JPH0819003B2 - Nucleated granule and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to a nuclear granule having high granule strength and excellent disintegration and a method for producing the same in the fields of food, medicine and the like.

(Prior Art) In recent years, many studies have been carried out on drug release control systems (drug delivery systems), and in particular, as oral dosage forms, so-called coated granules in which various coatings have been applied to granules are often used. It has been developed as a capsule or by filling a capsule.

The reason for this is that from the viewpoint of biopharmaceuticals, granules have less individual difference in gastric emptying rate, absorbability, etc. than tablets, and are hardly affected by diet. There is.

Regarding the production of spherical granules, a method of spheroidizing using rolling granulation after extrusion granulation is generally known,
It is said that it is difficult to prepare a controlled-release preparation with high accuracy because it is difficult to coat uniformly because of poor sphericity and large particle size distribution.

On the other hand, as a method for obtaining granules having a good sphericity, it has been studied to granulate using a centrifugal fluidized coating granulator (hereinafter sometimes referred to as a CF device).

In this method, the surface of the spherical core granules or cores is sprayed with water or a solution containing a binder, and if necessary, a spraying agent is used for coating, which has a high sphericity and a particle size distribution width. Spherical granules of small size are obtained. [Drug Development and Industrial Pharmacy (Drug Development and Industrial Pharma
cy), 11 (8), 1523-1541 (1985)] In order to prepare a drug release-controlled preparation, the surface of the obtained spherical granules is coated with wax or a polymer for the purpose of controlling drug release. However, as these coating methods, CF coating using a CF device and fluidized coating using a fluidized bed coating machine are generally under study.

(Problems to be Solved by the Invention) However, in CF coating and fluidized coating, obstacles such as destruction of spherical granules and scratches often occur at the initial stage. The obstacle not only impairs the controlled release function of the drug in the coated granules, but also has a great influence on the yield in the production of spherical granules and coated granules. In addition, when distributed in the market as granules,
In the distribution process, the granules are easily broken and, for example, polyvinylpyrrolidone is added as a binder in order to increase the strength of the granules [Sakamoto et al., Pharmaceutical Science, 45 (2) 181-187.
(1985)]. In addition, when the strength of the granules is increased, the disintegration property of the granules tends to be deteriorated, and there has been a demand for granules that rapidly disintegrate and have high strength.

(Means for Solving the Problems) In view of such circumstances, the inventors of the present invention have diligently studied a spherical granule having strong granule strength and quick disintegration using a CF device, and as a result, a low substitution degree hydroxy. When propyl cellulose is added to the spraying liquid during coating and granulated, spherical granules with surprisingly strong granule strength and excellent disintegration are obtained. Furthermore, low-substituted hydroxypropyl cellulose is used as a dusting agent. In this case, it was confirmed that there was almost no powder scattering at the time of production, which was a problem, and the present invention was completed.

That is, the present invention is characterized in that the dispersion of low-substituted hydroxypropyl cellulose is sprayed onto the core granules so that the content of the low-substituted hydroxypropyl cellulose in the dry granules is 0.1 to 15% by weight. The present invention relates to a method for producing a nucleated granule and a nucleated granule obtained by the method.

The hydroxypropoxyl group content of the low-substituted hydroxypropyl cellulose (hereinafter sometimes referred to as L-HPC) used in the present invention is generally about 4.
-20%, preferably 5-16%, more preferably 10%
~ 13%. The average particle size of the L-HPC is generally 200 μm or less, preferably 100 μm.
m or less, more preferably 30 μm or less.

Examples of the nuclear granules used in the present invention include nonpareils coated with sucrose (75 parts by weight) with corn starch (25 parts by weight) by a method known per se, and spherical granules using crystalline cellulose. Further, the core granules themselves may be other main drug components different from the intended main drug. Further, the core granules may be coated with wax or polymer to form cores.

The dispersion liquid sprayed in the present invention can be obtained by uniformly dispersing and / or dissolving L-HPC in water, an organic solvent such as ethanol, or a mixed liquid thereof.

In addition to L-HPC, the main component and other additives may be uniformly dispersed and / or dissolved in the dispersion liquid.

The main drug is not particularly limited as long as it can be administered as a granule, for example, as a central nervous system drug, diazepam, idebenone, aspirin, ibuprofen, paracetamol, naproxen, piroxicam, diclofenac, indomethacin, sulindac, lorazepam, nitrazepam, phenytoin. , Acetaminophen, etenzamid, ketoprofen, etc., as cardiovascular drugs molsidomine, vinpocetine, propranolol,
Methyldopa, dipyridamole, furosemide, triamterene, nifedipine, atenolol, spironolactone, metoprolol, pindolol, captopril, isosorbide dinitrate, etc. As a systemic drug, 2-{[3-methyl-
4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl} benzimidazole (hereinafter,
Compound A may be referred to) and 5-methoxy-2
-[(4-Methoxy-3,5-dimethyl-2-pyridyl)
Methylsulfinyl] benzimidazole and other benzimidazole drugs having antiulcer action, cimetidine, ranitidine, pancreatin, bisacodyl, 5-aminosalicylic acid and the like, and antibiotics and chemotherapeutic agents include cephalexin, cefaclor, cefradine and amoxicillin. , Pivampicillin, bacampicillin, dicloxacillin, erythromycin, erythromycin stearate, lincomycin, doxycycline, trimethoprim / sulfamethoxazole, etc. , As vitamin drugs, vitamin B ₁ , vitamin
Examples include B ₂ , vitamin B ₆ , vitamin C, and fursultiamine.

Examples of the additive include additives that are generally blended when producing granules, and examples thereof include excipients (eg, lactose, corn starch, sucrose, talc, crystalline cellulose, mannitol, light anhydrous silicic acid, carbonic acid). Magnesium, calcium carbonate, L-cystine, etc.), binder (eg, pregelatinized starch, methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, pullulan, dextrin, gum arabic, etc.), disintegrant (carboxymethylcellulose) Calcium, starches, cross-linked sodium carboxymethyl cellulose,
Cross-linked insoluble polyvinylpyrrolidone, etc.), colorants (titanium oxide, red iron oxide, tar dyes, etc.)
And the like, and two or more of these may be used.

Further, in the present invention, a powdery spraying agent obtained by uniformly mixing the above-mentioned main drug and additives may be sprayed while spraying the dispersion liquid onto the core granules. The particle size of the dusting agent is generally about 100 μm or less, preferably about 50 μm or less.

The blending ratio of L-HPC to the dispersion varies depending on the types of main additives and other additives to be blended, the blending ratio, etc., but is usually 0.5 to 50% by weight, especially 5 to 30% by weight. Is preferred. Generally, if the compounding ratio is less than 0.3%, it is not preferable to coat in an amount necessary to increase the strength of the granule, because the concentration in the liquid is low and it takes time. Also, if it rubs 60%, problems such as an increase in the viscosity of the liquid may occur, causing troubles during granule production. Further, of course, the blending ratio of L-HPC to the dispersion liquid may be changed continuously or stepwise during the coating depending on the purpose. In that case, the dispersion may be generally coated in an amount exceeding 0.5 to 50% by weight. Furthermore, when the main drug and other additives are dispersed at the same time, their compounding ratios may be changed.

In addition, the content of L-HPC in the obtained granules with high strength and rapid disintegration is usually preferably 0.1 to 15% by weight. An addition rate of less than 0.05% is not sufficient to increase the granule strength. On the other hand, if it exceeds 20%, the rate of addition of other coating components becomes low, which is not preferable.

Next, the method for producing the dry-coated granules of the present invention will be described in more detail. While granulating a liquid in which L-HPC and, if necessary, a main drug and / or an additive are dissolved and / or dissolved in the core granules, the liquid is sprayed with a powdery spraying agent as needed to granulate.
At this time, if there is no problem with the stability of the main drug, it is not necessary to adjust the temperature of the liquid during production, and generally room temperature (1 to 30 ° C.) may be used. Further, by drying the granulated product and then sieving it, spherical nucleated granules having a uniform particle size can be obtained. The sieve used may be, for example, a 12-32 mesh round sieve, and granules that pass 12 mesh but not 32 mesh may be selected.

The thus-obtained nucleated granules may be coated by a method known per se for the purpose of imparting taste masking, enteric properties, gastric properties, persistence, etc., and further, when the compounding properties of the main drug are poor. May be coated during the production of the dry granules for the purpose of stabilization. Alternatively, the capsule may be filled by a method known per se. Furthermore, tablets may be produced by mixing with other ingredients.

Examples of the coating agent include hydroxypropyl methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyoxyethylene glycol, Tween 80, Pluronic
F68, castor oil, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, acrylic acid copolymer, carboxymethylethylcellulose, polyvinyl acetal diethylaminoacetate, shellac, waxes, and talc, titanium oxide,
Examples include pigments such as red iron oxide.

(Example) Hereinafter, the present invention will be described more specifically with reference to Examples, Reference Examples and Experimental Examples. The raw materials used in these are all in powder form.

Example 1 2700 g of non-pareil (20 to 28 mesh) was added to a CF device (CF-3
60, made by Freund), rotor speed 200 rpm
In 2000 ml of water, L-HPC (hydroxypropoxyl group substitution degree: 10.0 to 13.0% (W / W), average particle diameter of 30 μm or less, the same substitution degree and average particle diameter as in the following Examples and Experimental Examples. 3% (W / W) and 2% (W / W) of hydroxypropylcellulose were dispersed and dissolved at a rate of 25 ml / min, while spraying 2000 g (compound A, compound A,
Magnesium carbonate, granulated sugar and corn starch were mixed in an equal amount) at a rate of 25 g / min for coating, and 12 to 32 mesh spherical nucleated granules were obtained using a round sieve.

The obtained spherical nucleated granules (3800 g) were placed in a fluid coating machine Glatt WSG-15 (Grat, West Germany), and the air temperature was controlled at 50 ° C and the product temperature at 40 ° C, and an enteric film solution of the following composition was sprayed at 50 ml / min. Coating
Enteric-coated nucleated granules were obtained. The obtained granules are uniformly coated with an enteric coating without particle breakage during coating.
11 Compliant with the particle size and enteric disintegration test prescribed by the revised Japanese Pharmacopoeia.

[Enteric film solution]

Eudragit L-30D-55 628g Talc 192g Polyethylene glycol 6000 64g Titanium oxide 64g Tween 80 32g Water 4400g Example 2 Non-pareil (24-32 mesh) 42kg in CF device (CF-13
00, manufactured by Freund Co., Ltd., the rotor speed is 60 rpm, and a coating solution of the following composition prepared in advance is used:
Granulated by spraying with 0 ml / min × 2 gun. The granulated product was vacuum-dried at 40 ° C. for 16 hours, and then 12 to 32 mesh spherical nucleated granules were obtained using a round sieve.

[Coating liquid]

Serapeptase 3000g L-HPC 1600g Lactose 160g Granulose 1600g Talc 1600g Ethanol 11500g Water 9700g The obtained spherical nucleated granules 48kg are flow coated (FL)
O-60, Freund / Okawara Co., Ltd.), blast temperature 60
C., the exhaust temperature was controlled to about 40.degree. C., and an enteric film solution of the following composition prepared in advance was sprayed at 170 g / min.times.3 gun for coating to obtain enteric coated nucleated granules. The obtained granules were uniformly coated with an enteric coating without particle breakage during the coating, and were suitable for the particle size and enteric disintegration tests specified in the 11th revised Japanese Pharmacopoeia.

[Enteric film solution]

Hydroxypropyl methylcellulose phthalate 220824
11600g Shellac 2800g Polyethylene glycol 6000 660g Ethanol 56300g Acetone 131500g Enteric-coated nucleated granules 420g obtained above, aluminum hydroxide / sodium hydrogencarbonate coprecipitate 270g, crystalline cellulose 580
g, 150 g of cross-linked sodium carboxymethyl cellulose, 20 g of magnesium stearate, and 1440 g of tableting granules prepared in advance by the following method were mixed with a tumble type mixer (TM-15, Showa Kagaku Kikai Seisakusho) for 3 minutes ( Mixing conditions: 10 rpm, 3 minutes). The mixture was tableted at a compression pressure of 1 ton / cm ² using Pure Press Collect 19K (manufactured by Kikusui Seisakusho) and an oblong type punch. Each tablet weighs 480 mg, the major axis is 15 mm and the minor axis is
A white plain tablet having a thickness of 6.5 mm, a thickness of 6.4 mm and a disintegration time of 1.2 minutes was obtained.

[Granule for tableting]

Acetaminophen 900 g, chlorpheniramine maleate 7.5 g, noscapine 48 g, anhydrous caffeine 75 g, dihydrocodeine phosphate 24 g, d1-methylephedrine hydrochloride 60
g, 1389.6 g by adding crystalline cellulose to a mixture consisting of 72 g of cross-linked carboxymethyl cellulose sodium and 72 g of corn starch, and thoroughly mixed with a vertical granulator (FM-G25 type, manufactured by Fuji Sangyo Co., Ltd.), mixing conditions: 400 rpm, 15 minutes, hydroxypropyl cellulose 5
An aqueous solution in which 0.4 g was dissolved was kneaded. Use a fluidized dryer (FD-3S, manufactured by Fuji Sangyo Co., Ltd.) to mix the white kneaded material at a blast temperature of 60 ° C for 30 minutes.
The granules were dried for a minute and sieved through a 1.5 mmφ punching screen using a power mill (P-3 type, Showa Kagaku Kikai Seisakusho) to give tableting granules.

Example 3 85 g of non-pareil (24-32 mesh) was put in a mini CF device (manufactured by Freund), and the rotation speed of the rotor was 400 rpm,
L-HPC 30% (W / W) and hydroxypropyl cellulose 1% (W / W) were dispersed or dissolved in 50 g of ethanol, respectively, and the resulting coating solution was sprayed at 2.5 g / min. 10g sugar, corn starch
A spraying agent obtained by uniformly mixing 30 g was sprayed at 5 g / min, and the coating liquid was sprayed even after the spraying was completed to obtain a granulated product. Granulate 40
After vacuum drying at ℃ for 16 hours, 12-32 mesh spherical nucleated granules were obtained using a round sieve. No. 2 hard capsules (weight: 65 mg) were filled with 240 mg of the granules using a capsule filling machine (manufactured by Park Davis Co., Ltd.) to produce capsules.

Example 4 85 g of non-pareil (24-32 mesh) was put into a mini CF device (manufactured by Freund), and the rotation speed of the rotor was 400 rpm,
Disperse 5 g of L-HPC and 4 g of talc in 50 g of water, and further dissolve 6 g of fursultiamine hydrochloride, 4 g of granulose sugar and 1 g of hydroxypropyl cellulose to obtain 2.
A granulated product was obtained by spraying at 5 g / min. The granulated product was vacuum dried at 40 ° C. for 16 hours, and 12 to 32 mesh spherical nucleated granules were obtained using a round sieve.

Example 5 Spherical nucleated granules were produced by granulating the coating solution used in Example 2 with L-HPC and granuose in a coating solution in which the amounts were varied as shown in the table below in the initial, middle and latter stages of coating. The nucleated granules thus obtained were uniformly coated with an enteric coating without particle destruction during coating.
11 Compliant with the particle size and enteric disintegration test prescribed by the revised Japanese Pharmacopoeia.

Reference Example 1 In the method of Example 4, fursultiamine hydrochloride, L-HPC, granulose sugar and talc in the coating liquid were deleted, and fursultiamine hydrochloride, L-HPC, granule sugar and talc were uniformly mixed. To prepare a spray.
The spraying agent was spray-coated at 1.2 g / min while spraying the coating solution at 3 g / min, vacuum-dried at 40 ° C. for 16 hours, and then 12-32 mesh spherical nucleated granules were obtained using a round sieve.

Reference Example 2 In the method of Example 4, L-HP in the coating liquid was used.
Spherical nucleated granules were produced by granulating C with a coating solution in which crystalline cellulose, corn starch, pregelatinized starch, hydroxypropyl cellulose, pullulan, carboxymethyl cellulose or lactose was changed. Using a round sieve, 12 to 32 mesh spherical nucleated granules were obtained.

Experimental Example 1 5 g of the granules (12 to 32 mesh) obtained in Example 4, Example 5, Reference Example 1 and Reference Example 2 were put into a 50 ml stainless cylinder (50 ml internal volume, diameter 32 mm), and specs mill. After shaking for 15 minutes (Specs, Germany), it was passed through a 32 mesh round sieve and the amount on the sieve was measured to determine the residual ratio of the granules, which was defined as the granule strength. Furthermore, the disintegration time of the granules was measured according to the Japanese Pharmacopoeia (11th revision) Disintegration Test Method.
As a result, as is clear from Table 1, the dry-coated granules of the present invention had high strength and excellent disintegration property.

Experimental Example 2 As a result of comparing the yield of the granules obtained in Example 4 with the yield of the granules (control) obtained in Reference Example 1 and the content of fursultiamine hydrochloride, as shown in Table 2, the yield of Example 4 and The content was higher than that in Reference Example 1, and it was confirmed that the production method of the present invention caused almost no powder scattering of the active ingredient during production.

(Effects of the Invention) The nucleated granules obtained in the present invention have high granule strength and excellent disintegration. Moreover, compared to the case of spraying L-HPC in powder form, the powder dispersion of the main drug contained in the granules is less, so the main drug content can be kept constant,
Furthermore, there is an advantage that the granule strength is also strong.

 ─────────────────────────────────────────────────── ─── Continuation of front page (56) Reference JP 62-30709 (JP, A) JP 59-5122 (JP, A) JP 63-83025 (JP, A) JP 61- 176533 (JP, A) European Patent Publication 277741 (EP, A)

Claims (5)

[Claims] 1. A dispersion of low-substituted hydroxypropyl cellulose is sprayed onto the core granules so that the content of the low-substituted hydroxypropyl cellulose in the dry granules is 0.1 to 15% by weight. A method for producing nucleated granules. 2. The method according to claim 1, wherein the powdery spraying agent is sprayed while spraying the dispersion liquid. 3. The method according to claim 1, wherein the dispersion is mixed with a main drug. 4. The powdered dusting agent containing a main drug (2).
Alternatively, the production method of (3). 5. A dry-coated granule obtained by the method according to any one of claims (1) to (4).