JPH0443048B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an agent for treating or preventing allergic rhinitis that is applied to the nasal mucosa. More specifically, it is a drug-free coating and protective agent that adheres to the nasal mucous membrane, absorbs moisture from the mucus on the nasal mucosa, and is in a viscous liquid state with appropriate adhesiveness and appropriate fluidity. The present invention relates to an allergic rhinitis treatment or prevention agent for spray administration, which coats and protects the nasal mucosa and is effective in treating or preventing diseases such as allergic rhinitis. Hitherto, no drug-free formulation for coating and protecting the nasal mucosa has been known. On the other hand, JP-A No. 56-20509 discloses a long-acting nasal preparation containing a cellulose ether such as hydroxypropyl cellulose, methyl cellulose, hydroxyethyl cellulose, or hydroxypropyl methyl cellulose, and an effective amount of one or more drugs. A long-acting nasal preparation is disclosed. However, this publication does not contain any information regarding whether or not a drug-free formulation made of cellulose ether can be used as a coating and protective agent for the nasal mucosa and is effective in treating or preventing allergic rhinitis, etc. None have been disclosed. The present inventor has found that for the treatment or prevention of allergic rhinitis, etc., it is effective to some extent to simply coat and protect the nasal mucosa without using drugs, and that such a coating and protectant is effective to some extent. ℃
Cellulose lower alkyl ether, which has a viscosity of about 5 centipoise or more in an aqueous solution of 2% by weight, absorbs water on the nasal mucosa when administered to the nasal cavity and becomes viscous with appropriate adhesiveness and fluidity. A formulation consisting of cellulose lower alkyl ether is extremely suitable for producing a liquid state in which approximately 90% by weight or more of the particles have an effective particle size between approximately 20 and approximately 250 microns, and is suitable for intranasal administration. We have arrived at the present invention by discovering that when administered, little amount reaches the lungs or dissipates outside the nasal cavity, making it extremely suitable for intranasal administration. That is, the present invention comprises a cellulose lower alkyl ether having a viscosity of about 5 centipoise or more in a 2% by weight aqueous solution at about 37°C;
This is a substantially drug-free agent for treating or preventing allergic rhinitis in which at least % by weight of the particles have an effective particle diameter of between about 20 and about 250 microns. According to the present invention, when administered to the nasal cavity, it adheres to the nasal mucosa, absorbs moisture on the nasal mucosa, generates a viscous liquid state with appropriate adhesiveness and appropriate fluidity, and Therefore, by covering the nasal mucosa as a substantial fluid surface and gradually renewing the contact surface with the nasal mucosa and gradually flowing over the nasal mucosa, the nasal mucosa is covered and protected over a wide area. death,
Provided is a drug-free formulation for spray administration that prevents external stimuli such as antigens and is effective in treating or preventing allergic rhinitis and the like. The cellulose lower alkyl ether used in the present invention is one in which a plurality of hydroxyl groups of cellulose are at least partially substituted with the same or different lower alkyl ether groups. The lower alkyl group of the lower alkyl ether group may be substituted with a substituent. Preferred examples of such substituents include hydroxyl groups and alkali metal carboxylate groups such as sodium carboxylate groups. Examples of the optionally substituted lower alkyl group include a methyl group, a hydroxy lower alkyl group having 2 to 3 carbon atoms, or a carboxy lower alkyl group having 2 to 3 carbon atoms, in which the hydrogen atom of the carboxyl group is substituted with an alkali metal. Preferable examples include carboxylate groups corresponding to those described above. Examples of such optionally substituted lower alkyl groups include methyl, ethyl, n-propyl,
iso-propyl or β-hydroxyethyl, β-
Hydroxypropyl or carboxymethyl, α-
Examples include carboxylates of carboxyethyl or β-carboxyethyl with alkali metals. Examples of the cellulose lower alkyl ether include methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylhydroxyethylcellulose, sodium carboxymethylcellulose, and the like. Among these, methylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose are preferred because they are substantially free of odor and irritation, especially when administered to the nasal mucosa, which is sensitive to odor and irritation. Furthermore, among these, hydroxypropylcellulose is particularly preferred because it exhibits the property of easily absorbing moisture from the nasal mucosa until it provides appropriate adhesion and appropriate fluidity on the nasal mucosa. In the present invention, these hydroxy lower alkyl ethers may be used alone or in combination of two or more. According to the research of the present inventor, the agent for treating or preventing allergic rhinitis of the present invention is applied as a powder onto the nasal mucosa, absorbs moisture on the nasal mucosa, and forms a fluid that gradually flows over the nasal mucosa. The desirable properties of
A 2% by weight aqueous solution of cellulose lower alkyl ether is prepared and has a viscosity of greater than or equal to about 5 centipoise, preferably between about 5 and about 5000 centipoise, when measured at about 37°C or 37°C ± 0.2°C. It has been clarified that the properties of the cellulose lower alkyl ether can be approximately representative. Therefore, any degree of ether substitution may be used as long as the cellulose lower alkyl ether satisfies the above values. Generally, those having a degree of ether substitution of 0.1 to 6, particularly 0.4 to 4.6 are preferably used. The degree of ether substitution refers to the amount of 1 that constitutes cellulose.
It refers to the average total number of all other etheric oxygen atoms present per glucose unit, excluding the cyclic ether groups of glucose and the ether groups present between adjacent glucose units. Therefore, hydroxypropyl cellulose with an ether substitution degree of 3 may be composed of repeating units represented by the following formulas (a) and/or (b), for example. The allergic rhinitis treatment or prevention agent of the present invention includes:
Consisting of the above cellulose lower alkyl ether,
Moreover, more than 90% by weight of the particles have an effective particle diameter of approximately
It is required to be between 20 and about 250 microns. When the allergic rhinitis treatment or prevention agent of the present invention having such a viscosity distribution is administered as a powder into the nasal cavity through the nostrils, it adheres to a large proportion of the nasal mucosa, particularly the inferior nasal turbinate, nasal septum, and inferior nasal meatus. It adheres well to. Approximately 10 particles smaller than approximately 20 microns in effective particle diameter
If the amount is more than 10% by weight, more particles will reach the lungs or dissipate out of the nostrils when sprayed, whereas if the amount is more than 10% by weight, particles with an effective particle diameter of more than about 250 microns will Even if they adhere to the nasal mucosa, they tend to separate from the mucous membrane before absorbing water from the mucous membrane, so both are not preferred as agents for treating or preventing allergic rhinitis when sprayed into the nasal cavity. The agent for treating or preventing allergic rhinitis of the present invention is particularly preferably one in which about 90% by weight or more of the particles have an effective particle diameter of about 20 to about 150 microns. The allergic rhinitis treatment or prevention agent of the present invention includes:
In addition to the above-mentioned cellulose lower alkyl ether, in order to improve the physical properties, appearance or odor of the preparation, etc.
If necessary, one or more of known lubricants, binders, diluents, colorants, flavoring agents, preservatives, surfactants, etc. may be included. As a lubricant,
For example, talc, stearic acid and its salts, waxes, etc.; binders include, for example, starch,
Dextrin, tragacanth, gelatin, polyvinylpyrrolidone, polyvinyl alcohol, etc.; diluents include starch, crystalline cellulose, dextrin, lactose, mannitol, sorbitol, anhydrous calcium phosphate, etc.; flavoring agents include menthol, citrus flavor, etc. These usually have a maximum of about 10% by weight of the total weight.
It is possible to contain up to The allergic rhinitis treatment or prevention agent of the present invention includes:
It is produced by taking one or more of the cellulose lower alkyl ethers, mixing and sifting the above additives if necessary, or compressing these powders into flakes, and then crushing and sieving. It is made by dividing. The allergic rhinitis treatment or prevention agent of the present invention includes:
As a preferred form for administration, it can be filled into capsules, such as hard gelatin capsules. As a method for administering the formulation of the present invention by spraying into the nasal cavity, for example, a capsule filled with powder is set in a special spray device equipped with a needle, and the needle is passed through the capsule, thereby creating minute holes at the top and bottom of the capsule. There is a method of opening the container and then blowing air in with a rubber bulb or the like to blow out the powder. According to the research of the present invention, by maintaining the water content of the powder of the present invention at about 9% by weight or less, the particles forming the powder do not agglomerate, and therefore, it can be sprayed by the above-described spraying method. It was revealed that the drug was administered intranasally in an extremely well dispersed state. Therefore, the powders of the present invention preferably have a moisture content of about 9% by weight or less. In particular, the agent for treating or preventing allergic rhinitis of the present invention can be preferably applied to treating or preventing nasal diseases such as allergic rhinitis and vasomotor rhinitis. Hereinafter, the present invention will be explained in detail with reference to examples, but the examples are provided to explain the present invention and are not described to limit the scope of the present invention. Note that throughout this specification, the effective particle size and viscosity are defined and measured as follows. Effective particle size The effective particle size was determined by the opening of the sieve. For example, particles having an effective particle diameter (d) of 37<d≦44 microns refer to particles that pass through a 44-micron sieve but do not pass through a 37-micron sieve. The effective particle size of particles with an effective particle size larger than 37 microns was measured using a vibrating sieve, and the effective particle size of particles with an effective particle size of 37 microns or less was measured using a sonic sieve (manufactured by Tsutsui Rikagaku Kikai Co., Ltd.). The measurement was performed using a micro hand shifter (SWM-2 model). The openings (μ) of the sieves used are as follows. 500, 420, 350, 297, 250, 210, 177, 149,
125, 105, 88, 74, 63, 53, 44, 37, 25, 20
(μ). Viscosity A 2wt% aqueous solution of cellulose lower alkyl ether is poured into cold water to hot water (for example, about 5°C to about 5°C).
30°C) and stirring, or a method that provides a history of raising and lowering the temperature of the yarn, for example, by stirring in hot water at about 80°C to disperse the cellulose lower alkyl ether, and then, for example, dispersing the cellulose lower alkyl ether at about 5°C. It can be prepared by cooling to a completely homogeneous solution. For cellulose lower alkyl ether, one of the above methods is appropriately selected depending on the type of cellulose lower alkyl ether. The viscosity of the prepared 2wt% aqueous solution was determined by Tokyo Keiki.
Measurement was carried out using a B-type viscometer BL model manufactured by Co., Ltd. at 37°C ± 0.2°C by a conventional method with the rotor and rotor rotation speed appropriately selected according to the viscosity of the sample solution. Generally, it is recommended that the rotor and rotor rotational speed be adopted based on the measurement upper limit table below, depending on the viscosity of the aqueous solution.

[Table] Example 1 This example aims to clarify the sensory properties of cellulose lower alkyl ether when sprayed into the nasal cavity. This is a test for the feeling of a foreign body in the nasal cavity when water is absorbed on the mucous membrane. Take 40 mg of cellulose lower alkyl ether powder, in which 90% by weight or more of the particles have an effective particle size of 37 to 149 microns, fill it into a #2 hard gelatin capsule, and insert the capsule into a needle to make a hole in the capsule. and a special spray tool with a rubber bulb for blowing air. A needle with a diameter of 0.8 mm is passed through the set capsule,
A hole is made at each end of the capsule, and then a rubber bulb is pressed to send air, causing the cellulose lower alkyl ether powder to be ejected from the nozzle tip of the spray tool. The tip of this nozzle was inserted into the nasal cavities of 10 volunteer patients with perennial allergic rhinitis, and 40 mg (total amount) of cellulose lower alkyl ether was sprayed into the nasal cavities by spraying 4 times on each side alternately. Sensory tests were conducted on the properties, adhesion to mucous membranes, and the sensation of a foreign body in the nasal cavity after absorbing water and swelling. The results are shown in Table 1. Odor and irritation were evaluated as follows: 9 to 10 people agreed that they could continue to use the cellulose lower alkyl ether as an intranasal spray formulation because it had almost no odor or irritation. 〇 mark means that 6 to 8 people said that it has a slight odor and irritation but is OK to continue using it; △ mark means that 5 people said that it has an odor and irritation but that it is OK to continue using it. If there were 3 or more people who did not wish to continue using the service, or who did not wish to continue using it, it was indicated by an x. In addition, the adhesion to the nasal mucosa was evaluated as follows: After spraying cellulose lower alkyl ether into the nasal cavity, 8 or more people showed that the cellulose ether did not come off as a white powder from the nasal cavity within 10 minutes. If there are 8 or more people from whom a very small amount of the cellulose ether powder has fallen off, △ if there are 3 people from whom a considerable amount (approximately 4 mg or more) of the cellulose ether has fallen off. Cases where the above is true are indicated by an x mark. The feeling of a foreign body in the nasal cavity after the sprayed cellulose lower alkyl ether absorbed water and swelled in the nasal cavity was evaluated as follows: Those who hardly felt any foreign body sensation were rated 9-9.
If there are 10 people, mark ○, if 6 to 8 people hardly feel the foreign body sensation, and if 2 to 4 people feel it, mark △, if 5 or more people feel an unpleasant foreign body sensation. The cases are indicated with an x mark. In addition, carboxymethyl cellulose calcium,
A comparison was made using cellulose acetate phthalate and polyacrylic acid, and the results are shown in Table 1.

【table】

[Table] Example 2 In this example, in order to clarify the appropriate range of particle size distribution of the formulation of the present invention, cellulose lower alkyl ethers with different effective particle size distributions were prepared,
It was sprayed into the nasal cavity and the sensual sensation was tested. The viscosity of a 2% by weight aqueous solution at 37±0.2℃ is
Hydroxypropyl cellulose exhibiting 1550 centipoise or methyl cellulose exhibiting 650 centipoise methyl in a 2% by weight aqueous solution at 37 ± 0.2°C was classified using a micro hand shifter SWM-2 model manufactured by Tsutsui Rikagaku Kikai Co., Ltd., and the classified powder was A powder having the effective particle size distribution shown in Table 2 was obtained by mixing appropriately. 40 mg of each of these powders was filled into #2 hard gelatin capsules. The powder in these gelatin hard capsules was sprayed onto Subject 5 using the spray tool described in Example 1.
The powder was sprayed into the left and right nasal cavities of the nose, and a sensory test was conducted to determine the discomfort in the nasal cavity based on the dispersibility of the powder.
As a result, 20% or 13 particles smaller than 20 microns
% content, the powder reaches the larynx and laryngeal orifice at the same time it is sprayed, and 4 people felt uncomfortable because they may choke on it reflexively. Five people said that the amount of fine powder dissipated was too large, which made them uncomfortable, and it became clear that the agent of the present invention was not suitable for treating or preventing allergic rhinitis. Furthermore, in the case of powders in which particles exceeding 250 microns account for 10% by weight or more, when sprayed into the nasal cavity, the powder tends to adhere to the nasal hairs, or even if it adheres to the nasal mucosa, it easily separates, so it should be immediately removed from the nostril after administration. There were 5 people who said that they felt uncomfortable due to the large amount of powder coming off during the treatment, and it became clear that the agent of the present invention is not suitable for treating or preventing allergic rhinitis. From these results 20
It has been found that a powder in which 90% by weight or more of particles having an effective particle size of 20 to 149 microns is preferred, and a powder in which 90% by weight or more of particles having an effective particle size of 20 to 149 microns is particularly preferably used. Furthermore, 100 mg of each of the powders listed in Table 2 above was similarly filled into #2 hard gelatin capsules, and the following tests were conducted. These capsules were set in the spray tool described in Example 1, and the tip nozzle of this spray tool was set in the center of the horizontal surface of a box measuring 100 cm long, 60 cm wide, and 50 cm high, and the rubber balls were sprayed as much as possible. Press strongly and instantly to send air and spray the powder inside the box. After repeating this operation 10 times, the weight of the powder that had settled and fallen from the tip nozzle to the bottom of the box in an area 12 cm wide and 70 cm long was measured, and the dispersibility of these powders was determined. The results are also shown in Table 2 as collection rate (%). The collection rate (%) indicates the ratio of the amount that fell in the area to the amount that was sprayed. It can be seen that those determined to have a preferable effective particle size distribution by the above sensory test have a collection rate of about 80 to 94% by weight.

[Table] Example 3 In this example, in order to clarify the changes in the condition over time when the agent for treating or preventing allergic rhinitis of the present invention, which is made of cellulose lower alkyl ether, is sprayed into the nasal cavity, the powder was examined using an endoscope. The adhesion to mucous membranes, swelling, fluidization, and coating state were observed. 50 g of hydroxypropyl cellulose, a 2 wt. By rotating the powder, the surface of the powder is constantly renewed.
An ethanol solution prepared by dissolving 0.5 g of Brilliant Blue in 1 ml of ethanol was sprayed little by little, and this operation was repeated while the ethanol was volatilized to obtain a powdered composition in which the hydroxypropyl cellulose particles contained the Brilliant Blue pigment. Fill 10 mg of this product into a hard gelatin capsule, set it in the spray tool described in Example 1, spray it to the lower part of the inferior nasal turbinate of the subject, and treat the sprayed powder over time after administration. Changes were observed using an endoscope and photographs were taken.
Figures 1, 2, 3, and 4 are drawings of the state of the powder when it is administered into the nasal cavity, based on photographs. FIG. 1 shows a state immediately after spraying in which the sprayed powder adheres to the lower part of the inferior nasal turbinate part 3. Figure 2 shows the state of the same area 1 hour after administration, where hydroxypropyl cellulose absorbs water from the nasal mucosa and changes into a film on the nasal mucosa, but it is not yet fluidized. It is shown that. Figure 3 is after administration
This is the state of the same area after 2.5 hours, showing that the hydroxypropyl cellulose layer containing the dye becomes fluid and gradually flows deeper while covering the inferior nasal turbinate mucosa. FIG. 4 shows the state 4 hours after administration, and there is already no hydroxypropyl cellulose containing dye at the lower tip of the inferior nasal turbinate. This is because it flows deeper along the lower surface of the inferior nasal turbinate. For these reasons, by spraying the powder composition of the present invention into the nasal cavity, the powder adheres to the nasal mucosa, absorbs moisture from the mucus on the nasal mucosa, and has appropriate adhesiveness and fluidity. Generate a viscous liquid state that has the following properties, thereby covering the nasal mucosa as a substantial fluid surface, and reaching the deep part of the nasal cavity while slowly renewing the contact surface with the nasal mucosa on the nasal mucosa. From these findings, it is inferred that the agent for treating or preventing allergic rhinitis comprising cellulose lower alkyl ether of the present invention covers and protects the nasal mucosa over a wide range. Furthermore, using capsules filled with 40 mg or 60 mg of hydroxypropyl cellulose containing a dye, we conducted the same test as above, and found that they adhered over a wider area and took less than 2 to 2 hours to pass through the area visible with an endoscope. Almost the same behavior was observed except for a 3 hour extension. Example 4 This example tested the effect of moisture on the jetting properties of powders from gelatin capsules in unit dosage form. The viscosity of a 2% by weight aqueous solution at 37±0.2℃ is
1550 centipoise, with more than 90% by weight of particles
100 mg of hydroxypropylcellulose having an effective particle size of 37 to 149 microns is packed into hard gelatin capsules with 0.5 mg of magnesium stearate as a powder in unit dosage form, at relative humidity of 55%, 65%, and 70%. The water was left in an atmosphere of 75% for one day to reach equilibrium, and then a spray test was conducted using the spray tool described in Example 1 (needle diameter: 0.8 mm) to determine the amount of spray compared to the weight of the powder in the capsule. The weight ratio of the powder, that is, the ejection rate (%) was determined. The results are shown in Table 3.

[Table] Example 5 The viscosity of a 2% by weight aqueous solution at 37±0.2°C is
Hydroxypropylcellulose having a particle size of 1550 centipoise is classified to obtain a powder in which particles with an effective particle diameter of 20 μ or less account for 7% or less and particles with a size of 20 to 250 μ account for 93%. This is made into #2 hard capsules.
A 30 mg dose was administered to 10 patients with perennial nasal allergies using the spray device described in Example 1.
When spraying, when inhaling, spray 1 from one nostril.
It was sprayed twice, and the other nostril was closed. Next, the same operation was performed for the other nostrils, and each capsule was sprayed 8 times in total, 4 times on each side. Two capsules per day were administered for one week in a row, and the degree of improvement in combing, nasal discharge, and nasal congestion was observed and divided into marked improvement, improvement, slight improvement, no change, and worsening. The total improvement was 40%, and the improvement was 60%, indicating that there were no side effects, and this drug was clinically shown to be effective as the allergic rhinitis treatment or prevention agent of the present invention.

[Brief explanation of drawings]

FIG. 1 shows the state of the agent for treating or preventing allergic rhinitis of the present invention immediately after it is administered to the inferior turbinate region of the nasal cavity. FIG. 2 shows the state of the agent for treating or preventing allergic rhinitis 1 hour after administration. Figure 3 shows the state of the agent for treating or preventing allergic rhinitis 2.5 hours after administration. FIG. 4 shows the state of the agent for treating or preventing allergic rhinitis 4 hours after administration. In Figure 1, 1 indicates the nasal cavity, 2 indicates the middle nasal turbinate, and 3 indicates the inferior nasal turbinate. Indicates the condition of the agent.

Claims (1)

[Claims] 1. Consists of cellulose lower alkyl ether having a viscosity of about 5 centipoise or more in a 2% by weight aqueous solution at about 37°C, and about 90% by weight or more of the particles have an effective particle size of about 20 to about 250 microns. A treatment or prevention agent for allergic rhinitis that is substantially drug-free. 2. A patent in which the cellulose lower alkyl ether has at least one of a methyl group, a hydroxy lower alkyl group having 2 to 3 carbon atoms, and a carboxylate group with an alkali metal of a carboxy lower alkyl group having 2 to 3 carbon atoms as a lower alkyl group. The agent for treating or preventing allergic rhinitis according to claim 1. 3. The agent for treating or preventing allergic rhinitis according to claim 2, wherein the cellulose lower alkyl ether is methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylhydroxyethylcellulose, or carboxymethylcellulose sodium. 4. The agent for treating or preventing allergic rhinitis according to claim 2, wherein the cellulose lower alkyl ether is methylcellulose, hydroxypropylcellulose, or hydroxypropyl, methylcellulose. 5 Claim 2 in which the cellulose lower alkyl ether is hydroxypropylcellulose
The agent for treating or preventing allergic rhinitis described in Section 1. 6. The treatment of allergic rhinitis according to any one of claims 1 to 5, wherein the viscosity of a 2% by weight aqueous solution of cellulose lower alkyl ether at about 37°C is between about 5 and about 5000 centipoise. Or preventive agent. 7 Approximately 90% by weight or more of the particles have an effective particle size of approximately 20 to approximately
Claims 1 to 150 microns
The agent for treating or preventing allergic rhinitis according to any one of Item 6. 8. The agent for treating or preventing allergic rhinitis according to any one of claims 1 to 7, which is filled in a capsule. 9. The agent for treating or preventing allergic rhinitis according to claim 8, wherein the capsule is a hard gelatin capsule.