasant taste. ~ 5,000,000 poly (ethylene oxide) is preferred. The content of the dispersant (C) in the liquid composition is from 0.25 to 3.0% by weight from the viewpoint of preventing a decrease in fluidity and dispersibility and preventing a decrease in compliance with a patient due to deterioration of taste. %, Especially 1.
0 to 2.0% by weight is preferred.

In the present invention, (B) a thickener and (C)
The content ratio by weight of the dispersant [(B) :( C)] is from 4: 5 to
1: 3, especially 2: 5, is preferred. In addition, the contents of (B) the thickener and (C) the dispersant together are 0 from the viewpoints of ensuring the adherence of the medicinal component to the oral mucosal tissue and preventing a decrease in jettability due to an increase in viscosity. It is preferably from 0.4 to 4.0% by weight, particularly preferably from 1.3 to 2.5% by weight.

Examples of the solubilizing agent (D) used in the present invention include water and polyhydric alcohols such as glycerin and polyethylene glycol, and water, glycerin and polyethylene glycol (average molecular weight: 200 to 600) are particularly preferable. The content of glycerin and polyethylene glycol varies depending on the type and concentration of the medicinal component, the type of solubilizer used in combination, the combination, etc., but usually, for example, 0 to 300 parts of glycerin per 1 part by mass of the medicinal component, Polyethylene glycol is 0 to 200 parts.

In the present invention, a compound such as a cyclodextrin may be added as a solubilizing agent to improve the solubility of the medicinal component and prevent precipitation of the medicinal component by crystallization. In addition, parabens can be used as a preservative of the chemical solution used in the present invention.

The spray agent of the present invention is obtained by filling a liquid composition containing the above components into a spray container. Here, the spray container is not particularly limited as long as it has a structure capable of spraying a chemical solution in a mist state. The diameters of the valves and buttons constituting the spray container and the combinations thereof can be freely used as long as they are generally used, and are not particularly limited. 0.3 to 10.0 mm, the button nozzle hole is 0.3 to 15.0 mm, and a straight and / or mechanical break-up type is preferable. If a nozzle with a straight nozzle hole is used here, the drug solution is sprayed directly and can be locally administered in the oral cavity.On the other hand, if a mechanical breakup is used, the drug solution is sprayed in a wide-angle shape. Can be widely administered throughout the oral cavity. These types may be switched.

The stomatitis spray of the present invention is applied to a patient with stomatitis due to various causes, for example, a patient undergoing cancer treatment, once an appropriate amount (for example, spraying 1 to 5 times) once a day.
It may be administered several times, for example, three to six times. Preferably, the administration is sprayed into the oral cavity by the patient himself.

In a preferred embodiment of the spray of the present invention, a composition comprising a thickener, a dispersant and water thereof is selected from allopurinol, rebamipide, enprostil, camostat mesylate and gabexate mesylate as radical scavengers. Sprays filled with a medicinal solution prepared by mixing at least one or more medicinal ingredients and filling the prepared medicinal solution may be mentioned. As a result of using the spray for more than 30 cases of cancer patients, good prevention and treatment effects for the onset of stomatitis have been obtained in cancer therapy such as chemotherapy and radiation therapy.

In another preferred embodiment of the spray of the present invention, allopurinol as a radical scavenger may be added to a composition comprising a thickener, a dispersant and water.
In addition to one or more active ingredients selected from rebamipide, enprostil, camostat mesylate and gabexate mesylate, aspirin and / or salicylic acid as an anti-inflammatory analgesic, dibucaine, procaine, lidocaine and salts thereof as a local anesthetic Or a mixture filled with a component containing at least one selected from fibrinolysin deoxyribonuclease, streptokinase, streptodornase and sodium azulene sulfonate as a mucosal repair agent, and a spray filled with a medicinal solution prepared in combination Agents. The spray is used for cancer patients 7
As a result of using it for 0 or more cases, favorable preventive and therapeutic effects on the onset of stomatitis have been obtained in cancer therapies such as chemotherapy and radiation therapy.

As a further preferred embodiment of the spray of the present invention, allopurinol and rebamipide as radical scavengers are added to an aqueous composition containing a total of 0.45 to 4.0% by weight of a thickening polysaccharide and poly (ethylene oxide). , Enprostil, camostat mesylate and / or gabexate mesylate, aspirin and / or salicylic acid as an anti-inflammatory analgesic, dibucaine as a local anesthetic, procaine, lidocaine and salts thereof, or fibrinolidine as a mucosal repair agent. A spray is prepared by filling a spray container with 40 to 200 mL of a drug solution containing at least one or more selected from deoxyribonuclease, streptokinase / streptodornase and sodium azulene sulfonate in a weight% set according to the respective active ingredients. It is below.

The spray for stomatitis according to the present invention comprises an over- or under-definable medicinal component capable of exerting a preventive and / or therapeutic effect on stomatitis by filling the spray solution with the drug solution designed and designed as described above. Because it can be administered to the whole oral cavity without, it is possible to avoid waste such as a drug solution that is thrown away by gargling, and it is not necessary to use the polyethylene solution containing the drug solution in small portions as necessary, as in the past, and There is no problem such as contamination due to the subdivision, and the spray button can be easily used simply by pressing the finger with the finger. For example, gargle during treatment, and can be sprayed on the bed without moving to the washroom, thereby reducing the burden on the patient. Further, since the liquid medicine is ensured in an airtight and airtight state, the stability of not only the liquid medicine but also the medicinal component can be improved. In addition, the use of a spray makes it possible to spray the entire oral cavity with a small amount of a drug solution.
/ 10 to 1/20, and labor saving and labor saving in the preparation can be achieved. At the same time, the induction of nausea, which has been recognized by gargle, can be effectively suppressed.

[0025]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the present invention is limited thereto.

Example 1 500 mg of allopurinol and 2.0 g of iota-type carrageenan (trade name Inagel F-13) were placed in a sterilized mortar, mixed, and heated at 40 to 50 ° C., followed by 4% poly (ethylene oxide). 125 mL (molecular weight: 300,000, trade name: Alcox E-30) is added little by little, and the mixture is stirred and dissolved in sterilized purified water. To this solution, a solution prepared by dissolving 0.13 g of ethyl p-hydroxybenzoate and 0.13 g of p-hydroxybenzoate in 2 mL of ethanol was added little by little, sterilized purified water was added, and the mixture was uniformly mixed.
Thus, a drug solution of allopurinol 1 mg / mL was obtained. 50 mL of this chemical solution was filled into a PET-only metering pump type spray container having a single injection amount of 500 μL to prepare a spray agent.

Example 2 Rebamipide (100 mg), Inagel F-13 (2 g) and Alcox E-305 (5 g) were mixed in a sterilized mortar, and sterilized purified water was added to the mixture, followed by stirring to dissolve. To this solution, a solution prepared by dissolving 0.13 g of ethyl p-hydroxybenzoate and 0.13 g of p-hydroxybenzoate in 2 mL of ethanol was added little by little, and sterile purified water was added thereto and mixed uniformly.
A drug solution of 00 mL of rebamipide 0.2 mg / mL was obtained. 50 mL of this liquid medicine is filled into a container for exclusive use of a fixed-quantity pump type spray made of PET with a single injection amount of 500 μL, and sprayed 2-3 times at a time, and used 3 to 5 times a day.

Example 3 50 μg of emprostil, 2 g of Ingel F-13 and 305 g of Alcox E-305 were mixed in a sterilized mortar, and then sterilized purified water was added and dissolved by stirring. A solution prepared by dissolving 0.13 g of ethyl p-hydroxybenzoate and 0.13 g of propyl p-hydroxybenzoate in 2 mL of ethanol was added little by little to this solution, and sterile purified water was added thereto and mixed uniformly.
A drug solution of 0.1 mL of emprostil 0.1 mL / mL was obtained.
50 mL of this liquid medicine is filled into a container for exclusive use of a fixed-quantity pump type spray made of PET with a single injection amount of 500 μL, and sprayed 2-3 times at a time, and used 3 to 5 times a day.

Example 4 Camostat mesylate 100 mg, Inagel F-13 2
g and Alcox E-30 (5 g) are mixed in a sterilized mortar, and sterile purified water is added to the mixture and stirred to dissolve. Add p-
A solution prepared by dissolving 0.13 g of ethyl hydroxybenzoate and 0.13 g of p-hydroxybenzoate in 2 mL of ethanol was added little by little, and sterile purified water was added thereto and uniformly mixed. A total of 500 mg of camostat mesylate 0.2 mg / mL
Was obtained. A single injection volume of 500 mL of this chemical 50 mL
Into a PET-only metering pump spray container,
Spray 2-3 times at a time and use 3-5 times a day.

Example 5 Allopurinol (500 mg), aspirin (20 g), Inagel F-13 (2 g) and Alcox E-30 (5 g) were mixed in a sterilized mortar, and sterilized purified water was added and dissolved by stirring. 0.13 g of ethyl p-hydroxybenzoate and
A solution prepared by dissolving 0.13 g of p-hydroxybenzoate in 2 mL of ethanol was added little by little, and sterilized purified water was added thereto and uniformly mixed to obtain a total amount of 500 mL of the drug solution. This chemical 5
0 mL is filled into a container for exclusive use of a metering pump type spray made of PET having a single injection amount of 500 μL, and is sprayed 2-3 times at a time.
Used 3-5 times a day.

Example 6 After dissolving 2.5 g of sodium bicarbonate in sterile purified water, add 2.5 g of salicylic acid and dissolve with stirring. To this solution were added 500 mg of allopurinol, 2 g of Ingel F-132 and 5 g of Alcox E-305. Further, a solution prepared by dissolving 0.13 g of ethyl p-hydroxybenzoate and 0.13 g of propyl p-hydroxybenzoate in 2 mL of ethanol was added little by little, and sterile purified water was added thereto and mixed uniformly.
A total of 500 mL of the drug solution was obtained. 50 mL of this liquid medicine is filled into a container for exclusive use of a fixed-quantity pump type spray made of PET with a single injection amount of 500 μL, and sprayed 2-3 times at a time, and used 3 to 5 times a day.

Example 7 500 mg of allopurinol, 200 mg of sodium azulene sulfonate, 2 g of Inagel F-13 and 5 g of Alcox E-30 were mixed in a sterilized mortar, and sterilized purified water was added and stirred to dissolve. Into this solution, a solution prepared by dissolving 0.13 g of ethyl p-hydroxybenzoate and 0.13 g of p-hydroxybenzoate in 2 mL of ethanol was added little by little, and sterile purified water was added thereto and mixed uniformly. I got 50 mL of this drug solution is filled into a container for exclusive use of a metering pump type spray made of PET with a single injection amount of 500 μL, and
Sprayed 2-3 times a day, used 3-5 times a day.

Example 8 Allopurinol 500 mg, 4% lidocaine hydrochloride solution
5 mL, 2 g of Ingel F-13 and Alcox E-3
After mixing 0.5 g in a sterilized mortar, sterile purified water is added and the mixture is stirred and dissolved. To this solution, 0.13 g of ethyl p-hydroxybenzoate and 0.1 p-propyl benzoate were added.
A solution prepared by dissolving 3 g in 2 mL of ethanol was added little by little, and sterilized purified water was added thereto and mixed uniformly to obtain a total of 500 mL of the drug solution. PET with a single injection volume of 500 μL of 50 mL of this drug solution
Into a metering pump spray-only container made of
~ 3 sprays, used 3-5 times a day.

Example 9 Allopurinol 500 mg, 4% lidocaine hydrochloride solution
5 mL, sodium azulene sulfonate 200 mg, streptokinase / streptodornase (300,000 units each
75,000 units), 2 g of Inagel F-13 and 305 g of Alcox E-305 are mixed in a sterilized mortar, and then sterilized purified water is added and stirred to dissolve. To this solution, a solution prepared by dissolving 0.13 g of ethyl p-hydroxybenzoate and 0.13 g of p-hydroxybenzoate in 2 mL of ethanol was added little by little, and sterile purified water was added thereto and uniformly mixed.
Was obtained. A single injection volume of 500 mL of this chemical 50 mL
Into a PET-only metering pump spray container,
Spray 2-3 times at a time and use 3-5 times a day.

Example 10 Allopurinol 500 mg, 4% lidocaine hydrochloride solution
5 mL, sodium azulene sulfonate 200 mg, fibrilidine deoxyribonuclease (125 units / 75,000 units each), 2 g of Ingel F-13 and 5 g of Alcox E-30 were mixed in a sterilized mortar, and sterilized purified water was added. Stir to dissolve. Into this solution, a solution prepared by dissolving 0.13 g of ethyl p-hydroxybenzoate and 0.13 g of p-hydroxybenzoate in 2 mL of ethanol was added little by little, and sterile purified water was added thereto and mixed uniformly. I got 50mL of this chemical solution is injected once
It is filled in a container for exclusive use of a fixed quantity pump type spray made of PET of 00 μL, sprayed 2-3 times at a time, and used 3 to 5 times a day.

Example 11 In a sterilized mortar, 500 mg of allopurinol and 2.0 g of purified gelatin having an average molecular weight of 3,000 to 4,000 were mixed, mixed, and heated, and Alcox E-30 125 mL was heated.
Is added little by little, and stirred and dissolved in sterile purified water. 0.13 g of ethyl p-hydroxybenzoate and p-
0.13 g of propyl hydroxybenzoate in ethanol 2
The solution dissolved in mL was added little by little, and sterilized purified water was added and mixed uniformly to obtain a total of 500 mL of the drug solution. This chemical 50
mL is injected into a container for exclusive use of a metering pump type spray made of PET with a single injection amount of 500 μL, and sprayed 2-3 times at a time, and used 3 to 5 times a day.

Reference Example 1 500 mg of allopurinol and CMC-Na were placed in a sterilized mortar.
After taking 5 g and mixing, the mixture is stirred and dissolved in sterilized purified water little by little while heating at 40 to 50 ° C. so as not to lump. Separately, 0.13 g of ethyl p-hydroxybenzoate and 0.13 g of propyl p-hydroxybenzoate are dissolved in 2 mL of ethanol. In the suspension of alpurinol,
Ethanol solutions of ethyl p-hydroxybenzoate and propyl p-hydroxybenzoate were added little by little and stirred, and the total amount was made up to 500 mL with sterile purified water to give an allopurinol gargle.

Test Example 1 Viscosity test for drug solution (Preparation of test drug solution) Preparation of allopurinol drug solution using Alcox E-30 and Inagel F-13: Allopuril 500 according to the drug solution preparation method for preparation of allopurinol spray in Example 1.
mg was dissolved in an ingel solution having various concentrations (0 to 1.0%) by heating, and Alcox E-30 was added so as to have various concentrations (0 to 3.0%). And After preparation, it was stored at room temperature until it was used for each test.

Preparation of Comparative Control Solution: Allopurinol gargle of Reference Example 1 was prepared.

(Measurement of Viscosity of Chemical Solution) Single Rotation Viscometer VS-
Using A type (Shibaura system), at each rotation speed,
The value after 3 minutes was measured, and the shear rate and shear stress were determined.

(Evaluation Method of Adhesiveness of Chemical Solution) As a device, a creep meter Model 3305 (manufactured by Yamaden) was used. Allopurinol solution 40 in beaker (diameter 45mm, depth 25mm)
Pour mL and use a 20 mm diameter plunger
After loading at a compression speed of 1 mm / s to a depth of 1 mm, the plunger was separated at the same speed. The adhesive force and the distance (strain) until the plunger completely separated from the surface of the allopurinol drug solution were measured (Pharmaceutical Magazine, 120, 12).
09-1216, 2000).

(Test Results) Alcox E-30 as a control solution and a dispersant prepared using CMC-Na
When the adhesive force of the allopurinol test drug solution prepared using Inagel F-13 as a thickener was examined, Inagel F-13 showed high adhesive force even at a low concentration. However, strain (Displaceme), which is an index of spinnability,
Comparing nt), Alcox E-30 showed a higher value as the concentration increased, and was considered to be a material suitable for an oral retentive formulation (FIGS. 1-4). From these results,
It turns out that a combination use of a thickener and a dispersant is useful in addition to the medicinal component and the solubilizer.

Test Example 2 Sensory Test on Chemical Solution (Preparation of Test Chemical Solution) Preparation of Allopurinol Chemical Solution by Alcox E-30: A small amount of sterilized purified water was added to 500 mg of allopurinol and dissolved by heating. Cox E-3
0, and the same amount of preservative as that of the drug solution at the time of preparation of the allopurinol spray of Example 1 was added.
It was 0 mL.

Preparation of Comparative Control Solution: Allopurinol gargle of Reference Example 1 was prepared.

(Evaluation Method by Sensory Test) The contents of the test were described in nine healthy subjects who gave their consent after explanation. First,
30 mL of an allopurinol gargle containing CMC-Na as a dispersion medium was taken as a comparative control solution. Thereafter, containing an allopurinol drug solution containing 1% Alcox E-30,
The taste, aftertaste, mouthfeel, and adhesion to the oral mucosa were compared with a comparative control solution by a five-point evaluation.

(Results) As for taste, allopurinol, Alcox E-30, Inagel F contained in the test solution were used.
-13 is tasteless, but the control solution is CMC-Na
It was considered to have been improved over the comparative control solution since it contained unpleasant taste. The aftertaste was almost the same as the control solution. Regarding the adhesiveness, many subjects felt that the adhesiveness increased when Alcox E-30 was contained. With respect to mouthfeel, the allopurinol solution containing 1% Alcox E-30 was good. Thus, it can be seen that the addition of the thickener and the dispersant in addition to the medicinal component and the solubilizer improves the mouthfeel, bitterness, aftertaste, and the like.

The allopurinol spray of the present invention and the allopurinol gargle (CMC-N) as a comparative example are described below.
a), a clinical example is shown. Clinical Test Example 1 [Subjects] 63 inpatients from January 1998 to January 2001 who underwent chemotherapy for esophageal cancer and metastatic esophageal cancer.

[Preparation of Formulation] Test drug: Allopurinol spray The allopurinol spray of Example (1) was prepared. Comparative control drug: Allopurinol gargle The allopurinol gargle of Reference Example (1) was prepared.

[Administration method] (Allopurinol spray) An allopurinol spray was sprayed for 1 hour before administration of the anticancer agent and 3 to 5 times a day after administration, and 2-3 times at a time for 14 days. When radiation therapy was used in combination, the treatment was performed until the radiation therapy was completed. (Allopurinol gargle) Gargling was performed for 14 days with about 10 to 30 mL of allopurinol gargle 1 hour before administration of the anticancer agent and 4 to 6 times a day after administration. When radiation therapy was used in combination, the treatment was performed until the radiation therapy was completed.

[Contents of Chemotherapy] Table 1 shows the contents of chemotherapy for the allopurinol spray administration group and the allopurinol gargle administration group.

[0051]

[Table 1]

[Test Results] The therapeutic effect was determined based on the criteria for stomatitis as a side effect of the Japanese Society of Cancer Therapy (Table 2).

[0053]

[Table 2]

The results are shown in Tables 3 and 4. In the allopurinol spray group, 3 cases of stomatitis developed
Eight of the four cases were stomatitis, and the degree of stomatitis was also about one degree as a side effect judgment standard of the Japanese Society of Cancer Therapy. The degree of stomatitis,
The average is 0.24 (Table 3), and the incidence rate is 23.5%
(Table 4). On the other hand, the degree of stomatitis in the 29 cases of the allopurinol gargle administration group was 0 degree 16 cases, 1 time 5 cases, 2 times 6 cases, and 3 times 2 cases from the Japanese Society of Cancer Therapy side effect criteria, with an average of 0.79 (Table 3), and the incidence is 4
It was 4.8% (Table 4). Allopurinol spray-administered groups showed significant differences in p <0.01 and p <0.05 in the preventive effect on stomatitis and the incidence of stomatitis, respectively, as compared with the allopurinol gargle administration group.

[0055]

[Table 3]

[0056]

[Table 4]

[0057]

Industrial Applicability The stomatitis spray of the present invention is much more effective in preventing and treating stomatitis than gargles, and furthermore, wastes the use of a chemical solution which has been a problem of gargles. The solution was sought from the viewpoints of stability, hygiene, and simplicity of chemicals and chemicals. That is, conventionally, a large amount of the conventional drug solution was consumed during the treatment period, so that it was not necessary to spend a long time to prepare the liquid solution each time during the treatment period, and the medical treatment was eliminated. Extremely useful.

[Brief description of the drawings]

BRIEF DESCRIPTION OF DRAWINGS FIG. 1 is a view showing an adhesive force and a strain curve when 0.4% Ingel F-13 and various concentrations of Alcox E-30 are used in combination.

FIG. 2 is a view showing an adhesive force and a strain curve when 1.0% Alcox E-30 and various concentrations of ingel are used together with F-13.

FIG. 3 is a view showing an adhesive force and a strain curve when 0.4% Ingel F-13 and various concentrations of Alcox E-30 are used in combination.

FIG. 4 is a diagram showing an adhesive force and a strain curve when 1.0% Alcox E-30 and various concentrations of ingel are used in combination with F-13.

────────────────────────────────────────────────── ─── of the front page continued (51) Int.Cl. ⁷ identification mark FI theme Court Bu (reference) A61K 31/245 A61K 31/245 31/4704 31/4704 31/519 31/519 38/54 45/06 45 / 06 47/32 47/32 47/36 47/36 47/42 47/42 A61P 1/02 A61P 1/02 17/02 17/02 A61K 37/62 F term (reference) 4C076 AA11 AA24 BB22 CC04 CC19 DD41 EE03 EE30G EE42G FF17 4C084 AA02 AA17 AA18 AA20 AA23 AA24 BA44 DC02 MA02 MA05 MA13 MA16 MA57 NA14 ZA672 ZB112 4C086 AA01 AA02 BC28 CB05 DA17 MA03 MA05 MA13 MA17 MA57 NA14 ZA11 ZB11 A37 MAB MAB MAB MA

Claims (10)

[Claims] 1. A radical scavenger (A), and (B) a radical scavenger.
A spray for stomatitis obtained by filling a spray container with a liquid composition containing a thickener, a dispersant (C), and a solubilizing agent (D). 2. The spray for stomatitis according to claim 1, wherein (A) the radical scavenger is selected from allopurinol, a therapeutic agent for peptic ulcer and a protease inhibitor. 3. The spray for stomatitis according to claim 1, wherein the liquid composition further comprises (E) an anti-inflammatory analgesic, a local anesthetic and / or a mucosal repair agent. 4. The spray for stomatitis according to claim 1, wherein the radical scavenger (A) is allopurinol, rebamipide, enprostil, camostat mesylate and / or gabexate mesylate. 5. The anti-inflammatory analgesic is aspirin and / or salicylic acid, and the local anesthetic is dibucaine, procaine,
The spray for stomatitis according to claim 3, which is lidocaine or a salt thereof, and the mucosal repairing agent is fibrinolidine deoxyribonuclease, streptokinase / streptodolase and / or sodium azulene sulfonate. 6. The liquid composition according to claim 1, wherein the content of the thickener (B) is 0.2 to 1.0% by weight.
A spray for stomatitis according to the above item. 7. The thickener (B) is selected from kappa-type carrageenan, iota-type carrageenan, lambda-type carrageenan, pectin, locust bean gum, guar gum, tamarind gum, xanthan gum, juran gum, cod gum, gum arabic and gelatin. The spray for stomatitis according to any one of claims 1 to 6, comprising at least one species. 8. The spray for stomatitis according to claim 1, wherein the content of (C) the dispersant is 0.25 to 3.0% by weight in the liquid composition. (C) The dispersant has an average molecular weight of 100,000 to 5
1 million poly (ethylene oxide).
The spray for stomatitis according to any one of 8 above. 10. The content ratio by weight of (B) a thickener and (C) a dispersant [(B) :( C)] is 4: 5 to 1: 3,
The total content of (B) the thickener and (C) the dispersant is 0.45.
The spray for stomatitis according to any one of claims 1 to 9, which is from 4.0 to 4.0% by weight.