JPS59175416A - External preparation for remedy of keratonosis of skin and mucosa - Google Patents

Abstract

PURPOSE:To prepare an external drug having improved stability of interferon and useful as a remedy for lichen planus, leukoplakia, etc., by adding a sugar alcohol having a valency of >=3 and an organic acid buffering agent to an interferon. CONSTITUTION:An external drug containing >=1X10<4> IU, per 100g of the composition, of an interferon having a titer of >=1X10<5> IU is added with >=15wt%, preferably 25-70wt% of a sugar alcohol having a valency of >=3 (e.g. glycerol, erythritol, sorbitol, etc.) and >=0.01mol, based on 1kg of the drug, of an organic acid buffering agent such as citrate, lactate, acetate, etc. to adjust the pH of the external drug to 3-6. The drug is applied directly to the diseased part by coating or spraying.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an external preparation for treating dyskeratosis of the skin and mucous membranes containing interferon as an active ingredient.

Lesions observed on the skin and mucous membranes include stomatitis caused by infections such as herpes simplex virus and herpes zoster, viral diseases such as herpes simplex and herpes zoster, and candidiasis caused by fungi. There are infections caused by pathogenic microorganisms, such as lichen planus, and keratinization abnormalities whose etiology is completely unknown, such as lichen planus and leukoplakia.

Among these JM changes of the skin and mucous membranes, it is known that antiviral drugs, antibiotics, antifungal exfoliators, antiinflammatory drugs, etc. are effective in treating viral diseases and infectious diseases whose etiology is clear. ing. However, for the treatment of abnormal keratosis such as lichen planus leprosy and leukoplakia, the etiology of which is unknown, currently only vitamin preparations and corticosteroids are administered, and no effective means have yet been found.

1 meter of flat moss? +a Chronic inflammation accompanied by keratinization seen on the skin and mucous membranes, such as the mucous membranes in the oral cavity.It is common in middle-aged and older people, samurai, and women.When erosion occurs in the oral cavity, it stains when eating or causes stiffness. It is painful, and there are several types, but the ulcer type and vesicular type are said to be more likely to turn into cancer. Leukoplakia is a white spot-like lesion caused by hyperkeratosis of the mucosal epithelial layer of the oral mucosa, etc., and is said to occur more commonly in middle-aged and older men, and some cases can turn into cancer.

In this way, abnormal keratosis of the skin and mucous membranes, such as hemorrhoids and albinism, is a type of precancerous disease, but because the etiology is unknown, there is no effective treatment, and its appearance is difficult to understand. 1
<It is requested.

In view of these 11 circumstances, the present inventors conducted intensive research to find an effective treatment for abnormalities of keratosis of the skin and mucous membranes such as moss planus and leukoplakia. It was found that it has a remarkable therapeutic effect on abnormalities.

In other words, since interferon was discovered as a factor that inhibits the growth of viruses produced by microfoam, subsequent research has revealed various pleiotropic biological effects. It has become possible to mass produce interferon derived from a microorganism with a human interferon gene and to make it suitable for clinical application, and it can be used to treat herpetic keratitis, hepatitis B, viral lesions, brain tumors, cutaneous intoxication melanoma, etc. The clinical application of this technology is progressing.

However, interferon is an extremely unstable substance, and especially when it is purified to the extent that it can be used clinically, its activity is slowly lost due to temperature (high temperature) or physical pressure. Therefore, at present, interferon is mostly applied clinically as a freeze-dried product, and before use, it is dissolved in physiological saline, @seizu, etc., and administered in the form of an injection or an eye drop.

However, the present inventors have found that the stability of interferon is significantly improved when interferon is coexisted with trivalent or higher valent sugar alcohols and organic acid buffers, and that interferon-containing topical products containing these ingredients have been developed. It has been found that lichen has a remarkable therapeutic effect on abnormal keratosis of the skin and mucous membranes of unknown etiology, such as lichen planus and leukoplakia. Until now, there have been no pharmacological or clinical reports showing that interferon is effective against these abnormalities of keratosis.O The present invention was completed based on the knowledge obtained over the past 3 years, and contains interferon as an active ingredient and is a trivalent compound. The present invention provides an external use for treating abnormal keratosis of skin, cloth, and mucous membranes - 1, which contains the above-mentioned sugar alcohol and organic acid buffer.

According to the present invention, it is effective to treat abnormal skin keratosis of unknown etiology such as Fukuhira lichenosis and albinism, as well as keratosis abnormalities caused by mucous membranes, by simply applying interferon to the lesioned area using the simple method of external application. can be treated.

The interferon used as the active ingredient in the external use 41 of the present invention may be of any human origin, for example, human leukocytes, normal diploid cells, or recombinant DNA.
There are 13 microorganism-derived products that incorporate the human interferon gene using the A technique. The compounding layer is not particularly limited and can be selected as appropriate depending on the actual formulation used as an external preparation, but from the viewpoint of effectiveness, it is generally composed of interferon having a titer of 1 x 105 international units or more. It is preferable to fertilize at a rate of 1 x 104 international units or more per 1005' of the material.

Examples of trivalent or higher sugar alcohols used include glycerin,
Examples include erythritol, arabitol, xylitol, sorbitol, mannitol, etc. These may be used alone or in combination of two or more, and from the viewpoint of stability of interferon, the blended layer should be added as a sugar alcohol to the entire external preparation. It is desirable to set it to 15% (@mold width, same below) or more, preferably 25 to 70%.

The organic acid buffer may be a conventional buffer consisting of an organic acid or its salt, such as a citric acid-sodium-disodium citrate mixture, a citric acid-trisodium citric acid mixture, a citric acid-citric acid- succinate buffers such as sodium succinate mixtures, succinate buffers such as succinic acid-sodium succinate mixtures, succinic acid-sulfur hydroxide mixtures, succinate-sulfur succinate-sodium mixtures; tartrate buffers such as agents, tartaric acid-sodium tartrate mixtures, tartaric acid-potassium tartrate mixtures, /tetrataric acid-sodium hydroxide mixtures, fumaric acid-7maric acid-
Sodium mixture, fumaric acid-disodium 7-marate mixture, fumaric acid-sodium-disodium fumaric acid compound, such as sodium fumaric acid-sodium gluconate mixture, gluconic acid-sodium gluconate mixture, glufum) V-hydroxylation Sodium mixture compounds, gluconate salt compounds such as gluconic acid-potassium gluconate mixtures, Shujun-sodium oxalate mixtures, oxalic acid-sodium hydroxide mixtures,
Oxalate buffers such as oxalic acid-potassium oxalate mixtures, lactic acid-lactic acid l-Q rum mixtures, lactic acid-hydroxide mixtures, lactate buffers such as lactic acid-potassium lactate mixtures, acetic acid Examples include acetate buffers such as an acetic acid mixture, an acetic acid-hydroxide mixture, and the like. From the viewpoint of interferon stability, these organic buffers are
．． It is desirable to add at least 9 to 0.1 mol/mole, preferably at least 9 to 0.1 mol/mole, and adjust the pH of the external preparation to 3 to 6.

The external preparation of the present invention can be in the form of an ointment, a paste, a gel shaver, a spray, a shaved shape suitable for external use, such as before nighttime use. These can be manufactured according to conventional I/1-11 conversion techniques, and interferon may be added in the final step of manufacturing. Other ingredients are not particularly limited as long as they do not affect the stability of interferon, and any of those commonly used in this type of preparation may be used. In particular, in the case of solid W/IJ, it is preferable to use carboxymethyl cellulose as the caking agent 4 from the viewpoint of stability of interferon.

In order to use the topical preparation of the present invention for the treatment of abnormal keratosis of the skin or mucous membranes such as lichen planus or leukoplakia, the topical preparation ~j may be applied directly to the affected area by coating or spraying. Although there are no particular limitations, when applying the topical f11, bandages, adhesive plasters, etc. may be used to prevent interferon from being removed from the affected area, and to promote its absorption and enhance the therapeutic effect. It is preferable to cover it with In particular, when applying to the affected area on the internal mucosa of the mouth, an oral mucosal adhesive bandage (for example, an oral mucosal adhesive bandage (e.g.,
11299) etc.)
The effect can be increased.

The dosage is 10 to 10 per administration (one time).
It is preferable to use 108 international units of interferon, for example, a gel containing interferon of 104 to 10,912 m units/1005' external preparation, or 105 to 1010 international units/10 (
1- Soft 1- that is gold-plated with interferon, an external medicine! : When using the agent, apply 0.0 per dose according to the size of the affected area.
It is sufficient to apply 1 to 10 doses to the affected area 2 to 3 times a day with your hands, spatula, etc.

Next, the present invention will be explained in more detail with reference to Examples and Test Examples. The interferon used in the following examples and test examples was obtained from human foreskin-derived fibroblasts, and passed the standards for clinical application established by the National Institute of Preventive Health. The safety of the product has been confirmed in dairy clinical trials required by the Ministry of Health and Welfare.

Example 1 Gel base formulation ingredients Sodium lauryl sulfate 0.2 Carboxymethylcellulose 2.0 Glycerin 40.00.4 mol/
l! Citric acid, salt buffer (pi-14,5,) 25.0 Purified water The remaining components were mixed to obtain a base, and per 1007 of the base, interferon was mixed at a ratio of 1 x 107 international units and published as a topical gel. I got it.

Example 2 Gel base formulation ingredients % Carboquine methyl cellulose 2.0 Glycerin 45.00.4 mol/l Citrate buffer (pH 4,5) 25.0 Purified water Remaining components were mixed to form a base. Interferon was mixed with rI at a ratio of 1×10 6 international units per 1002 units to obtain a gel for external use.

Example 3 Ointment base formulation ingredients % Carboxymethyl cellulose 0.2 Glycerin 30.0° White petrolatum 20 Stearyl alcohol 220.4 mol/l citrate buffer 25 Purified water
The remaining components were combined to obtain a base, and per 1007 of the base, interferon was mixed at a ratio of 1 x 106 international units to obtain a soft and sharp base.

Example 4 Pasta base formulation ingredients % Carboxymethyl cellulose 2.0 Glycerin 25.0 Cetano 2.8 Glyceryl monostearate 9.3 Tween 80
2.0 glucuronic acid
1.00.4 mol/l citrate buffer 20 purified water
The remaining components were mixed to obtain a base, and interferon was mixed in at a ratio of 1 x 104 international units per 1005' of the base to attack the pasta shavings.

Example 5 Liquid base formulation ingredients % Carboxymethyl cellulose 0.1 Glycerin 150.4 mol/l
Citrate buffer (PH4,5) 0 Purified water The remaining components were mixed to obtain a base, and 100 g of the base was mixed with reinterferon at a ratio of 1×10 5 international units to obtain a liquid preparation.

Example 6 Spray formulation ingredients % Interferon solution obtained in Example 5 50 Freon 114 50ml of 50 solution
Freon 114 is placed in an aluminum container whose inner surface is treated with Teflon.
A spray was obtained.

Safety test (1) Primary skin irritation test New Sealant White female rabbit (weight 2.5~
3.0~) The backs of six birds were dehaired, and the gels of Examples 1 and 2 were applied to each part of the hair-removed part, and the hair was sealed for 24 hours.

The coated areas were observed 30 minutes after the gel was removed, but no abnormalities were observed.

(2) Skin sensitization test Hartle female white guinea pig (body weight 300-35 (1
) The gel preparations of Examples 1 and 2 were examined by intradermal injection sensitization using 23 fish. As a result, no sensitization was observed other than the effect of human serum albumin, which is contained as a stabilizer in the raw material interferon. moreover,
A 24-hour sealed patch test of these gels was conducted to elicit reactions, but no positive cases were observed.

(3) Human patch test A 24-hour closed patch test of the gels of Examples 1 and 2 was conducted on the upper backs of 10 healthy adult males.

The patched area was observed 60 minutes after the gel was removed, but no abnormalities were observed.

(4) Hydrocoal mucosal stimulation test The gels of Examples 1 and 2 were applied to the oral mucosa of 8 healthy adult males, covered with the oral mucosal adhesive bandage, and after 60 minutes the bandage was removed and observed. However, no abnormality was found in any of them.

Thus, the external preparation of the present invention has very high topical safety.

Clinical trial Effect test example 1 on lichen planus Subject: 73-year-old female At the first examination, red lesions with widespread edema were observed on both cheek mucosa, and a mixture of lace-like white streaks and white coating was observed in some areas. It was done. Clinically and histopathologically, it was determined to be lichen planus. Therefore, vitamins A, B complex, and C were administered and the progress was observed, but there was no change in the condition. Then, application of the gel of Example 1 was started. After the application started, it was applied four times, once on the 1st molar, 3rd day, 78th day, and 12th day of the bundle. After the fourth application, the red lesion became slightly stronger, but it was well localized from the mucous membrane around the lesion. It has been. Furthermore, on the 22nd day,
I continued applying the gel on the 36th day, the 43rd day, the 48th day, the 57th day, and the 62nd day. J6
After application on the second day (day and day), the lesion area shrunk, and then
Treatment was completed after three applications. By this time, the oral mucosal lesions had completely disappeared. No further recurrence is allowed.

Test Example 2 Subject: 51 years old, female, at the time of first examination, from the gingiva of both lower jaws to the gingiva of the teeth at a later date,
In addition, a mixture of erosions, ulcers, white coatings, and white streaks was observed in the red lesions on the buccal mucosa near the opening of Stensen's canal and the rough oral mucosa. Both clinically and histologically, the patient was diagnosed as having lichen planus. Application of the gel of Example 1 was started while anti-inflammatory treatment was being performed. After the start of application, it was applied four times, once on the 1st day, 3rd day and month, 6th day and month, and 10th day and month. From this section, the boundary between the mucosal lesion and the surrounding mucosa has become clearer, but the red lesion has become more intense and hemorrhagic.

If you continue to apply the gel, the 7th application (30th
From around 10:00 onwards, there was a tendency for the Witskam's striae to disappear and the bleeding to be reduced, and the mucosal lesions were localized and reduced in size. 6th
The gel was applied a total of 12 times up to the 2nd day, and a reduction in the oral mucosal lesions was observed. Afterwards, the disease condition was fixed, so we performed excision of the remaining oral mucosal lesion and skin grafting. The mucosal lesions were completely cured and no recurrence was observed.

Test Example 3 Subject Near A 3-year-old male subject underwent excision of the primary lesion and supragenoid lymph node dissection for treatment of recurrent oral mucosal carcinoma. Subsequently, the development of flat moss was observed from the gingiva to the buccal mucosa on the left side of the mandible. Therefore, application of the gel of Example 2 was started. The mucosal lesions increased in redness and swelling for a period after the application was applied three times, once on the 1st day, the 5th day, and the 10th day.After the 7th application was performed on the 25th day, the mucosal lesions started to show signs of erosion. A trend toward improvement was observed, and with continued application, the condition gradually improved. The 11th application was performed on the 62nd day and the treatment was completed. The lesion has almost completely healed, and no recurrence has been observed.

Effect test example 1 on leukoplakia Subject: A 63-year-old female subject developed vitiligo and erosion on the back of her left tongue. She continued to apply steroid ointment, but no improvement in symptoms was observed. Vitiligo, ulceration, and spontaneous pain were observed from the tongue margins to the sagittal region on both sides.

The patient was diagnosed with leukoplakia both clinically and pathologically. Therefore,
Application of the gel of Example 1 was started. 46th after starting application
The leukoplakia disappeared after the fifth application on the day and day, and no recurrence was observed thereafter.

Test Example 2 At the time of the first examination of a 263-year-old male subject, a white lesion was observed on the left-sided mucosa in an area measuring approximately 2.5 x 23 from below the opening of Stensen's canal to the rear molars, and which could not be removed by rubbing. The surface +1 was partially granular with mucosal erosion and edema mixed in. However, no significant ulcer formation was observed.

The patient was diagnosed with leukoplakia both clinically and by pathological diagnosis.

Therefore, application of the gel of Example 1 was started. From around the 4th application on the 19th day, the leukoplakia lesions on the buccal mucosa began to clear up, and by the 10th application on the 62nd day, only a white line showing a tendency to keratinization remained, and contact pain occurred. wlJ) was resolved, and the mucosal erosion and red discoloration also disappeared. In this case, the treatment was completed after the 10th application, but although white streaks with a tendency to keratinization remained, there were no subjective symptoms and no tendency for recurrence was observed.

Test Example 3 Subject Nia 0 years old 1 female A mucosal lesion containing a mixture of mucosal redness, erosion, and a white lesion that could not be removed by rubbing was observed in the area extending from the right lower lip to the buccal mucosa and also to the alveolar crest gingiva of the molar region. The patient was diagnosed with leukoplakia both clinically and by pathological diagnosis. Therefore, application of the gel of Example 2 was started. After the third application on the 27th day, the white stones on the oral mucosa gradually decreased. Furthermore, although the redness of the mucous membrane seemed to have increased temporarily, it gradually approached the normal mucosal image, and after the 10th application on the 84th day,
The leukoplakia lesions cleared up, and subjective symptoms such as contact pain disappeared.

As shown in the above clinical test examples, the external preparation of the present invention exhibits extremely excellent therapeutic effects on lichen planus and leukoplakia. During each clinical trial, no abnormalities were observed in the subjects' blood cell counts or biochemical values.

Patent applicant Sunstar Co., Ltd. Representative Patent Attorney Aoyama T or 2 people

Claims (1)

[Scope of Claims] (1) An external preparation for the treatment of dyskeratosis of the skin and mucous membranes, which contains interferon as an active ingredient, and contains a trivalent or higher valent sugar alcohol and a carrier acid buffer. (2) The external preparation according to item @(1) above for the treatment of lichen planus. 13) The external preparation according to item (1) above, which is for the treatment of leukoplakia. (4) ``An external preparation according to any one of Items (1) to (3) of Article IJ containing 10 to 108 international units of interferon per dosage unit. (5) The external preparation according to any one of the above items 11) to 141, which is in the form of ointment removal. (6) Items (1) to (4) above, which are shaping of the paste agent.
Item 1 or 1 topical agent j0 (7) Items (1) to 14 above, which are gel sharpeners.
(8) The external preparation according to any one of the above items (5) to (7), which contains carboxymethyl cellulose as a binder. (9) Spray dosage form 1liJ+15t11
External preparation according to any one of Items to Items (4). 00) An external preparation according to any one of the above-mentioned Otokozancho to item 14), which is a shaved liquid preparation.