JPH02174931A - Nucleate granule and its preparation - Google Patents

Abstract

PURPOSE:To obtain nucleate granules having high granule strength and satisfactory crumbliness by spraying a liquid dispersion of hydroxypropyl cellulose having low degree of substitution onto granules for forming nuclei, and granulating the sprayed product. CONSTITUTION:A liquid dispersion and/or soln. of hydroxypropyl cellulose having low degree of substitution together with, if necessary, a principal medicine and/or additives in an org. solvent such as water, ethanol, etc., is sprayed on granules for forming nuclei, and the sprayed product is granulated while continuing spraying. By sieving the granulated product after drying, spherical nucleate granules having uniform grain size are obtd. The nucleate granules prepd. by this process have high granule strength and satisfactory crumbliness. Moreover, almost no scattering of powder is caused during the prepn. when hydroxypropyl cellulose having low degree of substitution is used as dispersant.

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to nucleated granules with strong granule strength and excellent disintegration properties, and a method for producing the same, in the fields of food, medicine, etc.

(Prior art) In recent years, many studies have been conducted on drug release control systems (drug delivery systems), and in particular, as oral dosage forms, so-called coated granules, in which granules are coated with various types of coatings, are increasingly used. It has been developed as either granules or capsules.

The reason for this is that, from a biopharmaceutical point of view, granules are better than tablets because there are no individual differences in gastric emptying rate, absorption, etc., and they are also almost unaffected by meals. There is.

Regarding the production of spherical granules, it is generally known to use extrusion granulation followed by transfer granulation to make them spherical.However, due to poor sphericity and large particle size distribution, uniform coating is difficult and precision cannot be achieved. It has been difficult to prepare highly controlled release formulations.

On the other hand, as a method for obtaining granules with good sphericity, granulation using a centrifugal flow coating granulation device (hereinafter sometimes referred to as CF device) is being considered.

In this method, the surface of spherical core granules or cores is coated by spraying water or a solution containing a binder, using a spraying agent if necessary, to ensure high sphericity and a wide particle size distribution. Small spherical granules are obtained. [Drug Development and Industrial Pharmacy]
Industrial Pharmacy), 1
1(8), 1523-151 (1985) J To make controlled drug release preparations, the surfaces of the obtained spherical granules are coated with wax or polymers for the purpose of controlling drug release. Generally, CF co-coating using a CF apparatus and fluid coating using a fluidized bed coating machine are being considered as coating methods.

(Problems to be Solved by the Invention) However, in CF co-coating and fluid coating, problems such as destruction of spherical granules and shearing often occur in the early stages. This disorder not only impairs the drug release control function in coated granules, but also greatly affects the yield during the production of spherical granules and coated granules. Furthermore, when distributed on the market as granules,
The granules are easily damaged during the distribution process, and to increase the strength of the granules, for example, polyvinylpyrrolidone is added as a binder [Mizu et al., Pharmaceutical Science, 45(2), 181-
187 (1986) J. Further, when the granule strength is increased, the disintegration properties of the granules tend to deteriorate, and there has been a demand for granules that disintegrate quickly and have high strength.

(Means for Solving the Problems) Taking these circumstances into consideration, the present inventors used an OF device to intensively study spherical granules that have strong granule strength and are quick to disintegrate. When propylcellulose is added to the liquid sprayed during coating and granulated, spherical granules with unexpectedly strong granule strength and excellent disintegration properties are obtained.In addition, low-substituted hydroxypropylcellulose is used as a dispersing agent. The present invention was completed after confirming that there was almost no powder scattering during manufacturing, which can be a problem.

That is, the present invention relates to a method for producing cored granules, which is characterized by spraying a dispersion of low-substituted hydroxypropyl cellulose onto the core granules, and to the cored granules 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 to 4.
20%, preferably 5 to 16%, more preferably 10 to 13%.

In addition, the average particle diameter of the L-HPC is generally 20
It may be 0 μm or less, preferably 100 μm or less,
More preferably, it is 30 μm or less.

The nuclear granules used in the present invention include, for example, sucrose (7
5 parts by weight) coated with corn starch (25 parts by weight) by a method known per se.
il ) and spherical granules using crystalline cellulose, and the core granules themselves may be other crude drug components different from the target crude drug. Furthermore, the core granules may be coated with wax or polymer to form the core.

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

In addition to L-RPC, a main drug and other additives may be uniformly dispersed and/or dissolved in the dispersion.

The main drug is not particularly limited as long as it can be administered as a granule, and examples of central nervous system drugs include diazepam, idebenone, aspirin, ibuprofen, valacetamol, naproxen, piroxicam, diclofenac, indomethacin, sulindac, lorazepam, nitrazepam, and phenytoin. , acetaminophen, ethenzamide, ketoprofen, etc., as cardiovascular drugs.
Molsidomine, bingocetine, propranolol, methyldopa, diviridamol, furosemide, triamterene, nifedipine, atenolol, spironolactone, metoprolol, pindolol, captopril, isosorbide nitrate, etc. Respiratory drugs include amlexanox, dextromethorphan, theophylline, pseudoephedrine, salbutamol, Guaifenesin and the like are gastrointestinal drugs such as 2-((3-methyl-4(2
,2,2-tripleoloethoxy)-2-pyridyl]methylsulfinyl Jbenzimidazole (hereinafter sometimes referred to as compound A) and 5-methoxy-2-((
Benzimidazole drugs with anti-ulcer effects such as 4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl J-benzimidazole, cimetidine, ranitidine, pancreatin, bisacodyl, 5-aminosalicylic acid, etc. are used as antibiotics and Chemotherapy agents include cephalexin, cefaclor, and cefrazine. Amoxicillin, pivampicillin, bacampicillin, isin stearate, lincomycin, doxycycline, trimethoprim/sulfamethoxazole, etc. Metabolic drugs include serrapeptase, lysozyme chloride, adenosine trifuphosphate, glibenclamide, potassium chloride, etc.
Vitamin drugs include vitamin B1 and vitamin Bt.
s Vitamin Be, vitamin C1 fursultiamine, and the like.

Examples of such additives include additives that are generally added when manufacturing granules, such as excipients (e.g., milk L cornstarch, sucrose, talc, Mi cellulose, mannitol, light silicic anhydride, magnesium carbonate, calcium carbonate, L-cysteine, etc.), binders (e.g., pregelatinized starch, methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, pullulan, dextrin, gum arabic, etc.), disintegrants (carboxylic Methylcellulose calcium, starches, cross-linked carboxymethylcellulose sodium,
cross-linked insoluble polyvinylpyrrolidone, etc.)
, colorants (titanium oxide, red iron oxide, tar pigments, etc.), and two or more of these may be used.

Further, in the present invention, while spraying the dispersion onto the core granules, the above-mentioned main ingredient and additives may be uniformly mixed to form a powdered dispersing agent. The particle size of the dispersant is generally about 100 μm or less, preferably about 50 μm or less.

The blending ratio of L-RPC to the dispersion varies depending on the type and blending ratio of the main drug and other additives, but it is usually 05 to 50% by weight, especially 5 to 50% by weight.
Preferably, it is a 30 weight spear. Generally, a blending ratio of less than 0.3% is not very preferable because the concentration in the solution is low and it takes time to coat the amount necessary to increase the strength of the granules. Furthermore, if 60% is strained, problems such as an increase in the viscosity of the liquid may occur, which may cause trouble during granule production. Furthermore, it goes without saying that the proportion of I, -I (PC) in the dispersion may be varied continuously or stepwise during coating, depending on the purpose. In some cases, coating may be performed with a dispersion liquid that exceeds the blending ratio of 0.5 to 50M.Furthermore, if the main drug and other additives are dispersed at the same time, the blending ratio of these may also vary. Good too.

In addition, the L-HPC content in the obtained granules with strong strength and quick disintegration is usually 01 to 15% by weight.
It is desirable that Addition rates of less than 0.05% are not sufficient to increase granule strength. Moreover, when it exceeds 20%, the addition rate of other coating components becomes low, which is not preferable.

Next, the method for producing nucleated granules of the present invention will be described in further detail. The core granules are sprayed with a liquid in which L-HP O and, if necessary, a main drug and/or additives are dispersed and/or dissolved, and are sprinkled with a powder dispersing agent as necessary to granulate the core granules. At this time, if there is no problem with the stability of the active ingredient, there is no need to particularly adjust the temperature of the liquid during production, and it is generally room temperature (1 to 30°C).
°C) is sufficient.

Moreover, by sieving the granulated product after drying, spherical alumina granules with uniform particle size can be obtained. The sieve used may have, for example, a round part with 12 to 32 meshes, and granules that pass through 12 meshes but do not pass through 32 meshes may be selected.

The thus obtained nucleated granules are used for taste masking,
For the purpose of providing enteric properties, gastric properties, sustainability, etc., coating may be performed by a method known per se.Furthermore, if the compatibility of the active ingredient is poor, coating may be applied during the production of cored granules for the purpose of stabilization. You may. Alternatively, it may be filled into capsules by a method known per se. Furthermore, tablets may be manufactured by mixing with other ingredients.

Examples of the coating agent include hydroxypropyl methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, 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 red iron.

(Example) The present invention will be described in more detail below by giving Examples, Reference Examples, and Experimental Examples. Note that the raw materials used in these are all in powder form.

Example 1 A non-barrel (20 to 28 mesh) 27005 was placed in an OF device (CF-360, manufactured by Freund), and L-HPO was added to 2000 ml of water at a rotor rotation speed of 20 Orpm.
(Hydroxypropoxyl group substitution degree: 10.Q to 13.
(0% CW/W), average particle size of 30 μm or less, and the same degree of substitution and average particle size were used in the subsequent Examples and Experimental Examples. 31 (w/w) and 2% (w/w) of droxypropyl cellulose and 2000 g of spraying agent (compound A1 magnesium carbonate, granulated sugar, cornstarch, etc.) were sprayed at 25 mtZ. The mixture was coated while being sprayed at 25 I/min, and spherical nucleated granules of 12 to 32 meshes were obtained using a round section.

The obtained spherical nucleated granules 3800.9 were placed in a fluid coating machine Glatt WSG-15 (Graft, West Germany), and the blowing temperature was controlled at 50°C and the product temperature was 40°C, and 50MtZ of enteric film liquid having the following composition was added. Coating was carried out by spraying with water to obtain enteric-coated cored granules. The obtained granules were uniformly coated with the enteric coating without particle breakage during coating, and met the particle size and enteric disintegration test stipulated in the 11th edition of the Japanese Pharmacopoeia.

[Enteric film liquid]

Eudragit Lion-55 Talc polyethylene glycol 6000 Titanium oxide Tween 80 28g 92g 4g 4g 2g 400g Water Example 2 Non-barrel (24-32 mesh) 42 and 9 were placed in CF device 1 (CF-1300, manufactured by Freund) , and the rotor rotation speed was set to 6 Orpm, and a coating liquid having the following composition prepared in advance was sprayed and granulated using 200*//min x 2 guns. After vacuum drying the granules at 40°C for 116 hours, spherical nucleated granules with 12 to 32 meshes were obtained using a round section.

[Coating liquid]

Serrapeptase aooooyL-RP
C1600g Lactose 160g0
g granula 1800g tarri
1 eooy etanol
11500 g water
9 was placed in a fluid coating machine (PLO-80, manufactured by Freund/Otawara Co., Ltd.) into 9,700 g of the obtained spherical nucleated granules 48, and the blowing temperature was controlled at 60°C and the exhaust temperature was approximately 40°C. Coating was performed by spraying an enteric film solution at 170 g/min with a X3 gun to obtain enteric coated cored granules. The obtained granules were uniformly coated with the enteric coating without particle breakage during coating, and met the particle size and enteric disintegration test specified in the 11th edition of the Japanese Pharmacopoeia.

[Enteric film liquid] Hydroxypropyl methylcell 11600g loin phthalate) -220824 Sera Riri
2800 g polyethylene glycol 60
00 660g ethanol
56300 grams 131500
g 420 g of the enteric coated cored granules obtained above, 270 g of aluminum hydroxide autosodium bicarbonate coprecipitate, 580 g of crystalline cellulose, cross-linked sodium carboxymethyl cellulose tsoy, 20 g of magnesium stearate, and previously prepared by the following method. 1,440 g of tableting granules were added to a tumble mixer (TM~15,
(Mixing conditions:
10 rpm.

3 minutes). Purepress Collect 19K
(manufactured by Kikusui Seisakusho) using an Oblong type punch at a compression pressure of 1 ton/am2. A white plain tablet was obtained with a weight of 480 grams, a major axis of 15 ff, a minor axis of 6.5 mm, a thickness of θ, 4 tx*, and a disintegration time of 1.2 minutes.

[Granules for tableting]

Acetaminophen 900 y1 Chlorpheniramine maleate 7.5f, Noskabine 48y, Anhydrous caffeine 75g, Dihydrocodeine phosphate 24f, dl-salt M methylephedrine 60g, Cross-linked carboxymethylcellulose sodium 72f and Corn starch 7
By adding crystalline cellulose to a mixture consisting of 2y, 1389
．． 6f and thoroughly mixed with a vertical granulator (FM025 type, manufactured by Fuji Sangyo Co., Ltd.), mixing conditions: 400 rp.
m.

The mixture was kneaded for 15 minutes with an aqueous solution in which 50.4% of hydroxypropyl cellulose was dissolved. The white mixture was dried in a fluidized fluid dryer (FD-38, Fuji Sangyo Co., Ltd.!!) at a blowing temperature of 60'C for 30 minutes, and then dried using a power mill CP-3 model, newly manufactured by Showa Kagaku Kikai Seizo. The mixture was sieved through a 51RMφ punching screen to obtain granules for tabletting.

Example 3 85 g of non-barrel (24 to 32 meshes) was placed in a mini CF device (manufactured by Freund), and the rotor rotation speed was set to 400.
rpm, and add 30 L-RPC to 50 g of ethanol.
% (W/W) and 1% hydroxypropylcellulose
(, W/W) While spraying 2.5 fl of the coating solution obtained by dispersing or dissolving each at a rate of 1 minute, a spraying agent homogeneously mixed with 10 f of idebenone, 10 g of granulated sugar, and 30 y of cornstarch was sprayed in 597 minutes, and the spraying was completed. After that, the coating liquid was also sprayed to obtain granules. 40 granules
Vacuum drying was carried out at °C for 16 hours, and 12 to 32 mesh spherical nucleated granules were obtained using the round section. The granules (240η) were filled into No. 2 hard capsules (weight: Ei 51151) using a capsule filling machine (manufactured by Parke-Davis) to produce capsules.

Example 4 A non-barrel (24 to 32 mesh) 85y was placed in a mini CF device (manufactured by Freund), and the rotor rotation speed was set to 40.
Orpm, dispersed 5 g of L-IIP C and 4 g of talc in 5 ay of water, and further added 6 g of fursultiamine hydrochloride.
1. A coating solution in which 4y of granulated sugar and 11% of hydroxypropyl cellulose were dissolved was sprayed at 2°59/min to obtain granules.

The granules were vacuum dried at 40°C for 16 hours, and spherical nucleated granules with 12 to 32 meshes were obtained using the round section.

Example 5 Spherical nucleated granules were produced by granulating L-RPC and granulated sugar of the coating liquid used in Example 2 with the coating liquid varied as shown in the table below at the initial, middle, and late stages of coating. The obtained cored granules had no particle breakage during coating, were uniformly coated with an enteric coating, and met the disintegration test for particle size and enteric coating stipulated in the 11th edition of the Japanese Pharmacopoeia.

Amounts of L-RPC and granulated sugar in coating solution Reference Example 1 In the method of Example 4, fursultiamine hydrochloride, L-HPC1 granulated sugar and talc were deleted, and fursultiamine hydrochloride, L- A dusting agent was prepared by uniformly mixing HP O1 granulated sugar and talc. The coating solution was sprayed at 5 g/min while the dusting agent was sprayed at 1.2 g/min, and after vacuum drying at 40°C for 16 hours, spherical nucleated granules with 12 to 52 meshes were obtained using a round section. .

Reference Example 2 In the method of Example 4, L-RP in the coating liquid
C is crystalline cellulose and cornstarch.

Spherical nucleated granules were produced by granulation with a coating liquid changed to pregelatinized starch, hydroxypropyl cellulose, pullulan, carboxymethyl cellulose, or lactose. Using the round part, 12 to 32 mesh spherical nucleated granules were obtained.

Experimental example 1 Example 4. Example 5. 5 g of the granules (12 to 32 meshes) obtained in Reference Example 1 and Reference Example 2 were placed in a 50 ml stainless steel cylinder (50 ml internal volume, diameter 32#+1
1), shaken for 15 minutes in a Spex mill (manufactured by Spex, Germany), passed through a 32-mesh round sieve, measured the amount on the sieve, and determined the residual rate of granules, which was defined as granule strength. Furthermore, the disintegration time of the granules was also measured according to the Japanese Pharmacopoeia (11th revision) disintegration test method. As a result, as is clear from Table 1, the cored granules of the present invention had high strength and excellent disintegration properties.

Table 1 Granule strength and disintegration time I recognized it.

Experimental Example 2 As a result of comparing the yield of the granules obtained in Example 4, the yield of the granules obtained in Reference Example 1 (control), and the content of fursultiamine hydrochloride, the yield of Example 4 and the content of fursultiamine hydrochloride were compared as shown in Table 2. The content is reference example 1
The nucleated granules obtained in the present invention have strong granule strength and excellent disintegration properties. Moreover, compared to when L-■PC is applied in powder form, there is less scattering of the main drug contained in the granules, so the crude drug content can be kept constant.
Furthermore, it has the advantage of high granule strength.

Claims (5)

[Claims] (1) A method for producing cored granules, which comprises spraying a dispersion of low-substituted hydroxypropyl cellulose onto core granules. (2) The manufacturing method according to claim (1), wherein the powdery dusting agent is sprayed while the dispersion is being sprayed. (3) Claim (1) or (2) that the main drug is blended into the dispersion.
) manufacturing method. (4) The manufacturing method according to claim (2) or (3), wherein the active ingredient is blended into the powder dusting agent. (5) Nucleated granules obtained by the production method according to claims (1) to (4).