JPH0347128A - Protecting drug of tunica mucosa nasi - Google Patents

Abstract

PURPOSE:To obtain protecting drug of tunica mucosa nasi useful for prevention and curing of nasal allergy such as pollinosis having tunica mucosa nasi- protecting action without adverse effect containing alkali metallic salt of saccharides sulfate as active ingredient. CONSTITUTION:Alkali metallic salt of saccharides (e.g., maltose or dextran) sulfate is contained in the aimed protecting drug. Said alkali metallic salt is obtained by treating said saccharides with, e.g., pyridine-SO3 complex or chlorosulfonic acid in DMF according to normal method. Alkali metallic salt of sulfate of polysaccharide such as cellulose or dextran is especially preferable as said salt. Said protecting drug of tunica mucosa nasi is the most preferably made to formulation in liquid and sprayed to tunica mucosa nasi. To increase staying property on tunica mucosa nasi, making to formulation with using polymer material (e.g. hydroxypropyl methyl cellulose) having 300-2000cps (20 deg.C) is preferable.

Description

DETAILED DESCRIPTION OF THE INVENTION 1. The present invention relates to a nasal mucosa protective agent containing saccharides, particularly saccharides of two or more monosaccharides as an active ingredient. Used as a preventive or therapeutic agent for allergies.

Antigens inhaled into the nasal cavity and deposited on the nasal mucosa combine with IgE antibodies on basophils within the mucus layer, and chemical mediators are released from these cells. Furthermore, the water-soluble antigen protein invades the lamina propria, binds to IgE antibodies on mast cells, and releases various chemical mediators.

These chemical mediators cause the three main symptoms of nasal allergy: sneezing, watery nasal discharge, and nasal congestion due to mucosal edema.

The nasal mucosal epithelium in patients with nasal allergies is severely damaged as a result of repeated episodes of three symptoms. Therefore, antigenic proteins easily reach the lamina propria of the mucosa and cause release of large amounts of chemical mediators, contributing to worsening of nasal allergy symptoms. Medications for the treatment of nasal allergies include inhibitors of the release of chemical mediators such as histamine and leukotrienes, competitive antagonists of released chemical mediators (antihistamines), vasoconstrictors,
There are also steroids and antihistamines, but other than antihistamines and steroids, they are not fast-acting, and even after long-term administration, no significant therapeutic effect has been obtained. Furthermore, although steroid drugs have a remarkable symptom-suppressing effect, they have problems in their frequent use, and in particular cannot be used in children.

In view of these circumstances, the present inventors conducted extensive research and found that alkali metal salts of sulfate esters of sugars, especially alkali metal salts of sulfate esters of sugars with two or more monosaccharides, penetrate the mucosal layer and lamina propria of antigens. They have found that it is useful for preventing or treating nasal allergies because it prevents the invasion of nasal mucosa and also has a protective effect on the nasal mucosa. It is known that, as an alkali metal salt of a saccharide sulfate ester, for example, a dextran sulfate ester is used as a hyperlipidemia improving agent. In addition, in recent years, it has been reported that dextran sulfate esters inhibit HIV reverse transcriptase and can be used as a therapeutic agent for AIDS (Lance et al.
1379), and it is also known that sulfate esters of synthetic oligosaccharides have a wound healing effect (Japanese Unexamined Patent Publication No. 82-1
90127). However, there is no known report that saccharide sulfate esters have a protective effect on the nasal mucosa and are effective in treating nasal allergies and the like. The nasal mucosa protective agent of the present invention does not have the side effects of conventionally used steroids, and is extremely excellent as a therapeutic agent for nasal allergies and the like based on a novel idea.

The first aspect of the present invention relates to a nasal mucosa protective agent containing an alkali metal salt of a sulfuric acid ester of a saccharide, preferably a disaccharide or more-L oligosaccharide or polysaccharide as an active ingredient.

In the present invention, saccharides are preferably oligosaccharides or polysaccharides, and specifically include oligosaccharides such as maltose, sucrose, maltotriose, and stachyose, polysaccharides such as dextran, dextrin, and cellulose, and acid hydrolysates thereof. Furthermore, it is a saccharide containing a nitrogen atom in the molecule, such as chitosan. The alkali metal salts of sulfuric esters of saccharides of the present invention are produced by treating these saccharides in a conventional manner, for example, with pyridine-5O3 complex, chlorosulfonic acid, etc. in dimethylformamide. In the salt of the saccharide sulfate ester of the present invention, saccharides with different substitution positions and numbers of sulfonic acid groups are produced depending on the raw materials and the sulfonation method, and any of them can be used as the nasal mucosa protective agent of the present invention. A particularly preferred example is an alkali metal salt of a sulfate ester of a polysaccharide such as cellulose or dextran, and the number of substitutions of the sulfate ester of these saccharides is as follows: The S content (ratio of S in the entire molecule) is 15% or more.

The nasal mucosa protective agent of the present invention is most preferably used by formulating it into a liquid form and spraying it onto the nasal mucosa. For this purpose, the drug can be dissolved as it is in a suitable solvent, such as physiological saline, and administered directly to the nasal mucosa, but the better the nasal mucosa retention, the better the therapeutic or preventive effect. Therefore, they are formulated using various polymeric materials to increase their viscosity. The formulation has a viscosity (E method) of 300 CPS to 200
A range of 0 CPS (at 20° C.) is preferred. Examples of polymeric materials used for this purpose include hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, ponyvinylpyrrolidone, gelatin, sodium alginate, carboxyvinyl polymer, carboxymethylcellulose, sodium carboxymethylcellulose, and macrogol 60.
00, methylcellulose, calcium carboxymethylcellulose, gum arabic, sodium starch glycolate, hydroxyethylcellulose, hydroxypropyl starch, Dragont gum, and the like.

The mode of formulation of the alkali metal salt of saccharide sulfate ester of the present invention using these polymeric materials is not limited to liquid form, but can also be formulated and used in fine powder form.

The nasal mucosal protective agent of the present invention is usually used in adults depending on the symptoms.
Appropriately select from the range of 0.1g to 100mg per animal, 1
It is administered to the nasal mucosa once or several times a day.

Manufacturing example 1. Preparation of cellulose sulfate ester sodium salt 10 g of cellulose was suspended in dimethylformamide 20061, and 60 g of chlorosulfonic acid 141 was added at 0° C. under nitrogen.
Drip in minutes. After 5 hours, carbonate the reaction solution) IJ
Pour into an aqueous solution of aluminum, neutralize, and then dialyze. 50% dialysate
1, add ethanol 5001, and collect the precipitate by filtration. Wash with ethanol and dry to obtain 11 g of white precipitate Average molecular weight: 50000 Elemental analysis value C6Hg05・(SO3Na)2・2f
Calculated value of CHS as l, O (%) 17.91 2.99 15.92
Actual value (%) 17.7G 3.02 15.5
Production Examples 2 to 8 Dextran, dextrin, chitosan, sucrose, and mannose were used as raw materials and treated in the same manner as in Production Example 1 to obtain the following compounds.

Production example 2. Dextran sulfate ester sodium salt average molecular weight: 500000 Elemental analysis (11Ct-HtOs・C3OJa)3・H2
CHS as O Calculated value (%) 14.81 1.85 19.75
Actual value (%) 14. fi8 2.92 20.2
3 Manufacturing example 3. Dextran sulfate ester sodium salt average molecular weight: 4300 Elemental analysis value C1zH40+o ・(SO3Na)4
・3II! OCHS calculated value (%) +4.54 2.02 m9.3
9 Actual value (%) 14.90 2.33 18.7
B production example 4. Chitosan sulfate ester sodium salt average molecular weight: 25000 Elemental analysis value C4H9 (NOa 1sOINa) 2.5
・2u2゜Calculated value (%) lG, 44 2.85 3
．． 20 19.211i actual measurement value (%) 15.44 2
．． 69 3.10 18.7 Production example 5. Average molecular weight of sucrose sulfate ester sodium salt: 1194 Elemental analysis value clZIl=o, l ・(SO3Na)g・
CH as 2H20 Calculated value (%) 12.08 1.51 Actual value (%)
12.10 1.7721.48 20.58 Production example 6. Mannose sulfate ester sodium salt average molecular weight Near 08 Elemental analysis value C6Hg05・(SOJa)5−・112
H8 calculated value (%) 10.17 1.27 22JO actual value (%) 10.57 1.37 22.57 Example 1゜ (experimental method) Hartley female guinea pig (4al+, = 10Mg/
The mice were sensitized by intraperitoneal injection of a physiological saline solution containing ml ovalbumin (OVA), 4 g/l aluminum hydroxide, and 2 x i o 10 killed B. pertussis bacteria. 1
Two days before the second booster immunization, a physiological saline solution of cyclophosphamide was injected intraperitoneally at 250 μg/kg. Thereafter, four booster immunizations were performed every 28 days in the same manner.

Eight days after the final immunization, whole blood was collected and serum was prepared. 8-day PCA of the anti-OVA guinea pig serum thus obtained
titer+, i B days 640 times, 4 hours 25
60x and 8-day PCA titer of heat-treated serum
was 20 times or less. Anti-OVA prepared as above
Guinea pig serum was added to 0.2. ＠i was intravenously injected into Nor＼-tray male guinea pigs (10 weeks old) to passively sensitize them.

Reaction induction was performed 8 days later. The guinea pig was fixed in a cylindrical chamber with its head protruding outward. An adapter with a differential pressure transducer was placed over the patient's head to measure respiratory volume and rate, which could then be recorded on a pen recorder. The immobilized animal was allowed to stand still for 5 minutes, and after confirming that the respiratory disturbance had subsided, a 20 μm thick saline solution of the compound of Preparation Example 1 of the present invention was injected into both nasal cavities. After 10 minutes, breathing was measured and it was confirmed that the patient was sedated. Subsequently, induction was performed by nasally instilling 10 μl of a 3 mg/ml OVA solution in physiological saline into both nasal cavities.

Since nasal symptoms (nasal discharge, nasal congestion) appear immediately after antigen challenge, they were examined by observation for 10 minutes after nasal injection. As a control group, 20 μl of physiological saline was instilled into the nose instead of the compound of the present invention.

(Experimental results) In the control group (10 cases), within 10 minutes after inducing a reaction, 6 cases had a decrease in respiratory rate accompanied by hypernasal discharge, followed by a decrease in respiratory volume! l
The appearance of (``abare'' as a systemic symptom) (this was used as an indicator of ``nasal allergy symptom expression'') was observed. One case presented with polynasal discharge, and ``abare'' appeared immediately after the observation was completed.

In the remaining three cases, there were no changes in breathing after that.

In contrast to this control group, 2 of the 5 patients in the group administered with the compound described in Production Example 1 of the present invention had no change in breathing at all, but the remaining 3 patients also had slightly excessive nasal discharge, and there was no decrease in their breathing rate. However, it did not lead to the ``abare'' observed in the control group.

Experimental Example 2 (Experimental Method) Similar to Experimental Example 1, anti-OV was administered to male Hartley guinea pigs.
Guinea pig serum A was intravenously injected for passive sensitization, and 8 days later, a 100 μm/1 saline solution of the compound of Preparation Example 2 of the present invention was injected into both nasal cavities in an amount of 20 μm for use in experiments.

(Experimental Results) Among the group (5 cases) administered with the compound of Production Example 2 of the present invention, "cracking" was observed within 10 minutes after the reaction was induced in only one case. 2
In this case, there was no change in breathing. The remaining two cases had a slightly excessive nasal discharge, but did not become ``abare''.

Experimental Example 3 Production Examples 3 and 4 were carried out using the same experimental method as described in Example 1.
Experiments were conducted on the compounds obtained in 5 and 8. As a result, when the effect of the sodium salt of cellulose sulfate ester obtained in Production Example 2 (described in Example 1) was set to an inhibition rate of about 70 to 80%, the compounds obtained in Production Examples 3, 4, and 5 had a suppression rate of about 5%.
The compound obtained in Production Example 6 exhibited an inhibition rate of about 20 to 0%.
It showed an inhibition rate of 30%.

Claims (1)

[Scope of Claims] 1) A nasal mucosa protective agent containing an alkali metal salt of a saccharide sulfate ester as an active ingredient; 2) A nasal mucosal protective agent according to claim 1, wherein the saccharide is a saccharide having two or more monosaccharides; 3) A saccharide. 4) The nasal mucosa protective agent according to any one of claims 1 to 3, wherein the saccharide is a oligosaccharide or a polysaccharide; 4) The nasal mucosal protective agent according to any of claims 1 to 3, wherein the saccharide is cellulose, dextran, or a derivative thereof; 5) nasal allergy or , the nasal mucosa protective agent according to each item of claims 1 to 4, which is a prophylactic or therapeutic agent for hay fever.