JPH0558888A - Inhalant - Google Patents

Abstract

PURPOSE:To obtain a readily usable inhalant, useful as an airway mucilage regulating and a mucous membrane normalizing agents excellent in adsorptivity by placing an aqueous solution containing carbocysteine and a stabilizer in a container, replacing the spatial part of the container with an inert gas and then hermetically sealing the container. CONSTITUTION:The objective inhalant is obtained by placing an aqueous solution containing 0.5-30wt./vol.% carbocysteine as an active ingredient and 0.005-20 wt./vol.% (based on the carbocysteine) one or more stabilizers such as sodium citrate or sodium edetate at pH 6.0-7.5 (an aqueous solution of sodium hydroxide is used for regulating the pH) in a container, replacing the spatial part of the above-mentioned container with nitrogen gas and then hermetically sealing the container.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an inhalant containing carbocysteine which is an airway mucus regulating / mucosal normalizing agent.

[0002]

2. Description of the Related Art Carbocisteine reduces the viscosity of mucus by normalizing the composition ratio of sialic acid and fucose in airway mucus, and at the same time, repairs the ciliated cells of the bronchial mucosal epithelium. It has the action of promoting sputum discharge. Carbocysteine formulations have traditionally been tablets (250 mg), fine granules (0.5 mg) for oral administration.
%) And a syrup (5%) have been developed and used.
However, the dose of carbocysteine is 500 for adults once.
It was as large as mg, and in the case of tablets, it became a large tablet, which was sometimes difficult to take. In addition, carbocysteine is poorly soluble in water, and a large dose had to be taken to form a syrup. In order to reduce the dose of carbocisteine and to exert its effect more effectively, inhalation from the respiratory tract and administering high concentration of carbocisteine directly to the airway cell surface,
It was desired to enhance the pharmacological effect.

However, the aqueous solution of lubocysteine has a change in color and the generation of decomposition products due to long-term storage and light,
There was a problem with stability.

A syrup preparation of 5%, which is a commercially available preparation, contains a high concentration of saccharides in order to enhance its stability (Japanese Patent Laid-Open No. 63-63113).
-156719). However, this solution became highly viscous and was not sprayed even with an ultrasonic nebulizer as an inhaler, so it was not used as an inhalant.

[0005] Due to these problems, while the development of an inhalant as a means for direct application to the respiratory tract has been desired, an inhalant containing carbocysteine has not been developed.

[0006]

In order to solve the above problems, the present inventors have earnestly studied the development of an inhalant as a dosage form which is easy to use and can be expected to have a rapid effect. As a result, a stable solution having a low viscosity in which carbocysteine was dissolved was completed, and an inhalant containing carbocysteine of the present invention as an active ingredient was completed.

That is, the present invention is characterized in that an aqueous solution containing carbocysteine and a stabilizer and having a pH of 6.0 to 7.5 is put in a container, the space of the container is replaced with an inert gas, and then the container is sealed. The present invention relates to an agent, and particularly 0.5 to 30 w / v% with carbocysteine as an active ingredient.
The present invention relates to inhalants contained therein.

The stabilizer in the present invention is at least one selected from sodium citrate, sodium edetate, sodium bisulfite, calcium gluconate, sodium thiosulfate, potassium dihydrogen phosphate, ammonium sulfate and tartaric acid. Cysteine 0.
005-20 w / w% amount.

The inhalant of the present invention containing carbocysteine as an active ingredient is a nebulizer which uses an ultrasonic atomizer as a method for inhaling directly or diluting a solution of rubocysteine, or atomizes it together with compressed air. Is an inhalant. Alternatively, it may be an inhalant filled with a propellant for use.

The solubility of carbocysteine in water is 1
Since it was as low as mg / ml or less and its pH was as low as 2.9, physiologically administration to the airway mucosa was not desirable.
A method of dissolving carbocysteine at a higher concentration and preparing an aqueous solution of carbocysteine in a physiologically acceptable pH range is possible by dissolving carbocysteine in an aqueous sodium hydroxide solution. Further, the stability of the carbocysteine aqueous solution varies depending on the pH, and decomposition occurs in extremely acidic or alkaline solutions. In terms of stability, the desirable pH range of the aqueous solution of carbocysteine was 6.0 to 7.5 (JP-A-63-156719).
issue). As the pH adjuster, a commonly used alkaline agent may be used, and the most suitable is an aqueous sodium hydroxide solution.

The aqueous solution of carbocysteine has a pH of 6.0 to
Even after adjusting to 7.5, yellow coloring is observed even after long-term storage. Therefore, a stabilizing method for preventing these was studied earnestly.

Various additives were added to a 5% aqueous solution of carbocysteine, the mixture was filled in a 50 ml glass bottle, and a part of the sample was purged with nitrogen gas, and then stored at 50 ° C. for 30 days. The effect on the stability of the agent was investigated. The results are shown in Table-1.

The measurement was performed as follows. -Appearance measurement conditions: A sample placed in a colorless glass bottle was visually observed from the side of the container with white as a background under diffused light in a room.

Carbocysteine content measurement method: Carbocysteine was measured by high performance liquid chromatography (HPLC).

Equipment: Hitachi L-6200 type Column: Nucleosyl 5C ₁₈ (φ4 mm × 150 mm) Moving layer: 0.1% trifluoroacetic acid solution Flow rate: 0.1 ml / min Detection: UV absorptiometer, wavelength 240 nm

[0016]

[Table 1]

Although sodium citrate, sodium edetate, and sodium hydrogen sulfite as additives were effective in preventing discoloration of the aqueous solution of carbocysteine as compared with those without addition, the effects were not sufficient. Further, the effect of preventing coloration was recognized by a method of only replacing the space in the container with nitrogen gas, but the effect was not sufficient when nitrogen gas was replaced alone. However, it was newly found that the colorant can be completely prevented by adding a stabilizer such as sodium citrate, sodium edetate and sodium bisulfite together with nitrogen gas substitution. As a result of examining the amount of sodium citrate added and the effect of preventing coloration, sodium citrate was found to be 1 to 20 w / w% of carbocysteine.
It was found that the effect was shown by adding the amount. Also, the amount of sodium edetate or sodium bisulfite added is 0.005-1 w /
It was found that the effect was shown by w%.

Furthermore, additives that can be stabilized in addition to the carbocysteine inhalation solution were searched for. The additives used for medical treatment were examined, and some of the results are shown in Table-2.

[0019]

[Table 2]

Those which had an effect of preventing coloration were sodium edetate, sodium hydrogen sulfite, sodium citrate, sodium gluconate, tartaric acid, sodium thiosulfate, potassium dihydrogen phosphate and ammonium sulfate.

The amount of the stabilizer added is sodium edetate,
Sodium bisulfite and sodium thiosulfate are 0.01 to 1 w / w% of carbocysteine, and sodium citrate, sodium gluconate, tartaric acid, potassium dihydrogen phosphate and ammonium sulfate are 0.2 of carbocysteine.
It was shown to be effective at ~ 5 w / w%.

The concentration of the carbocysteine aqueous solution used for the inhalant is preferably 0.5 to 30 w / v%. 0.5 w / v
No pharmacological effect can be expected at a low concentration of less than%. In addition, carbocysteine is about 70 w / when an alkaline agent is used.
It is possible to prepare up to v% aqueous solution, but if the concentration exceeds 30 w / v%, the viscosity of the solution becomes extremely high, making it difficult to atomize using a nebulizer and causing irritation of the solution as an inhalant. It has drawbacks.

From the above results, in order to obtain a stable carbocysteine inhalation solution, carbocysteine is added to an aqueous solution of sodium hydroxide and dissolved, and as a stabilizer, for example, sodium citrate is added to carbocysteine in an amount of 1 to 20. %
Is added to adjust the pH to 6.0 to 7.5. This solution could be prepared by filling a glass bottle or a glass ampoule, substituting the space of the bottle with an inert gas such as nitrogen gas, and sealing the space.

To prepare this preparation, a flavoring agent, a sweetening agent, a coloring agent and the like which are added to usual inhalants can be added.

When this carbocysteine solution is used as an inhalant, the inhalant of the present invention can be prepared by any method, such as an ultrasonic nebulizer as an inhaler, a pressure nebulizer or an aerosol encapsulated with a propellant. be able to.

[0026]

The carbocysteine inhalant of the present invention thus obtained has good absorbability, can be used in patients with difficulty in excreting sputum, and is convenient to apply.
Can be quickly applied to the target site. In addition, the powder may cause mechanical irritation to the trachea during administration, but the present invention does not have this problem, is easy to use, and provides a formulation that can be administered using any inhalation device. it can.

[0027]

EXAMPLES Hereinafter, various modes of embodying the invention will be described with reference to examples, but the exemplifications are merely for explanation, and do not limit the invention.

Example 1 To 5 g of carbocysteine, 500 ml of purified water was added and stirred, and 11 ml of a 10 w / v% sodium hydroxide aqueous solution was added and dissolved with stirring. To this, 1 g of sodium citrate was added and dissolved, 10 w / v% sodium hydroxide aqueous solution was added to adjust the pH to 7.0, and then purified water was added to make the total amount 1000 ml. Add 50 parts of this solution to a 50 ml glass bottle.
It was filled with each ml, and the container space was replaced with nitrogen gas, and the container was sealed and prepared. When this liquid was inhaled with an ultrasonic nebulizer, a spray having an average particle diameter of 6 μm was obtained.

Example 2 To 300 g of carbocysteine, 500 ml of purified water was added and stirred, and 345 m of a 20 w / v% sodium hydroxide aqueous solution was added.
1 was added and dissolved by stirring. Sodium citrate 1
0 g, 0.01 g of sodium saccharin, 0.01 g of fruit essence, and 0.001 g of caramel were added and dissolved, and 10 w / v% sodium hydroxide aqueous solution was added to adjust the pH.
After adjusting to 7.0, add purified water to bring the total amount to 1000.
ml. This liquid was filled in 50 ml glass bottles by 50 ml, the container space was replaced with nitrogen gas, and a stopper was prepared.

Example 3 To 50 g of carbocysteine, 500 ml of purified water was added and stirred, and 115 ml of a 10 w / v% sodium hydroxide aqueous solution was added.
Was added and dissolved by stirring. Add sodium edetate 0.
1 g was added and dissolved, 10 w / v% sodium hydroxide aqueous solution was added to adjust the pH to 7.0, and then purified water was added to make the total volume 1000 ml. This liquid was filled in 50 ml glass bottles by 50 ml, the container space was replaced with nitrogen gas, and a stopper was prepared.

Example 4 To 50 g of carbocysteine, 500 ml of purified water was added and stirred, and 115 ml of a 10 w / v% sodium hydroxide aqueous solution was added.
Was added and dissolved by stirring. Calcium gluconate 5
g was added and dissolved, 10 w / v% sodium hydroxide aqueous solution was added to adjust the pH to 7.0, and then purified water was added to make the total volume 1000 ml. This liquid is filled in 50 ml glass bottles by 50 ml, and the container space is replaced with nitrogen gas.
Prepared by stoppering.

Example 5 To 10 g of carbocysteine, 500 ml of purified water was added and stirred, and 23 ml of a 10 w / v% sodium hydroxide aqueous solution was added and dissolved with stirring. Add to this sodium bisulfite 0.
1 g was added and dissolved, 10 w / v% sodium hydroxide aqueous solution was added to adjust the pH to 7.0, and then purified water was added to make the total volume 1000 ml. This liquid was filled in 50 ml glass bottles by 50 ml, the container space was replaced with nitrogen gas, and a stopper was prepared.

Reference Example 1 To 300 g of carbocysteine, 500 ml of purified water was added and stirred, and 345 m of 20 w / v% sodium hydroxide aqueous solution was added.
1 was added and dissolved by stirring. After adding a 10 w / v% sodium hydroxide aqueous solution to this to adjust the pH to 7.0,
Purified water was added to make the total volume 1000 ml. This liquid 5
It was prepared by filling 50 ml each into a 0 ml glass bottle and capping it.

Reference Example 2 To 50 g of carbocysteine, 500 ml of purified water was added and stirred, and 115 ml of a 10 w / v% sodium hydroxide aqueous solution.
Was added and dissolved by stirring. To this, 10 w / v% sodium hydroxide aqueous solution was added to adjust the pH to 7.0, and then purified water was added to make the total volume 1000 ml. 50 this liquid
It was prepared by filling 50 ml each in a ml glass bottle and stoppering it.

Next, the appearance changes of the carbocysteine solutions of Examples 1 to 4 of the present invention and Reference Examples 1 and 2 were stored at 50 ° C. for comparison. The results are shown in Table-3.

[0036]

[Table 3]

The inhalant of Reference Example was colored from one month, while the inhalant of the present invention was colorless and clear even after 2 months.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI technical display area A61K 47/12 J 7329-4C

Claims (3)

[Claims] 1. An inhalant characterized in that an aqueous solution containing carbocysteine and a stabilizer and having a pH of 6.0 to 7.5 is placed in a container, the space of the container is replaced with an inert gas, and then the container is sealed. 2. Carbocisteine as an active ingredient in an amount of 0.
The inhalant according to claim 1, which contains 5 to 30 w / v%. 3. As a stabilizer, at least one selected from sodium citrate, sodium edetate, sodium bisulfite, calcium gluconate, sodium thiosulfate, potassium dihydrogen phosphate, ammonium sulfate and tartaric acid is used as a stabilizer of carbocysteine. 0.005 to 20
The inhalant according to claim 1, which comprises a w / w% amount.