JP2001089383A - Composition for oral cavity and ophthalmology - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a composition for oral cavity and ophthalmology which possesses high safety, exhibits excellent MMP and cysteine protease inhibitory activity and is effective on the prophylaxis or treatment for periodontal disease, corneal abscess or the like. SOLUTION: This composition for oral cavity or ophthalmology is obtained by including an eggshell membrane decomposition substance. This eggshell membrane is a thin membrane stuck on the inside of the egg of birds and not only prevents microorganisms from invading but also forms an air room constructed by two sheets in the egg dull end to protect the egg. The eggshell membrane decomposition substance is a decomposition product obtained by hydrolyzing this eggshell membrane to solubilize.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an oral and ophthalmic composition having a protease inhibitory action.

[0002]

2. Description of the Related Art The extracellular matrix plays the most important role in inflammatory diseases involving destruction of connective tissue or subsequent bone resorption, such as periodontal disease or corneal ulcer. It is a protease that destroys. In inflammatory lesions, a series of inflammatory reactions via cytokine networks are expanded, and various types of proteases are released from immune cells such as fibroblasts, leukocytes, and monocytes / macrophages, and connective tissue or bone matrix Destruction proceeds. Among them, matrix metalloproteases (MMPs) that form a protease family with many common features such as zinc and calcium ion dependence in activity expression and secretion as a precursor
Is a group of proteases having Zn2 ⁺ as an active center, collagen which forms connective tissue or bone matrix, directly decomposes extracellular matrix components such as fibronectin, and the likelihood of high frequency Since the activity is detected, in recent years, a number of new compounds have been developed as inhibitors thereof, such as hydroxamic acids having a metal chelating ability, malonic acid-based derivatives, and tetracycline antibiotics. However, most of these substances are newly synthesized substances, and problems have been pointed out in their use, such as side effects caused by their by-products and the emergence of resistant bacteria due to the frequent use of antibiotics. Agents are desired. In addition, studies of bone matrix destruction and tumor invasion mechanism following the destruction of connective tissue in recent years have indicated that not only MMP but also cysteine protease is involved in these inflammatory reactions (Ca
ncres. 57:23, 1997, Canc.
er; 76: 3, 1995), and cysteine protease (cathepsin B, D, L, K) activity is also frequently detected in tissues of diseased patients (Arthriti).
s Rheum. 41: 8, 1998; Cli
n. Perio. ; 24: 6, 1997), it has been shown that these enzymes not only destroy extracellular matrix components like MMPs, but also degrade precursors of MMPs to mature forms.

Therefore, it is considered that a bifunctional inhibitor that also inhibits cysteine protease activity can be a more effective preventive or therapeutic agent than an inhibitor of MMP alone.

[0004]

Means for Solving the Problems and Embodiments of the Invention In view of the above circumstances, the present inventor has high safety, inhibits the activity of both MMP and cysteine protease, and binds to periodontal disease and corneal ulcer. As a result of intensive studies on oral and ophthalmic compositions that can effectively prevent or treat inflammatory diseases accompanied by tissue destruction, eggshell membrane degraded products were found to be M
It has been found that it has a high inhibitory activity against both MP and cysteine protease enzymes, and that the oral and ophthalmic compositions containing this eggshell membrane decomposition product have excellent protease inhibitory activity.

Hereinafter, the present invention will be described in more detail. The oral and ophthalmic compositions of the present invention contain an egg shell membrane decomposition product as an active ingredient having a protease inhibitory action.

[0006] Here, the eggshell membrane is a thin film that adheres to the inner surface of the eggshell of a bird egg, and prevents the invasion of microorganisms. At the blunt end of the egg, it forms two air chambers to protect the eggs. I have. The egg shell membrane decomposition product used in the present invention is a decomposition product obtained by hydrolyzing and solubilizing the eggshell membrane. JP-A-1-27551
No. 2, JP-A-4-148649 describes a purification method thereof, and JP-A-3-255014 discloses a cosmetic composition having a beautiful skin and enhanced moisturizing effect. In addition, Japanese Patent Application Laid-Open No. Hei 5-97897 discloses a method for purifying the same and a cosmetic having a high effect of improving rough skin.
However, there is no report on the protease inhibitory effect of the eggshell membrane decomposition product, which has been found for the first time.

[0007] The compounding amount of the eggshell membrane decomposition product can be in the range of 0.001 to 20% by weight of the whole composition.

[0008] The composition of the present invention may contain known components depending on the type of the composition.

That is, in the case of an oral composition, a dentifrice such as toothpaste, a gingival massage cream, a topical application, a mouthwash,
Various dosage forms such as troches and chewing gums are possible, but, for example, in the case of dentifrices, abrasives, binders, thickeners, sweeteners, flavors, and the like can be blended in usual amounts. .

In this case, the abrasives include calcium hydrogen phosphate dihydrate, tertiary calcium phosphate, calcium carbonate, calcium pyrophosphate, aluminum hydroxide,
1 such as silicic anhydride, aluminum silicate, insoluble sodium metaphosphate, tribasic magnesium phosphate, magnesium carbonate, calcium sulfate, bentonite, zirconium silicate, polymethyl methacrylate, and other synthetic resins
Species or two or more species may be blended within a range that does not impair the effects of the present invention.

Examples of the binder include cellulose derivatives such as carrageenan, sodium carboxymethylcellulose, methylcellulose, and hydroxyethylcellulose; alginic acid derivatives such as sodium alginate and propylene glycol alginate; gums such as xanthan gum, gellan gum, tragacanth gum, and karaya gum; One or more kinds of synthetic binders such as alcohol, sodium polyacrylate and carboxyvinyl polymer, and inorganic binders such as silica gel, veegum and laponite may be blended.

As humectants, glycerin, sorbit, propylene glycol, polyethylene glycol,
One or more polyhydric alcohols such as xylitol, maltitol and lactitol may be blended.

As the surfactant, an anionic surfactant such as sodium lauryl sulfate, a nonionic surfactant such as decaglyceryl laurate and diethanolamide myristate, and an amphoteric surfactant such as betaine can be blended. .

The fragrance component includes menthol, anethole, carvone, eugenol, limonene, n-decyl alcohol, citronellol, α-terpineol, cineol, linalool, ethyl linalool, crocodile, thymol, peppermint oil, spearmint oil, wintergreen oil, T-shaped oil, fragrances such as eucalyptus oil can be blended alone or in combination, saccharin sodium,
Sweetening agents such as stevioside, glycyrrhizin, perillartin, thaumatin and the like can be added.

Further, in the oral composition of the present invention,
Cationic fungicides such as chlorhexidine, benzethonium chloride, benzalkonium chloride, cetylpyridinium chloride, decanium chloride, phenolic compounds such as triclosan, hinokitiol, and biosol, dextranase, mutanase, lysozyme, amylase, protease, lytic enzyme , enzymes such as superoxide dismutase, vitamin E, vitamins such as vitamin B _6, sodium monofluorophosphate, alkali metal monofluorophosphate salts such as potassium monofluorophosphate, sodium fluoride, etc. stannous fluoride Fluoride, tranexamic acid, epsilon aminocaproic acid, aluminum chlorohydroxyl allantoin, dihydrocholestanol, glycyrrhizic acids, glycyrrhetinic acid Bisabolol, glycerophosphate, chlorophyll, sodium chloride, a known active ingredient, such as water-soluble inorganic phosphoric acid compounds may be formulated alone or in combination.

On the other hand, the ophthalmic composition can be prepared as an eye drop, an eye wash, or the like, and various components usually used for preparing a liquid composition such as an eye drop may be blended in a usual amount. it can.

Specific examples of the above components include decongestant components such as epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, phenylephrine hydrochloride, dl-methylephedrine hydrochloride, and pinto such as neostigmine methyl sulfate. Regulatory ingredients, epsilon-aminocaproic acid, allantoin, berberine chloride, berberine sulfate, sodium azulene sulfonate, dipotassium glycyrrhizinate,
Anti-inflammatory and astringent components such as zinc sulfate, zinc lactate and lysozyme chloride, antihistamines such as diphenhydramine hydrochloride and chlorpheniramine maleate, sodium flavin adenine dinucleotide, cyanocobalamin, retinol acetate, retinol palmitate, pyridoxine hydrochloride, panthenol, pantothenic acid Calcium, sodium pantothenate, vitamins such as tocopherol acetate, sulfamethoxazole, sodium sulfamethoxazole,
Sulfa drugs such as sulfisoxazole and sulfisomidine sodium, anti-allergic drugs such as sodium cromoglycate, tranilast and pemirolast, potassium chloride,
Inorganic salts such as calcium chloride, sodium chloride, sodium hydrogen carbonate, sodium carbonate, dried sodium carbonate, magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, boric acid, borax, citric acid, Buffers such as sodium citrate, L-glutamic acid, sodium L-glutamate, glacial acetic acid,
Polyvinyl alcohol, polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylmethylcellulose, chondroitin sulfate, hyaluronic acid, sodium hyaluronate, methylcellulose, thickeners such as dextran 70, glycerin, concentrated glycerin,
Glucose, isotonic agents such as D-mannitol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, methyl parahydroxybenzoate, ethyl paraoxybenzoate, butyl paraoxybenzoate, propyl paraoxybenzoate, alkylpolyaminoethyl Preservatives such as glycine, ethanol, urea, propylene glycol, polyoxyethylene hydrogenated castor oil,
Dissolution aids such as polyoxyethylene hydrogenated castor oil 60, polysorbate 80, poloxamer, macrogol 4000, monoethanolamine, sodium bisulfite,
Stabilizers such as dried sodium sulfite, sodium thiosulfate, sodium pyrosulfite, sodium metabicarbonate and the like can be blended as long as the effects of the present invention are not impaired.

[0018]

The oral and ophthalmic compositions of the present invention are highly safe, have excellent MMP and cysteine protease inhibitory activities, and are effective in preventing or treating periodontal diseases, corneal ulcers and the like.

[0019]

EXAMPLES Hereinafter, the present invention will be described in detail with reference to experimental examples and examples, but the present invention is not limited to the following examples.

[Experimental Example] The MMP inhibitory activity and the cysteine protease inhibitory activity of the eggshell membrane decomposition product were measured by the following methods.

<Method for MMP Inhibitory Activity Measurement> The inhibitory activity against MMP was measured using a kit for assaying I collagenase activity manufactured by Yagai. Samples were prepared at a final concentration of 10 mg /
Two-fold serial dilutions from ml to buffer were used. The inhibition rate (%) was calculated with the fluorescence intensity released from the fluorescence-labeled I collagen in which active I collagenase was decomposed at 37 ° C. for 3 hours as 100. The fluorescence intensity was measured with a fluoroscan ascent (Dainippon Pharmaceutical Co., Ltd.). FIG. 1 shows the results of plotting the inhibition rate with respect to each dilution concentration.

<Measurement of Cysteine Protease Inhibitory Activity> The cysteine protease inhibitory activity was measured by the method of Eley et al. (J. Period).
ont. Res. 27, 1992). The sample was diluted and used as described above. The inhibition rate (%) was calculated assuming that the fluorescence intensity released from a fluorescent substrate (z-Arg-Arg-MCA, Peptide Institute) in which cathepsin B was decomposed at 37 ° C. for 15 minutes was 100. The fluorescence intensity was measured with a fluoroscan ascent (Dainippon Pharmaceutical Co., Ltd.). FIG. 2 shows the results of plotting the inhibition ratio for each dilution concentration.

When the 50% inhibitory concentration (IC ₅₀ ) was calculated from the regression linear equation obtained from the plot of the inhibition rate, the MM
The inhibitory activity was as high as 1.963 mg / ml for P-1 and 1.554 mg / ml for cathepsin B.

Examples of the composition containing the egg shell membrane decomposition product are shown below. In the following examples,% indicates% by weight.

Example 1 Toothpaste Precipitable silica 45.0% Sorbit 25.0 Glycerin 25.0 Polyvinylpyrrolidone 1.0 Lauroyl polyglycerin ester 1.0 Polyoxyethylene (60) sorbitan 0.5 Monolaurate Saccharin sodium 0.2 Ethyl paraoxybenzoate 0.1 Triclosan 0.1 Peptide derived from eggshell membrane 0.5 Tranexamic acid 0.05 Methyl salicylate 0.2 Perfume 1.0 Purified water Balance 100.0%

[Example 2] Toothpaste 20.0% dibasic calcium phosphate dihydrate 20.0% dibasic calcium phosphate anhydrous 20.0 Gelling silica 2.0 Sorvit 20.0 Propylene glycol 2.5 Xanthan gum 0 Lauryl diethanolamide 1.0 Sodium lauryl sulfate 1.5 Sodium lauroyl sarcosine 0.3 Saccharin sodium 0.1 Ethyl parahydroxysalicylate 0.1 Egg shell membrane decomposition product 1.0 Chlorhexidine gluconate 0.1 Perfume 0.8 Purified water 100.0% remaining

Example 3 Oral Pasta Liquid Paraffin 15.0% Cetanol 10.0 Glycerin 20.0 Sorbitan Monopalmitate 0.6 Polyoxyethylene (40) Sorbitan Monostearate 5.0 Sodium Lauryl Sulfate 0.0 1 Sodium saccharin 0.5 Benzethonium chloride 0.1 Tranexamic acid 0.1 Eggshell membrane decomposition product 0.5 Methyl salicylate 0.2 Perfume 0.5 Purified water Balance 100.0%

Example 4 Mouthwash Sorvit 10.0% Ethanol 5.0 Polyoxyethylene (60) hydrogenated castor oil 0.1 Sucrose monopalmitate 0.2 Sodium lauryl sulfate 0.05 Saccharin sodium 0.2 Xylit 5.0 Chlorhexidine gluconate 0.05 Eggshell membrane decomposition product 0.1 Ethyl salicylate 0.1 Perfume 0.6 Purified water Balance 100.0%

Example 5 Oral Lozenges Lactose 97.0% Polyoxyethylene (60) monostearate 0.2 Sodium lauryl sulfate 0.05 Chlorhexidine gluconate 0.02 Stevia extract 0.2 Tranexamic acid 0 .1 Eggshell membrane decomposition product 0.1 Methyl salicylate 0.2 Fragrance 0.02 Hydroxyethylcellulose Balance 100.0%

Example 6 Eye drops 3.0 g of polyoxyethylene (60) hydrogenated castor oil and 0.5 g of d-α-tocopherol acetate are heated and melted. The following components are added and dissolved, and sterile purified water is added to make the total volume 1,000 ml. The solution is aseptically filtered and filled into an eye dropper to give an eye drop (pH 5.5). Citric acid 0.15 g Sodium citrate 0.9 g Sodium ethylenediaminetetraacetate 0.02 g 10% benzalkonium chloride solution 1.0 g Propylene glycol 5.0 g Chlorobutanol 3.0 g l-Menthol 0.3 g Eggshell Membrane decomposition product 1.0 g Boric acid 1.5 g Sodium chloride 2.25 g

[Example 7] Medicinal ointment Liquid paraffin 15.0% Cetanol 10.0 Glycerin 20.0 Polyoxyethylene sorbitan fatty acid ester 5.0 Fragrance 0.5 Saccharin sodium 0.1 Eggshell membrane decomposition product 2.0 Purified water 100.0% remaining

[Brief description of the drawings]

FIG. 1 is a graph showing the inhibitory activity of eggshell membrane degradation products on MMP-1.

FIG. 2 is a graph showing the inhibitory activity of eggshell membrane decomposition products on Cathepsin B.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (reference) // A61K 9/06 A61K 9/06 9/08 9/08 F term (reference) 4C076 AA07 AA12 BB24 BB31 CC10 CC16 DD08 DD22 DD23Z DD37 DD37R DD38 DD43Z DD49R DD50 DD61T EE01 EE57A 4C083 AA071 AA072 AA112 AB172 AB292 AC022 AC072 AC102 AC122 AC132 AC302 AC402 AC422 AC432 AC442 AC472 AC482 AC542 AC622 AC662 AC692 AC742 AC782 AD412AAC31AD8227 AA02 BB61 CA03 MA01 NA14 ZA33 ZA67 ZC20

Claims (1)

[Claims] 1. An oral or ophthalmic composition comprising an eggshell membrane decomposition product.