JPH0558887A - Inhalant - Google Patents

Abstract

PURPOSE:To obtain a readily usable inhalant useful as an airway mucilage regulating and a mucous membrane normalizing agents by placing a carbocysteine-containing aqueous solution in a small container having a liquid filling volume corresponding to a dose for a time, replacing the container space with an inert gas and hermetically sealing the container. CONSTITUTION:The objective inhalant is obtained by placing an aqueous solution containing 0.5-20wt./vol.% carbocysteine as an active ingredient at pH 6.0-7.5 in a small container having a liquid filling volume corresponding to a dose for a time, replacing the above-mentioned container space with an inert gas and then hermetically sealing the container. The resultant inhalant is employed by using an inhaling tool such as an ultrasonic nebulizer.

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. Conventionally, carbocysteine preparations have been conventionally used as oral preparations such as tablets (250 mg) and fine granules (0.5 mg).
%) 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, an aqueous solution of carbocysteine has a color change and the generation of decomposition products due to long-term storage and light,
There was a problem in terms of 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, since this solution became highly viscous and was not sprayed even when it was applied to an ultrasonic nebulizer as an inhaler, 5% of syrup was not used as an inhalant. Due to such problems, the development of an inhalant as a means for direct application to the respiratory tract has been desired, but an inhalant containing carbocysteine has not been developed due to problems such as stability.

[0005]

In order to solve the above problems, the inventors of the present invention 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, according to the present invention, an aqueous solution containing carbocysteine having a pH of 6.0 to 7.5 is placed in a small container (for example, an ampoule of about 10 ml or less) having a liquid filling capacity equivalent to one use, and the space of the container The present invention relates to an inhalant, which is characterized in that a part is replaced with an inert gas and then sealed, and in particular 0.5 to 3 of carbocysteine as an active ingredient.
The present invention relates to an inhalant containing 0 w / v%.

The inhalant containing carbocysteine of the present invention as an inhalation method uses a nebulizer such as a method of directly or diluting a solution of carbocysteine and using an ultrasonic atomizer, or atomizing with compressed air. Inhale using. 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.

A 50 ml glass bottle was filled with the aqueous solution of carbocisteine, the space in the container was replaced with nitrogen gas, and the container was sealed and stored at 50 ° C. for 30 days. As a result, in the glass bottle, no change in discoloration was observed only in the case where the stabilizer was added and the space in the container was replaced with nitrogen gas. That is, discoloration could not be prevented by nitrogen gas or the stabilizer alone (Table 1).

The measurement was carried out 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 measuring 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

[0014]

[Table 1]

20% carbocysteine solution 2 in an ampoule
After filling with ml and replacing the ampoule space with nitrogen gas, the stability of the sealed sample was examined. The results are shown in Table-2.

[0016]

[Table 2]

As a result, when a 20% carbocysteine solution was placed in an ampoule and replaced with nitrogen gas and stored, it was stable without any change in coloration or reduction in content. No addition of stabilizer was necessary.

As described above, in the case of a container such as a glass bottle having a medium volume or more, in addition to the addition of the stabilizer to the inert gas, it was essential to replace the inert gas. It was found that the addition of a stabilizer is not necessary, and stabilization can be achieved only by replacing with an inert gas.

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 at a concentration of more than 30 w / v%, the viscosity of the liquid becomes extremely high, making it difficult to atomize using a nebulizer and causing irritation of the solution as an inhalant. There are 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 to adjust the pH to 6.0 to 7.5. Fill this solution into a small glass ampoule,
It could be prepared by sealing. Flavors, sweeteners, coloring agents and the like added to usual inhalants can also be added to this preparation.

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

Since the carbocysteine inhalant obtained by the present invention does not contain a stabilizer, only a pure drug can be inhaled and it is characterized by high safety.

[0023]

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.

[0024]

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 50 g of rubocysteine, 500 ml of purified water was added and stirred, and 115 ml of 10 w / v% sodium hydroxide aqueous solution was added.
Was added and dissolved with stirring, and the pH was adjusted to 7.0 by adding a 10 w / v% sodium hydroxide aqueous solution, and then purified water was added to make the total amount 1000 ml. This solution was filled in a 2 ml ampoule at a rate of 2 ml, the container space was replaced with nitrogen gas, and the container was sealed.

Example 2 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. Saccharin sodium 0.0
1g, fruit essence 0.01g, caramel 0.0
After 01 g was added to dissolve and 10 w / v% sodium hydroxide aqueous solution was added to adjust pH to 7.0, purified water was added to make 1000 ml in total. This solution was filled in a 2 ml glass ampoule at a rate of 2 ml and sealed.

Example 3 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, 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. 5 ml of this liquid
It was prepared by filling a screw vial and sealing it.

Reference Example 1 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. 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.
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
50 ml of each was filled in a ml glass bottle, and the bottle was stoppered.

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

[0031]

[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.

Claims (2)

[Claims] 1. A pH of 6.0 containing carbocysteine.
An inhalant characterized in that the aqueous solution of ~ 7.5 is put into a small container having a liquid filling capacity equivalent to one use, the space of the container is replaced with an inert gas, and then 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%.