JP2576927B2 - Fine grain nucleus - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a fine grain nucleus such as a coating nucleus for fine grains, a method for producing the same, and a fine granule using the same.

[0002]

2. Description of the Related Art Coating nuclei for fine granules are formed by adding excipients, disintegrants, binders, lubricants and the like, and if necessary, a main ingredient. Starch, sucrose, lactose, D-mannitol, dibasic calcium phosphate, and the like have been used as excipients for the coating nucleus for fine granules. On the other hand, as a general production method for obtaining a coating nucleus for fine granules, an extrusion granulation method, a layering method on nuclei, a stirring granulation method and the like are known.

[0003]

However, with such a conventional excipient, it was difficult to obtain a coating core for fine particles having a high sphericity and a small particle size distribution.

That is, when a coating agent for fine granules is produced by extrusion granulation using a conventional excipient, the obtained coating nuclei for fine granules do not have a uniform particle size distribution, and the fine nuclei of the coating nuclei are fine. However, since the coating nucleus is difficult to form and the shape is not spherical, there are problems such as poor efficiency and reproducibility when coating the obtained coating nucleus.

[0005] The layering method on a nucleus is a method in which a spherical coating nucleus is obtained by spraying an excipient onto a coating nucleus such as sucrose to obtain a spherical coating nucleus. There was a disadvantage. The obtained coating core for fine granules has a poor masking (coating) efficiency, and has a serious problem particularly when the main drug is difficult to take due to bitterness and other unpleasant tastes.

[0006] Furthermore, the stirring granulation method developed in recent years often has poor reproducibility when using conventional excipients, even if manufacturing conditions such as stirring speed, amount of binding solution and processing time are constant. There is a problem that a precise control of the manufacturing process is required. In fact, in order to solve this problem, the order of additives was changed (the 8th Summary of Formulation and Particle Design Symposium, 1991, P141), and the end point of stirring granulation was determined based on the amount of fluctuation in power consumption (6th edition). Summary of Formulation and Particle Design Symposium, 1989, P26; C
hem. Pharm. Bull, 38, 1977 (19
90)).

[0007] On the other hand, when a crystalline cellulose is used as an excipient of a coating nucleus for fine granules in an amount of about 3.9 to 25% by weight and produced by a stirring granulation method, a relatively good coating nucleus is obtained. Can be produced (the 5th formulation and particle design symposium abstracts, 1988, p. 6).
8; Summary of the 6th Symposium on Preparations and Particle Design, 198
9, P26; Summary of the 8th Symposium on Formulation and Particle Design, 1991, P141, P146; Pharmaceutical Journal 107,
317 (1987)). However, the coated nucleus for fine particles obtained in this way has a rough nucleus surface (cone-shaped projections are observed by microscopy) and is easily worn away, so that the uniformity of the coating is impaired and the formulation is not suitable. In this case, the release of the drug is not constant. Further, the coating nucleus for fine particles requires an excessive coating material, and has problems such as a long working time, and its efficiency is not satisfactory. further,
In many cases, these coating nuclei do not contain the active ingredient, and have problems such as adding a coating step of the active ingredient when producing fine granules. Was.

The present invention has been made in view of the above problems, and has as its object to provide a fine-grain nucleus containing a main drug having a high sphericity and a small particle size distribution.

[0009]

According to the present invention, the above object is achieved by a fine grain nucleus containing a main ingredient and at least 26% by weight of crystalline cellulose and having an average particle size of 80 to 400 μm.

The crystal cellulose used in the present invention may be a conventionally used one or a commercially available one (for example, Asahi Kasei Avicel (R) PH-101, PH-102, PH-30).
1, PH-302, or a crushed product thereof), and these can be used alone or in combination of two or more, but are not limited to these types.

The fine-grain nucleus of the present invention comprises: 2 microcrystalline cellulose
Its main feature lies in the use of 6% by weight or more. Here, when the crystalline cellulose is less than 26% by weight,
As with conventional cores, the core surface is rough and easily eroded, causing problems such as loss of coating uniformity, requiring excessive coating material, long working time, and inefficiency. .

In the present invention, the crystalline cellulose comprises 26
Although it can be used in various ratios from the weight% to the total amount excluding the main drug, it is particularly preferable to use 60 weight% or more. This is advantageous in that when the crystalline cellulose is 60% by weight or more, only water (purified water or the like) usually needs to be dropped in the granulation process, and there is no need to use any binder or the like. Because it has.

The main drug used in the present invention is not limited as long as it can be administered as a fine granule, but the effect of the present invention is remarkable particularly when applied to a drug having an unpleasant taste such as a bitter taste. Examples of such drugs include bacampicillin hydrochloride, sultamicillin tosylate, ester prodrugs of β-lactam antibiotics such as tarampicillin hydrochloride, macrolide antibiotics represented by azithromycin,
Examples include β-blocker, indenol hydrochloride, antidepressant hydralazine hydrochloride, tranquilizer, chlorpromazine hydrochloride, antitussive, benpropyline phosphate, triazole antifungal, fluconazole. The main drug may be used alone or in combination of two or more drugs.

The fine grain nucleus of the present invention only needs to contain the main ingredient, and the amount thereof is not particularly limited.

The fine nucleus of the present invention may contain a disintegrating agent, a binder, and a lubricant in addition to the crystalline cellulose and the active ingredient.

The disintegrating agent is preferably a disintegrating agent which swells in water but does not dissolve. Examples thereof include low-substituted hydroxypropyl cellulose (L-HPC) and carboxymethyl cellulose.
Examples thereof include scalcium, carboxymethylcellulose sodium, and alginic acid. These may be used alone or in combination of two or more, but are not limited thereto. The content of the swelling agent is not particularly limited, but is preferably 50% by weight or less. This is because, when the swelling agent exceeds 50% by weight, there is a disadvantage that the particles become large and spheroidization becomes difficult.

Examples of the binder include cellulose-based resins such as hydroxypropylcellulose, carboxymethylethylcellulose, hydroxypropylmethylcellulose and cellulose acetate, and acrylic polymer-based resins such as various aminoalkyls. Methacrylate polymers and the like, vinyl polymers such as polyvinyl acetal diethylaminoacetate and the like, or gum arabic, polyvinyl pyrrolidone, polyvinyl alcohol, pullulan, sucrose, shellac, gelatin and the like, alone or Two or more may be used in combination, but are not limited thereto.

The content of the binder is not particularly limited, but is usually preferably 25% by weight or less. This is because if the content exceeds 25% by weight, it is difficult to control the particle form and it is also difficult to form a sphere.

Further, in the fine nuclei and fine granules of the present invention, if necessary, pharmaceutically acceptable additives, for example, coloring agents such as talc, bengara and tar pigments, lubricants such as talc And a stabilizer such as magnesium stearate or magnesium carbonate.

Next, the method for producing fine grain nuclei of the present invention will be described. The method for producing fine-grain nuclei of the present invention is a wet granulation method,
Among them, it is preferable to use a rolling granulation method for rolling operation. Particularly preferred is a granulation method using a stirring granulator.

The fine-grain nucleus of the present invention comprises at least 26
% By weight of crystalline cellulose, if necessary 0-50% by weight
A disintegrant, which swells but does not dissolve in water, is added to a stirring granulator at 0 to 25% by weight of a binder, a lubricant, an additive, and the like, and a binder solution (purified water or the like) is metered in dropwise to produce a binder. Can be granulated. The preferred rotation speed of the stirrer in this case (the agitator may be called a main blade, a rotor disk or the like) varies depending on the model, the total capacity, etc., but is preferably 25 to 600 rpm, particularly preferably 60 to 550 rpm. The rotation speed of a pulverizer (a chopper, which is sometimes called a cross screw, a lamp breaker, or the like) varies depending on the model, the total capacity, and the like, but is 0 to 4600 rpm, preferably 260 rpm.
0 to 4600 rpm. The production temperature does not need to be particularly adjusted, and generally may be room temperature.
Cooling or the like can be performed.

The fine-grain nucleus of the present invention is preferably produced by the stirring granulation method as described above, but is not limited to this. Extrusion granulation, which is a general method conventionally used, is preferred. It may be manufactured by any granulation method, such as a method of lamination on a nucleus.

The fine-grain nuclei thus obtained generally have an average particle size of 500 μm or less, preferably 80 to 400 μm. Needless to say, by sieving after drying, spherical fine particles having a uniform particle size can be obtained. As a sieve to be used, for example, No. 18 (850 μm), 3
No. 0 (500 μm), No. 42 (355 μm), No. 50 (300 μm), No. 83 (180 μm), No. 100 (1
50 μm), No. 140 (106 μm), No. 200 (75
μm) and No. 330 (45 μm).

The fine-granule nucleus thus obtained may be coated as a fine-granule by a known method for the purpose of imparting taste masking, enteric or gastric solubility, and sustainability. Capsules may be filled by a known method, or tablets may be formed by a known method.

Granules often exhibit rolling properties during dispensing operations such as weighing and packaging, and separation occurs when mixed with other granulated preparations having different particle diameters or powdered powders. It has been pointed out that it is easy to use (12th revised Japanese Pharmacopoeia Commentary A-71). In order to solve this problem, granulated preparations having a smaller particle size than granules have been demanded in preparation, and so-called fine granules and granulated powders have been used.

In the present invention, the particle size can be easily designed and fine particles can be similarly adjusted by adjusting the mixing ratio of each component and the rotational speed of a stirrer (agitator) and a crusher (chopper). Can be manufactured.

[0027]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below with reference to embodiments. However, the present invention is not limited to the matters specified in these examples.

The fine-grain yield used herein was determined by the ratio of the amount of granules / the total amount of granules that passed through No. 30 sieve and remained on No. 200 sieve. The average particle size was determined from the particle size distribution by a load average generally used. Each evaluation item is a value measured for particles in the range. The sphericity (shape index) was obtained by placing a sample (30 samples) under a visual field of an optical microscope, taking a photograph at an appropriate magnification, measuring the ratio of the major axis to the minor axis, and expressing the average value. The apparent specific volume (sparse) is 30 g of sample and 100 m
1 was filled into a graduated cylinder, and the volume was converted to the volume per 1 g. The apparent specific volume (dense) was 30
g was filled into a 100 ml graduated cylinder, and then tapped until the volume did not decrease, and the volume was expressed in terms of the volume per 1 g. The friability is measured by a friability meter (Kayagaki)
10g sample and glass beads (diameter 6.9 ± 0.1m)
m, mass 0.47 ± 0.04 g) and 50 ± 0.5 g were rotated at 25 rpm for 30 minutes, and the weight loss due to powdering was expressed in%. As a comparative example, the formulation and particle design subcommittee described in the formulation and particle design symposium and the standard prescription of the particle processing technology subcommittee with the main drug added,
And those described in Pharmaceutical Journal 107, 377 (1987). The dissolution test was performed in purified water at 50 rpm based on the paddle method of the Japanese Pharmacopoeia.

(Example 1) Sultamicillin tosylate (100 g, Pfizer Pharmaceutical Co., Ltd.) and crystalline cellulose (2450 g, Asahi Kasei Kogyo, PH-101) were used as main ingredients in a stirring granulator (Fukae Kogyo, High Speed Mixer). FS-GS-
5), the agitator and the chopper were each set to a rotation speed of 500 rotations / minute and 3000 rotations / minute, and granulated at room temperature while purified water (2000 ml) was added dropwise.

Example 2 Sulfamicillin tosylate (100 g, Pfizer Pharmaceutical), crystalline cellulose (2150 g, Asahi Kasei Kogyo, PH-101), L-HP as main ingredients
Granulation was performed in the same manner as in Example 1 using C (100 g, Shin-Etsu Chemical), hydroxypropyl cellulose (50 g, Nippon Soda), and talc (50 g, Muramatsu Sangyo).

Example 3 After preparing fine-grain nuclei according to Example 2, a 5% by weight solution of polyvinyl acetal diethylaminoacetate (Sankyo) in ethanol using a CF-coating machine (Freund Corporation, CF-360). And 10 for nuclear
By weight% coating, fine granules were obtained.

Comparative Example 1 The same as in Example 1 except that sultamicillin tosylate (100 g, Pfizer Pharmaceutical), crystalline cellulose (250 g), lactose (1500 g), and cone starch (700 g) were used as the main ingredients. Granulation was performed by the method.

(Comparative Example 2) After preparing fine-grain nuclei according to Comparative Example 1, using a CF-coating machine, a 10% by weight coating was performed on the fine-grain nuclei with a 5% ethanol solution of polyvinyl acetal diethylaminoacetate. To obtain fine granules.

Table 1 shows the particle size distribution of the fine granules produced in Example 1, Example 2, and Comparative Example 1, and Table 2 shows the yield and characteristics.
Shown in (Hereinafter, margin)

[0035]

[Table 1]

As is clear from Table 1, the examples of the present invention have a smaller average particle diameter than the comparative examples. Therefore, conventional fine granules that tend to separate when they are mixed with powdered powders or granulated preparations with different particle diameters and powdered powders, which are often seen during dispensing operations such as weighing and packaging. Can improve the disadvantages. In addition, since the particle size distribution is sharp, a code with good efficiency and reproducibility is obtained.
Is possible.

[0037]

[Table 2]

As is clear from Table 2, the examples of the present invention have higher fine grain yields and higher efficiency than the comparative examples.
In addition, since the sphericity is high and the uniformity of the particle size distribution is high, more precise and efficient coating is possible. Furthermore, a small degree of friability means a high mechanical strength, which has the advantage of less cracking, chipping and powdering during coating.

Table 3 shows the dissolution rate of sultamicillin tosylate from the coated fine granules produced in Example 3 and Comparative Example 2.

[0040]

[Table 3]

The initial dissolution rate, which is considered to affect the taste, was suppressed to about 15% in 10 minutes in Example 3 and doubled to about 30% in Comparative Example 2. , The elution rate is different. This clearly shows the difference between coating precision and efficiency.

According to the surface electron microscope observation, many cracks were observed on the surface of Comparative Example 2. In the case of Comparative Example 2, since the surface of the core was rough, the coating agent penetrated into small holes or the like on the surface, and it is considered that uniform coating was not performed under the same conditions as in Example 3.

Table 4 shows the results of a taste test of sultamicillin tosylate for the coated fine granules produced in Example 3 and Comparative Example 2.

[0044]

[Table 4]

The comparative sensory test was carried out by a two-point preference test using a double blind test. As a result, it was further clarified that the coated fine granules of sultamicillin tosylate according to the present invention were easy to take without bitterness.

[0046]

According to the present invention, at least 26% by weight of the active ingredient
Containing crystalline cellulose, and having a mean particle size of 80 to 400 μm, so that the sphericity is high and the fine particle nucleus containing the main drug having a small particle size distribution is produced. It has an effect that a more precise and efficient coating can be formed.

Claims (6)

(57) [Claims] 1. Fine-granule nuclei comprising the active ingredient and at least 26% by weight of crystalline cellulose and having an average particle size of 80 to 400 μm. 2. The fine grain nucleus according to claim 1, wherein the content of the crystalline cellulose is 60% by weight or more. 3. The method according to claim 1, wherein the active ingredient is sultamicillin or a pharmaceutically acceptable salt thereof.
Or the fine-grain nucleus according to 2. 4. A method for producing a fine-grain nucleus according to claim 1, wherein the fine-grain nucleus according to claim 1 is produced by a stirring granulation method. 5. The rotating speed of a stirrer (agitator) is 2
The method for producing fine-grain nuclei according to claim 4, wherein the speed is 5 to 600 rpm, and the speed of the crusher (chopper) is 0 to 4600 rpm. 6. A fine granule obtained by coating the fine nucleus according to claim 1 or 2.