JPH04288013A - Suspended syrup agent - Google Patents

Abstract

PURPOSE:To facilitate oral administration and to make administration of carbocysteine of high dose possible even for a patient having difficulty in internal application of tablet and fine granule. CONSTITUTION:Crystal of carbocysteine is treated together with 0.5-5w/v% dispersant by a high-pressure homogenizer and average particle size of carbocysteine is made into <=15mum to give a suspended syrup agent containing 5-30w/v% carbocysteine.

Description

[Detailed description of the invention]

0001

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a suspension syrup containing carbocysteine, which is an agent for regulating airway mucus and normalizing mucous membranes.

0002

BACKGROUND OF THE INVENTION Carbocysteine is a known pharmaceutical compound. Its pharmacological action is to normalize the composition ratio of sialic acid and fucose in airway mucus, thereby reducing the viscosity of the mucus, restoring the ciliated cells of the bronchial mucosal epithelium, and promoting sputum excretion.

[0003] Carbocysteine preparations have conventionally been prepared for oral administration in the form of tablets (250 mg) and fine granules (0.5 mg).
%) and syrup (5%) have been developed and are being used in medical settings. However, the dose of carbocysteine for adults is as high as 500 mg at a time, and when it comes in tablet form, it is a large tablet, making it difficult to take.

[0004] As an oral dosage form suitable for patients who have difficulty taking tablets or fine granules, high concentration (10 w/v % or more)
An aqueous solution of carbocysteine was considered. However, the solubility of carbocysteine in water is as low as 1 mg/ml or less. A high concentration of carbocysteine in solution can be achieved by adding a high concentration of alkaline components such as sodium hydroxide, but as a result, a highly concentrated carbocysteine solution also contains a large amount of alkaline components, and such preparations It could not be used medically. Furthermore, high-concentration carbocysteine solutions have problems in terms of stability, such as color changes and the formation of decomposed products due to long-term storage or exposure to light.

[0005] It was thought that carbocysteine could then be developed as a suspending agent. However, when simply dispersed in water, carbocysteine crystals easily settle and cannot be provided as a suspension syrup. Furthermore, by using a dispersant commonly used as a suspending agent, it was possible to slow down the sedimentation rate of the crystals to some extent;
A uniform suspension state could not be maintained during long-term storage.

[0006] Due to these problems, although a highly concentrated carbocysteine syrup has been desired, it has not been developed.

[0007]

[Means for Solving the Problems] In order to solve the above-mentioned problems, the present inventors have conducted intensive research on the development of a suspension syrup that can contain carbocysteine at a high concentration. As a result, a stable suspension in which carbocysteine was uniformly dispersed was completed, and a suspension syrup containing carbocysteine as an active ingredient of the present invention was created. That is, carbocysteine crystals (average particle size 4
Surprisingly, when carbocysteine (5 μm) was treated with a dispersant and water in a high-pressure homogenizer, it was possible to simultaneously pulverize and disperse carbocysteine, creating a new method for preventing sedimentation as a stable suspending agent. It was discovered that by this treatment, the particle size of carbocysteine having an average particle size of 45 μm can be pulverized to 15 μm or less, and a stable dispersion suspension can be prepared, and the present invention has been completed.

Conventional methods for pulverizing crystals include various methods using various types of pulverizers. For example, using a dry jet mill, ball mill, roller mill, etc.
Particles can be micronized. Carbocysteine can also be pulverized with a jet mill to obtain a fine powder with an average particle size of 15 μm or less. Usually, a suspension is prepared by adding a dispersant and water to the thus-pulverized drug and stirring the mixture. However, it was not possible to produce a stable suspension of fine carbocysteine powder using this method (Table 1). Therefore, the present inventors conducted extensive research in order to obtain a suspension-stable syrup of carbocysteine. As a result, a new method was discovered in which a mixture of carbocysteine crystals (average particle size: 45 μm), a dispersant and water added and stirred was treated with a high-pressure homogenizer. According to this method, not only can carbocysteine having a powder particle size of 45 μm be micronized into fine particles of 15 μm or less, but also a stable suspension can be obtained by processing it simultaneously with a dispersant. (See Table 1).

[0009]

[Table 1]

[0010] A high-pressure homogenizer was the most suitable method for preparing a suspension syrup of carbocysteine. A high-pressure homogenizer is generally used as a device for emulsifying fats and oils such as milk, but there has been no example of it being used as a device for pulverizing crystal powder. As a result of extensive research, the present inventors have discovered that even crystalline powders such as carbocysteine can be pulverized by treatment with a high-pressure homogenizer, and that this is effective in stabilizing dispersion.

[0011] As a commercially available high-pressure homogenizer device,
Gorlin homogenizer (manufactured by Gorlin, 15MR-8
T type) and a microfluidizer (M-110-T type, manufactured by Microfluidisc). Grinding treatment (pressure 400~
1000 kg/cm2), optimal finely pulverized crystals (average particle size 10 μm) were obtained. Carbocysteine bulk powder (average particle size 45 μm) is suspended in water and treated with a high-pressure homogenizer to reduce the average particle size to 10 μm.
It is possible to obtain a fine powder of less than m. However, this micronized carbocysteine suspension had poor stability and poor redispersibility. The present inventors have discovered that in order to obtain a stable carbocysteine suspension, it is necessary to process a mixture of carbocysteine powder and a dispersant with a high-pressure homogenizer, and have completed the present invention.

[0012] The carbocysteine concentration during treatment with a high-pressure homogenizer is preferably 5 to 30 w/v%.

Preferred dispersants include methylcellulose, crystalline cellulose, carboxymethylcellulose and its salts, hydroxypropylmethylcellulose, sodium alginate, and crystalline cellulose/carboxymethylcellulose (Avicel RC). The amount of these dispersants added is preferably 0.5 to 5 w/v%. If the concentration was within this range, sedimentation of the fine particles could be suppressed, and even if they once sedimented due to long-term storage, they could be easily redispersed.

The carbocysteine concentration in the suspension syrup is preferably in the range of 5 to 30 w/v%. If it is less than 5w/v%, it will be inconvenient because the volume will be large when taking it, and if it is less than 30w/v%
If the amount is above, the amount of crystals will be large and the viscosity will be high, the fluidity will be reduced and it will be difficult to take. Most preferably 5 to 20
It is w/v%.

[0015] A liquid obtained by dispersing carbocysteine in water has a strong sour taste. By adding an appropriate sweetener to this, it can be made to have a taste that is easy to take. Therefore, as a suspension syrup, the addition of sweeteners is desirable to make it easier to take. As sweeteners it is best to use sugar alcohols such as D-sorbitol, xylitol or D-mannitol. The amount of sugar alcohol added is 10-60w/
v%, preferably 20 to 40 w/v%. As a sweetener, these sweeteners can be used alone or in combination. In addition, saccharin sodium, which is a synthetic sweetener, can also be used.

[0016] It is effective to add a flavoring agent to improve the ease of administration, and a small amount of fruit essence is added as a flavoring agent.

[0017] It is effective to add a preservative to enhance antiseptic properties, and as a preservative, sorbic acid, benzoic acid, dehydroacetic acid, or paraoxybenzoic acid esters may be added at 0.005 to 0.5 w/v%. do. Preferably 0.
Add 01 to 0.2 w/v%.

[0018] Furthermore, in order to improve usability, it is also possible to add a coloring agent. As the coloring agent, any colorant used in pharmaceuticals may be used.

Carbocysteine solution gradually decomposes when stored at room temperature for a long period of time. The carbocysteine suspension syrup obtained in Example 1 was tested for stability when stored at 40°, and the results are shown in Table 2.

[0020]

[Table 2]

Based on these results, a stable carbocysteine suspension syrup was completed.

[0022]

[Effects] The carbocysteine suspension syrup of the present invention thus obtained is easy to take orally, even patients who have difficulty taking tablets or fine granules, and has a high drug content. It is possible to provide a formulation that also allows for the administration of small amounts of carbocisteine.

[0023]

[Examples] Hereinafter, various embodiments of the invention will be explained with reference to Examples, but the examples are, of course, for illustrative purposes only and are not intended to limit the invention.

Example 1 500 ml of purified water was added to 100 g of carbocysteine, 10 g of crystalline cellulose/carboxymethyl cellulose (Avicel RC), and 1 g of sorbic acid, and the mixture was dispersed using a homogenizer.
A high pressure treatment of 650 kg/cm2 was carried out using a MR-8T model) to obtain a uniform suspension with an average particle size of 10.0 μm. To this, 400 g of xylitol and a trace amount of fragrance were added and dissolved, and purified water was added to make 1000 ml to prepare a carbocysteine suspension syrup. Example 2 500 ml of purified water was added to 200 g of carbocysteine and 50 g of methylcellulose, and the mixture was dispersed using a homogenizer.
A high-pressure treatment of 1000 kg/cm2 was performed using a mold) to obtain a uniform suspension with an average particle size of 11.1 μm. Add and dissolve 400 g of D-sorbitol, 0.5 g of benzoic acid, a trace amount of fragrance, and a trace amount of coloring agent, add purified water, and dissolve.
000 ml to prepare a carbocysteine suspension syrup.

Claims (2)

[Claims] [Claim 1] Carbocysteine crystals with a crystal content of 0.5 to
Treated with 5 w/v% dispersant and water using a high-pressure homogenizer to reduce the average particle size of carbocysteine to 15 μm.
Carbocysteine characterized by being produced as follows:
Suspension syrup containing 30 w/v%. 2. The suspension according to claim 1, which contains one or more selected from methylcellulose, hydroxyethylcellulose, sodium alginate, crystalline cellulose/carboxymethylcellulose, or hydroxypropylmethylcellulose as a dispersant. Cloudy syrup.