JP2003226644A - Remedy for stomatitis - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a remedy for stomatitis containing an anti-inflammatory steroid-agent and prostaglandins. <P>SOLUTION: The recovery of the stomatitis is promoted by improving the production of KGF in a tissue suffering from the stomatitis accompanying erosion and ulcer. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a therapeutic drug for stomatitis having a high healing promoting effect.

[0002]

BACKGROUND OF THE INVENTION Stomatitis is an inflammation that develops in the oral cavity, tongue and gingiva during severe illness, malnutrition, acute infectious disease and the like. Stomatitis, especially intractable stomatitis with erosion or ulcer (including glossitis), pain, malodor in mouth, anorexia, etc. may be involved, and early treatment is desired.

As a remedy for stomatitis, steroidal anti-inflammatory agents such as dexamethasone and triamcinolone acetonide are used in the form of ointments, topical tablets, topical sprays and the like.

[0004]

However, even if these remedies for stomatitis containing steroidal anti-inflammatory agents are not used, the healing power is not high, and it takes a long time to heal, so that the patient suffers from symptoms such as pain and anorexia. There was a problem that it would last for a long time. Therefore, the present invention is to provide a therapeutic drug for stomatitis, which has a higher healing-promoting effect than conventional drugs.

[0005]

Therefore, the present inventor has conducted various investigations on the cause of the low cure rate of steroidal anti-inflammatory agents, and found that steroidal anti-inflammatory agents are responsible for the proliferation and regeneration of lost skin and mucosal epithelium. Keratinocyte growth (growth) factor (Keratinocyte) which plays an important role
It has been found that since it inhibits the production of Growth Factor (KGF), it cannot promote the healing of stomatitis associated with sores and ulcers. As a result of further study, the combined use of steroidal anti-inflammatory drugs and prostaglandins (hereinafter referred to as PG) markedly improved KGF production and dramatically improved the healing power of stomatitis. The present invention has been completed and the present invention has been completed.

That is, the present invention relates to 1. 1. A remedy for stomatitis containing a steroidal anti-inflammatory drug and prostaglandins; Steroid anti-inflammatory drugs, dexamethasone, triamcinolone acetonide, beclomethasone, hydrocortisone, methylprednisolone, prednisolone, triamcinolone diacetate, cortisone, parametazone,
Triamcinolone, diflucortron, difluprednate, diflorazone, flumethasone, fluocinonide,
2. The remedy for stomatitis as described in 1 above, which is selected from fluocinolone acetonide, alclomethasone, fludrocortisone or a non-toxic salt thereof. Steroidal anti-inflammatory drugs include dexamethasone, triamcinolone acetonide, beclomethasone propionate,
Hydrocortisone succinate, methylprednisolone succinate, dexamethasone acetate, hydrocortisone acetate, prednisolone acetate, dexamethasone metasulphonic acid benzoic acid, triamcinolone diacetate, butyl acetate prednisolone phosphate, dexamethasone phosphate hydrocortisone phosphate, prednisolone phosphate, betamethasone phosphate, Prednisolone acid, cortisone acetate, parametazone acetate, methylprednisolone acetate, triamcinolone,
Hydrocortisone, Prednisolone, Betamethasone, Prednisolone valerate acetate, Diflucortron valerate, Dexamethasone valerate, Betamethasone valerate, Difluprednate acetate, Diflorazone acetate, Difluprednate, Betamethasone dipropionate, Flumethonide pivalate, Fluocinonide, Fluocononide 3. A therapeutic drug for stomatitis according to 1 above, which is selected from ronacetonide, alclomethasone propionate, beclomethasone propionate, clobetasone butyrate, hydrocortisone butyrate, hydrocortisone propionate butyrate, fludrocortisone acetate, dexamethasone palmitate, and methylprednisolone. Prostaglandins are prostaglandin E ₁ ,
Selected from prostaglandin E ₂ , prostaglandin F ₂ α, prostaglandin G, prostaglandin H, prostaglandin I, prostaglandin J, thromboxane A or their non-toxic salts, prodrugs and derivatives. 4. The remedy for stomatitis as described in 1 above; 5. A therapeutic drug for stomatitis according to 1 above, which contains a steroidal anti-inflammatory drug and a prostaglandin in a single preparation; The above-mentioned 1 characterized in that the steroidal anti-inflammatory drug and the prostaglandins are administered as separate drugs.
6. The remedy for stomatitis as described above; The present invention provides a stomatitis treatment kit containing a steroidal anti-inflammatory drug and a prostaglandin as separate drugs.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The steroidal anti-inflammatory drug used in the therapeutic agent for stomatitis of the present invention includes a corticosteroid anti-inflammatory drug such as dexamethasone, triamcinolone acetonide, beclomethasone, hydrocortisone, methylprednisolone, prednisolone, Examples thereof include triamcinolone diacetate, cortisone, parameterazone, triamcinolone, diflucortron, difluprednate, diflorazone, flumethasone, fluocinonide, fluocinolone acetonide, alclomethasone, fludrocortisone, and non-toxic salts thereof. Specifically, dexamethasone, triamcinolone acetonide, beclomethasone propionate, hydrocortisone succinate,
Methylprednisolone succinate, dexamethasone acetate,
Hydrocortisone acetate, prednisolone acetate, dexamethasone metasulphonic acid benzoate, triamcinolone diacetate, prednisolone butyl acetate, dexamethasone phosphate, hydrocortisone phosphate, prednisolone phosphate, betamethasone phosphate, prednisolone succinate, acetate cortisone, parametasone acetate, methylprednisoacetate , Triamcinolone, hydrocortisone, prednisolone, betamethasone, prednisolone valerate acetate,
Diflucortron valerate, dexamethasone valerate, betamethasone valerate, difluprednate acetate, diflorazone acetate, difluprednate, betamethasone dipropionate, flumetasone pivalate, fluocinonide, fluocinolone acetonide, alclomethasone propionate,
Examples include, but are not limited to, beclomethasone propionate, clobetasone butyrate, hydrocortisone butyrate, hydrocortisone butyrate propionate, fludrocortisone acetate, dexamethasone palmitate, and methylprednisolone. Of these, dexamethasone, triamcinolone acetonide, and beclomethasone propionate are preferable.

On the other hand, as PGs, PGEs and PGEs
, PGFs, PGGs, PGHs, PGIs, PGJ
And thromboxane As. Of these, P
GE ₁, PGE₂, PGF₂α is particularly preferable. Also, P
Even if G is compounded as a complex with cyclodextrin,
Good.

The steroidal anti-inflammatory drug and PGs used in the present invention include not only compounds known so far, but also steroidal anti-inflammatory drugs and PGs to be discovered in the future. The steroidal anti-inflammatory drug and PGs used in the present invention also include those in the form of non-toxic salts, prodrugs, or derivatives.

The preferred content ratio by weight of the steroidal anti-inflammatory agent and PGs in the therapeutic drug for stomatitis of the present invention varies depending on the kind of the drug used, but from the viewpoint of the effect of promoting healing of stomatitis, it is preferably 1: 1 to 1: 100.

The remedy for stomatitis of the present invention is effective for the treatment of stomatitis occurring in the oral cavity, tongue, gingiva, etc., especially intractable stomatitis and glossitis accompanied by sores or ulcers.

The remedy for stomatitis of the present invention comprises, in addition to the above components, other anti-inflammatory agents such as sodium azulene sulfonate, decalinium chloride, domiphen bromide, cetylpyridinium chloride, chlorhexidine hydrochloride, tetracycline hydrochloride, acetylchithasa. An antibacterial agent such as mycin may be contained.

The therapeutic drug for stomatitis of the present invention may be administered in the form of separate preparations of the steroidal anti-inflammatory drug and PGs, that is, in the form of combined administration. This co-administration includes simultaneous administration and administration with a time difference. For administration with a time difference, the steroidal anti-inflammatory drug may be administered first, and the PGs may be administered later. Further, the PGs may be administered first, and the steroidal anti-inflammatory drug may be administered later. Each administration method may be the same or different.

Further, the therapeutic agent for stomatitis of the present invention may be in the form of a single pharmaceutical composition containing a steroidal anti-inflammatory drug and PGs at the same time.

[0015]

[Application to Pharmaceuticals] As a dosage form of the drug for treating stomatitis of the present invention, a topical agent for application to an inflammatory site in the mouth is preferable. Examples include ointments, gargles, sprays, troches, oral mucosal inserts and patches. Of these, oral ointments and gargles are preferred.

In preparing these formulations, suitable additives such as distilled water for injection, purified water, carboxymethylcellulose calcium, sodium carboxymethylcellulose, lactose, sorbit, mannitol, sucrose, corn starch, crystalline cellulose, Lactitol,
Cellulose derivatives, gum arabic, tragacanth, gelatin, polysorbate 80, talc, magnesium stearate, water, ethanol, white petrolatum, glycerin, fats, fatty oils, glycols, higher alcohols such as stearyl alcohol, plastibase, paraffin, beeswax, Polyoxyethylene hydrogenated castor oil, saccharin, pine syrup and the like can be appropriately selected and used in combination.

The dosage of the remedy for stomatitis of the present invention varies depending on age, symptoms, dosage form, etc. For example, in the case of a topical preparation for normal adults, the content of the active ingredient in 1 g is 0.01 as a steroidal anti-inflammatory agent. -10 mg, PGs of 0.
01 to 10 mg is preferable.

[0018]

EXAMPLES The present invention will be described in more detail with reference to examples below, but these do not limit the scope of the present invention.

[0019]Steroid anti-inflammatory drugs and Prostagura
Effects on GGF production of gingival fibroblasts by ginseng
sound <Experimental method> 1. Gingival tissue collection Nihon University School of Dentistry, Dental Hospital
A piece of gingival tissue attached to a severed, surgically removed tooth
Parts were used as materials. It should be noted that for the patient, a part of the removed tissue
Explain in advance that this will be used in this experiment and agree
Obtained. This tissue piece was treated with high-concentration antibiotic (300 unit / mL
penicillin, 300μg / mL streptomycin, Sigma)
Dulbecco's Modified Eagle Medium (DMEM: Iwaki, Asahi)
Techno glass) several times and finely sterilized with a sterile feather knife.
It was separated. In this experiment, 3 gingival tissue pieces were used for each individual.
Used for. 2. Gingival fibroblast culture Gingival fibroblasts are prepared by fixing each piece of tissue in culture medium and
What was exogenous from this was used for this experiment. I.e. teeth
Small pieces of meat tissue (about 1 mm³) 6-well plate for tissue culture
(Iwaki Glass) is coated on the bottom with sterile silicon grease.
Inactivated 10% fetal bovine serum fixed with Burslip
(FBS: JRH Biosciences) and antibiotics (1
00 units / mL penicillin, 100 μg / mL streptomyci
Add 2 mL of DMEM containing n),
Culture (37 ℃, 5% CO ₂). About 2 weeks later
When the cells explanted from the tissue become confluent
Point, 0.05% trypsin-0.53 mmol / L EDT
Disperse the cells in solution A (Gibco) and subculture under the same conditions.
Culture was performed. The third passage was used for this experiment
It was 3. Quantification of KGF in culture supernatant 24 holes of gingival fibroblasts in DMEM containing 10% FBS
Plates were seeded. Incubate until confluent
After that, the medium is replaced with serum-free DMEM, and the medium is kept for 24 hours.
Incubated. In addition, known concentrations of PGE₁, PG
E₂Serum-free DME containing and / or dexamethasone
The medium was replaced with M, and after 24 hours, the culture supernatant was collected. This
The amount of KGF produced in the culture supernatant of
D Systems). Cell count is culture
After completion, add trypsin-EDTA solution to each well of the plate.
After adding the liquid to detach the cells, place the Coulter counter
Use, PGE₁, PGE₂And / or dex
That addition of methazone did not affect cell number
confirmed. <Results> PG on KGF production of gingival fibroblasts
E₁, PGE₂And / or of dexamethasone (DX)
The results of examining the influence are shown in Table 1-6.

[0020]

[Table 1]

[0021]

[Table 2]

[0022]

[Table 3]

[0023]

[Table 4]

[0024]

[Table 5]

[0025]

[Table 6]

In all cases, when dexamethasone was added in the absence of PG, the KGF production amount decreased in a dexamethasone concentration-dependent manner. However, PGE
_{When 1} or PGE ₂ was added, the presence of dexamethasone
KGF production was PGE ₁ or P regardless of absence
It increased in a GE ₂ concentration-dependent manner. In addition, PGE ₁ or P
When GE ₂ is present in high concentrations above 10 ^-7 mol, KG
F production increased in a dexamethasone concentration-dependent manner. From these results, the steroidal anti-inflammatory drug dexamethasone alone inhibits KGF production, but in the presence of high concentrations of PGE ₁ or PGE ₂ , synergistically K
It was suggested to enhance GF production.

[0027]

INDUSTRIAL APPLICABILITY By using the therapeutic agent for stomatitis of the present invention, the healing of stomatitis is promoted by improving the production of KGF in the tissues of stomatitis associated with sores and ulcers.

Claims (7)

[Claims] 1. A therapeutic drug for stomatitis containing a steroidal anti-inflammatory drug and prostaglandins. 2. The steroidal anti-inflammatory agent is dexamethasone, triamcinolone acetonide, beclomethasone, hydrocortisone, methylprednisolone, prednisolone, triamcinolone diacetate, cortisone, paramazone, triamcinolone, diflucortron, diflupredonate, diflorazone, flumethasone, fluocinonide. The remedy for stomatitis according to claim 1, which is selected from fluocinolone acetonide, alclomethasone, fludrocortisone or their non-toxic salts. 3. The steroidal anti-inflammatory agent is dexamethasone, triamcinolone acetonide, beclomethasone propionate, hydrocortisone succinate, methylprednisolone succinate, dexamethasone acetate, hydrocortisone acetate, prednisolone acetate, dexamethasone metasulfonate benzoic acid, triamcinolone diacetate. , Butyl acetate prednisolone, dexamethasone phosphate, hydrocortisone phosphate, prednisolone phosphate, betamethasone phosphate, prednisolone acetate succinate, cortisone acetate, parametazone acetate, methylprednisolone acetate, triamcinolone, hydrocortisone, prednisolone, betamethasone, valeric acid valerate valerate, Diflucortron, dexamethasone valerate, betamethasone valerate,
Difluprednate acetate, diflorazone acetate, difluprednate, betamethasone dipropionate, flumethasone pivalate, fluocinonide, fluocinolone acetonide, alclomethasone propionate, beclomethasone propionate, clobetasone butyrate hydrocortisone butyrate, hydrocortisone propionate butyrate, The therapeutic drug for stomatitis according to claim 1, which is selected from dorocortisone, dexamethasone palmitate, and methylprednisolone. 4. The prostaglandins are prostaglandin E ₁ , prostaglandin E ₂ , prostaglandin F ₂ α, prostaglandin G, prostaglandin H, prostaglandin I, prostaglandin J, thrombosis. The remedy for stomatitis according to claim 1, which is selected from xanthane A or non-toxic salts, prodrugs and derivatives thereof. 5. The remedy for stomatitis according to claim 1, which comprises a steroidal anti-inflammatory drug and a prostaglandin in a single preparation. 6. The remedy for stomatitis according to claim 1, wherein the steroidal anti-inflammatory drug and the prostaglandins are administered as separate drugs. 7. A stomatitis treatment kit containing a steroidal anti-inflammatory drug and a prostaglandin as separate drugs.