Title of Invention	A PRODUCTION METHOD OF SPHERICAL BASE GRANULES
Abstract	A production method of spherical base granules comprising a hardly water-soluble drug, comprising spraying a layering liquid to pharmaceutically inert spherical core particles and coating the particles with a drug-containing layer, wherein: the layering liquid comprises: from 0.01 to 50 mass% of hardly water-soluble drug particles having a maximum long diameter and a maximum short diameter of from 17% to 30% and of from 3% to 12%, respectively, of an average short diameter of the spherical core particles; from 0.1 to 2 mass% of a micronized microcrystalline cellulose; and from 0.01 to 1 mass% of an emulsifier.

Title of Invention

A PRODUCTION METHOD OF SPHERICAL BASE GRANULES

Abstract

A production method of spherical base granules comprising a hardly water-soluble drug, comprising spraying a layering liquid to pharmaceutically inert spherical core particles and coating the particles with a drug-containing layer, wherein: the layering liquid comprises: from 0.01 to 50 mass% of hardly water-soluble drug particles having a maximum long diameter and a maximum short diameter of from 17% to 30% and of from 3% to 12%, respectively, of an average short diameter of the spherical core particles; from 0.1 to 2 mass% of a micronized microcrystalline cellulose; and from 0.01 to 1 mass% of an emulsifier.

Full Text	DESCRIPTION METHOD FOR PRODUCING SPHERICAL BASE GRANULES COMPRISING HARDLY WATER-SOLUBLE DRUG Technical Field [0001] The present invention relates to a production method of spherical base granules comprising a hardly water-soluble drug. Background Art [0002] Pharmaceutical solid preparations sometimes have sustained release, enteric, or bitterness-masking film coating with a view to reducing side effects of a drug comprising in them, reducing the administration frequency, improving the effect of the drug, suppressing a bitter taste, stabilizing the drug, or the like. Drug-containing spherical granules having a dosage form suited for film coating thereon are called spherical base granules. [0003] As a production method of spherical base granules, a method of carrying out extrusion granulation using a drug and an excipient as raw materials and then spheronizing the resulting granule product (extrusion- spheronization method), a method of coating the surface of spherical core particles with a drug (layering method) (refer to, for example, Patent Document 1), and the like are known. [0004] In the layering method, granules are produced by spraying a layering liquid comprising a drug, a binder, and the like to spherical core particles to coat them with a coating layer. Specific examples of it include a method of simultaneously supplying drug powders and an aqueous solution of a binder and coating spherical core particles with them; a method of supplying a suspension of drug particles and coating the spherical core particles therewith; and a method of supplying an aqueous solution of a drug and coating the spherical core particles therewith. [0005] The layering method is suited as a method for producing spherical base granules to be film-coated, because spherical base granules having a high sphericity and a narrow particle size distribution can be obtained using spherical core particles having a high sphericity and a narrow particle size distribution. [0006] However, when a drug that is contained in the layering liquid has low water solubility (hardly water-soluble drug), dispersion in an apparatus having a high shear force is necessary to obtain a uniform suspension. Therefore, when such a layering liquid is prepared, vigorous foaming occurs, and foam breaking is sometimes necessary. In addition, in a layering liquid having a practical drug concentration, the drug particles precipitate with the passage of time. The layering liquid therefore must be stirred/mixed constantly to keep the suspension uniform. Even if the layering liquid is stirred/mixed constantly, there is a risk of a tube or spray nozzle being clogged with precipitated/agglomerated particles during a transfer of the layering liquid from a tank to the spray nozzle. When the drug has a large particle size, the above risk increases further, which leads to deterioration in adhesion to spherical core particles, a reduction in a recovery ratio, and an increase in agglomeration ratio due to inhibition of smooth tumbling. A reduction in the size of the drug particles improves suspension stability of the layering liquid and a recovery ratio, but it need's an extra pulverization (or grinding) treatment step of the drug particles. [0007] It is known to add various additives to the layering liquid for the purpose of preventing detachment of the coated drug, controlling a dissolution rate of the drug, or stabilizing the layering liquid (refer to, for example, Patent Documents 2, 3, and 4). These prior arts however fail to improve the suspensibility of a hardly water-soluble drug. Patent Documents 2 to 4 include no description on the use of both micronized microcrystalline cellulose and an emulsifier in combination Patent Document 5 discloses a technology of coating spherical core particles with a hardly water-soluble drug, an emulsifier, and the like in accordance with the layering method, but the technology specifically disclosed herein is a layering method in which drug powders and an aqueous solution of a binder are supplied simultaneously to coat therewith the particles. Patent Document 5 includes no description on the improvement of suspensibility during addition of a hardly water-soluble drug to a layering liquid. [0008] Patent Document 1: Japanese Patent Application Laid-Open No. 63-301816 Patent Document 2: Japanese Patent Application Laid-Open No. 9-165329 Patent Document 3: Japanese Patent Application Laid-Open No. 9-67247 Patent Document 4: Published Japanese translation of PCT international publication No.2005-536527 Patent Document 5: International Publication No. 2005/044240 Disclosure of the Invention Problems to be solved by the Invention [0009] An object of the present invention is to provide a method of producing, with an improved production efficiency, spherical base granules comprising a hardly water-soluble drug by using a layering liquid comprising the hardly water-soluble drug, having good suspension stability, and controlled to minimize foaming. Means for Solving the Problem [0010] The present inventors have carried out an extensive investigation with a view to overcoming the above-described problem. As a result, it has been found that by adding micronized microcrystalline cellulose and an emulsifier in a layering liquid, suspension stability of the layering liquid is improved and foaming is suppressed without extra pulverization treatment of a drug, leading to the completion of the present invention. The following is the details of the present invention. A production method of spherical base granules comprising a hardly water-soluble drug, which comprises spraying a layering liquid to pharmaceutically inert spherical core particles and coating the particles with a drug-containing layer, wherein the layering liquid comprises: (1) from 0.01 to 50 % by mass of hardly water-soluble drug particles having a maximum long diameter and a maximum short diameter of not greater than 30% and not greater than 12% of an average short diameter of the spherical core particles, respectively; (2) from 0.1 to 2 % by mass of micronized microcrystalline cellulose; and (3) from 0.01 to 1 % by mass of an emulsifier. Advantage of the Invention [0011] The method according to the present invention enables stable production of spherical base granules comprising a hardly water-soluble drug with high productivity. Best Mode for Carrying out the Invention [0012] The present invention will hereinafter be described specifically. The spherical core particles to be used in the present invention are pharmaceutically inert. This means that the core particles do not comprise a drug. The term "drug" as used herein means what is used for treatment, prevention, or diagnosis of human or animal diseases but what is not an instrument/machine. [0013] The spherical core particles may contain one or more pharmaceutical additive. Examples of such a pharmaceutical additive include excipients such as lactose, sucrose, D-mannitol, corn starch, powder cellulose, calcium hydrogen phosphate, and calcium carbonate; disintegrants such as low- substituted hydroxypropyl cellulose, carmellose calcium, pregelatinized starch , croscarmellose sodium, crospovidone, and carboxymethyl starch; binders such as hydroxypropyl cellulose, povidone (polyvinylpyrrolidone), and xanthan gum; coating agents such as hypromelose (hydroxypropylmethyl cellulose), methacrylic acid copolymer LD, and ethylcellulose aqueous dispersion; emulsifiers such as sucrose fatty acid ester, glycerin fatty acid ester, sodium lauryl sulfate, and polysorbate 60; and other additives such as talc, magnesium stearate, magnesium aluminometasilicate, titanium oxide, light silicic anhydride, microcrystalline cellulose carmellose sodium. [0014] Preferred examples of a formulation include spherical core particles composed only of sucrose, those composed of 70 % by mass of sucrose and 30 % by mass of corn starch, those composed of 30 % by mass or more of microcrystalline cellulose and another pharmaceutical additive, those composed only of microcrystalline cellulose, and those composed only of mannitol. Spherical core particles comprising 30 % by mass or more of microcrystalline cellulose are preferred because of having high strength and high water absorption capacity. Those comprising 70 % by mass or more of microcrystalline cellulose are more preferred, with spherical core particles composed only of crystalline cellulose being still more preferred. Spherical core particles composed only of microcrystalline cellulose are most preferred. [0015] The term "spherical" of spherical core particles means that the particles have a sphericity (= short diameter/long diameter) of 0.7 or greater. Particles which are not spherical are not preferred because they deteriorate uniformity of film coating. The spherical core particles having a sphericity of 0.9 or greater are preferred. As the spherical core particles, those having an average particle size of from about 50 to 1000 µm can be used. The particle size distribution is preferably sharp. The bulk density is preferably from about 0.5 to 2.0 g/cm3. The spherical core particles composed only of microcrystalline cellulose have generally a bulk density of from about 0.5 to 1.0 g/cm3. The mechanical strength is preferably higher. [0016] The layering liquid to be used in the present invention will next be described. First, hardly water-soluble drug particles to be incorporated in the layering liquid of the present invention will be described. The term "hardly water-soluble" as used herein means that the particles do not dissolve in water readily and they have solubility, in 1 cm3 of water at 20°C, of 0.001 g or less. Examples of the hardly water-soluble drug include amcinonide, ibuprofen, indomethacin, ethenzamide, erythromycin, cefotiam hexetil hydrochloride, nicardipine hydrochloride, omeprazole, prednisolone valerate acetate, diflucortolone valerate, dexamethasone valerate, betamethasone valerate, clarithromycin, griseofulvin, clonazepam, chloramphenicol, synthetic peptide compounds, cortisone acetate, diflorasone diacetate, dexamethasone acetate, triamcinolone acetate, paramethasone acetate, hydrocortisone acetate, fludrocortisone acetate, methylprednisolone acetate, diazepam, digitoxin, digoxin, difluprednate, beclometasone dipropionate, betamethasone dipropionate, sulpiride, sulfathiazole, cefuroxime axetil, dexamethasone, triamcinolone, triamcinolone acetonide, nicardipine, nifedipine, nilvadipine, noscapine, halcinonide, hydrocortisone, flumetasone pivalate, phenacetin, phenitoin, budesonide, prazepam, fluocinonide, fluocinolone acetonide, fluorometholone, fludroxycortide, prednisolone, alclometasone dipropionate, clobetasol propionate, dexamethasone propionate, deprodone propionate, betamethasone, migrenin, methylprednisolone, ubidecarenone, clobetasone butyrate, hydrocortisone butyrate, hydrocortisone butyrate propionate, riboflavin butyrate, lansoprazole, and riboflavin. [0017] The hardly water-soluble drug particles are preferably smaller. The maximum long diameter of them is 30% or less of the average short diameter of the spherical core particles and the maximum short diameter is 12% or less of the average short diameter of the spherical core particles. When each of the diameters exceeds the specified values, respectively, the drug particles are likely to detach from the spherical base granules, and the recovery ratio of the spherical base granules will decrease. In addition, presence of the drug particles detached from the granules inhibits tumbling of the spherical core particles, resulting in an increase in agglomeration of the spherical base granules. The maximum long diameter of the drug particles is preferably not greater than 20% of the average short diameter of the spherical core particles and the minimum short diameter of the drug particles is preferably not greater than 10%. [0018] The hardly water-soluble particles are added to the layering liquid in an amount of from 0.01 to 50 % by mass. When the amount is less than 0.01 % by mass, layering need to be performed for long hours to coat the spherical core particles with a necessary amount of the drug. When it exceeds 50 % by mass, on the other hand, the viscosity of the layering liquid becomes too high and prevents smooth spraying. It is preferably from 1 to 30 % by mass, more preferably from 5 to 20 % by mass. [0019] The micronized microcrystalline cellulose to be incorporated in the layering liquid of the present invention will hereinafter be described. The term " micronized microcrystalline cellulose" to be incorporated in the layering liquid in the present invention means microcrystalfine cellulose having an average particle size of 12 µm or less as measured in water. It is more preferably 9 urn or less. The term "microcrystalline cellulose" as used herein means that conforms to any of the standards "Microcrystalline cellulose" specified in the Japanese Pharmacopoeia, Fifteenth Edition, "Microcrystalline cellulose" specified in Japanese Standards of Food Additives, Seventh Edition, and "Microcrystalline cellulose-carmellose sodium" specified in Japanese Pharmaceutical Excipients 2003. [0020] The micronized microcrystalline cellulose is, for example, that obtained by dry or wet grinding of typical microcrystalline cellulose or that obtained by dispersing microcrystalline cellulose-carmellose sodium in water. Microcrystalline cellulose-carmellose sodium is preferred because a layering liquid comprising it can be prepared easily and at the same time, has high suspension stability, and spherical base granules available using it have high strength. [0021] The micronized microcrystalline cellulose is added to the layering liquid in an amount of from 0.1 to 2 % by mass. When the amount is less than 0.1 % by mass, a sufficient suspension stabilizing effect is not obtained. When it exceeds 2 % by mass, on the other hand, the layering liquid has a too high viscosity and cannot be sprayed smoothly. It is preferably from 0.2 to 1 % by mass, more preferably from 0.3 to 0.8 % by mass. [0022] Addition of the micronized microcrystalline cellulose to the layering liquid improves suspension stability of the hardly water-soluble drug particles in the layering liquid and solves the problem of clogging a tube and also a spray nozzle therewith. Moreover, it improves the adhesion of the hardly water- soluble drug particles to the spherical core particles so that it is also effective for raising a recovery ratio and reducing an agglomeration ratio. [0023] An emulsifier that can be comprised in the layering liquid of the present invention will next be described. in the present invention, the term "emulsifier" that may be comprised in the layering liquid means a substance having an emulsifying function to be used for the preparation of pharmaceutical formulations. Examples of the emulsifier include sucrose fatty acid esters, glycerin fatty acid esters, sodium lauryl sulfate, polysorbates, polyoxyethylene hydrogenated castor oils, carmellose sodium, and xanthan gum. The emulsifier is adequately selected, depending on the physical properties of the drug particles. Of these, polyoxyethylene hydrogenated castor oils are preferred from the viewpoint of their high foaming suppressing effect, with polyoxyethylene hydrogenated castor oil 60 being more preferred. The polyoxyethylene hydrogenated castor oil 60 is a nonionic surfactant obtained by addition polymerization of a hydrogenated castor oil with ethylene oxides and having an average molar number of added ethylene oxide of about 60. It has a CAS No. of 61788-85-0. The average molar number of ethylene oxide added to polyoxyethylene hydrogenated castor oil 60 is preferably from 52 to 68, more preferably from 55 to 65. [0024] The emulsifier is added to the layering liquid in an amount of from 0.01 to 1 % by mass. Amounts less than 0.01 % by mass do not sufficiently improve the affinity of the drug particles with water. Although there is no upper limit for the additive amount of emulsifier, the effect is not enhanced as much as expected when the additive amount exceeds 1 % by mass or greater. The amount is more preferably from 0.05 to 0.8 % by mass. [0025] Addition of the emulsifier to the layering liquid raises affinity of the drug particles with water, thereby suppressing foaming. Due to a synergetic effect of the emulsifier and micronized microcrystalline cellulose, the layering liquid becomes a stable suspension. Only slight stirring or, in some cases, no stirring is therefore necessary for maintaining the suspension state of the layering liquid. To a suspension such as a suspension syrup or dry syrup comprising sucrose at a concentration of 20 % by mass or a concentration as high as about 5 % by mass or greater, microcrystalline cellulose carmellose sodium and an emulsifier such as polysorbate have been sometimes added in combination in order to improve suspension stability. However, a problem of foaming does not originally happen in such a suspension, as it contains sucrose at a high concentration. Therefore, for those skilled in the art, it is unexpected that combination use of an emulsifier and micronized microcrystalline cellulose in the layering liquid that dose not comprise sucrose at high concentration produces not only a suspension stabilization effect but also an excellent foaming suppressing effect. [0026] Another pharmaceutical additive may be added to the layering liquid as needed, in particular, addition of a binder is especially preferred because it improves the strength of the drug-containing layer. Examples of the binder include hydroxypropyl cellulose, povidone, and hypromelose (hydroxypropylmethyl cellulose). [0027] A process of coating the spherical core particles with a layer comprising the hardly water-soluble drug by layering will next be described. Fluidized-bed coating apparatuses can be used for coating the spherical core particles with the layer comprising a hardly water-soluble drug. Examples of the fluidized-bed coating apparatus include, in addition to an ordinary fluidized bed type, a spouted fluidized-bed type having, inside thereof, a guide tube (Wurster column) and a tumbling fluidized-bed type equipped, on the bottom thereof, a rotation mechanism. Specific examples of such apparatuses include "Flow Coater" and "Spiral Flow", products of Freund Corporation, "WST/WSG Series" and "GPCG Series", products of Glatt GmbH, "New Marumerizer", product of Fuji Paudal Co., Ltd., and "Multiplex", product of Powrex Corporation. [0028] The layering liquid can be supplied by a method suited for each of apparatuses such as top spray, bottom spray, side spray, and tangential spray. It may be sprayed to the spherical core particles continuously or intermittently. After completion of spraying, the spherical base granules are dried. Drying of the spherical base granules may be performed as are or after controlling an air flow rate or temperature as needed, while not taking out the granules from the apparatus. [0029] The coating amount of the drug-containing layer can be determined based on the formulation design such as single dosage or size of the preparation. For example, it is generally from about 0.5 to 200 % by mass relative to the spherical core particles. [0030] Next, one example of a production method of the spherical base granules will be described. (a) Preparation of micronized microcrystalline cellulose: First, microcrystalline cellulose is dispersed in water and the resulting aqueous dispersion is micronized in a Manton-Gaulin Homogenizer. Micronization= treatment is performed for necessary times at high pressure, for example, at 50 MPa and five passes. When micronized microcrystalline cellulose (for example, "CEOLUS Cream" FP-03, product of Asahi Kasei Chemicals Corporation, solid content: 10 % by mass, average particle size: about 4 µm) or microcrystalline cellulose.carmellose sodium (for example, "CEOLUS" RC- A591NF, product of Asahi Kasei Chemicals Corporation) is used, the micronization step is not necessary. (b) Preparation of layering liquid: A layering liquid is prepared by adding a hardly water-soluble drug, the micronized microcrystalline cellulose, an emulsifier, and necessary pharmaceutical additives to water and stirring the mixture sufficiently until dissolved or suspended. During stirring, a rotary disperser is preferably used to fully minimize the micronized microcrystalline cellulose and mix it with the other components. Examples of the disperser include "T.K. Homomixer", product of Tokushu Kika Kogyo Co., Ltd. and "ULTRA TURRAX", product of IKA Company. A stirrer having a weak stirring power such as propeller stirrer is not so preferred. In order to confirm dissolution or dispersion, components may be dispersed sequentially. (c) Heating of spherical core particles and fluidized-bed coating apparatus: After spherical core particles are charged in a fluidized-bed coating apparatus, the core particles are fluidized (when the fluidized-bed coating apparatus is a tumbling fluidized-bed type is employed, the rotation portion of it is turned simultaneously) by supplying hot air from the bottom portion of the apparatus until an outlet-air temperature reaches a predetermined temperature. (d) Coating with drug layer: The layering liquid is sprayed at a predetermined spray rate continuously or intermittently or at a rate raised in a stepwise fashion. The supply of the layering liquid is terminated when the coating amount reaches a predetermined amount. (e) Drying of spherical base granules: The spherical base granules are dried while adjusting the amount of hot air and temperature (rotation speed of the rotating portion when a tumbling fluidized-bed type is employed) if necessary. (f) Taking-out of spherical base granules: In the end, the resulting spherical base granules are taken out from the apparatus. [0031] The spherical base granules obtained by the present invention can be used as granules, capsules, tablets or the like after subjected to particle size regulation and sustained release film coating, enteric film coating, or bitter- taste masking film coating if necessary. Example 1 [0032] The present invention will next be described based on some examples. First, measuring methods of physical properties are described collectively. The shape of a sample is photographed using a digital microscope ("VH-7000", product of KEYENCE CORPORATION) (with a 50x or 100x lens) and a short diameter (D) and a long diameter (L) of 50 particles are measured using an image analyzer ("Image Hyper", product of Inter Quest). The terms "short diameter" and "long diameter" as used herein mean the length of a short side and the length of a long side of the smallest (in area) rectangle that circumscribes a boundary pixels of a particle, respectively. The sphericity is an average of a short diameter/long diameter (D/L) ratio The average short diameter is a value at which the cumulative distribution of short diameter (D), which is determined in the same manner as the measuring method of sphericity, reaches 50%. A 100-cm3 graduated cylinder is filled with 30 g of a sample and a tapped volume [cm3] after tapping about 30 times is measured. The bulk density is calculated in accordance with the following equation. This operation is performed three times and an average is adopted as a tapped bulk density. Apparent tapped density [g/cm3] = 30 [g]/tapped volume [cm3]. The layering liquid (30 cm3) is charged in a sample bottle having a diameter of 40 mm and a height of 50 mm and the state after five minutes is observed. A sample is prepared by dropping the layering liquid onto a slide glass and then, placing a cover glass thereon. The sample is photographed using an optical microscope (use of a 40 × lens). Long diameter and short diameter of each of 50 drug particles on the photograph are measured and the maximum long diameter [µm] and maximum short diameter [urn] are determined. In the same manner as that employed for the preparation of the layering liquid, micronized microcrystalline cellulose is dispersed in purified water and a median diameter [urn] of the resulting dispersion is determined using a laser diffraction/scattering particle-size distribution analyzer ("LA-910", product of Horiba, Ltd.) while setting a specific refractive index at 1.20. The above operation is performed twice and an average is used. The recovery ratio is determined in accordance with the following equation based on the recovery amount [g] of spherical base granules after layering and the total amount [g] of raw materials employed. Recovery ratio [% by mass] = {recovery amount [g]/total amount [g] of raw materials} x 100 After dispersion of spherical base granules on paper, the number [a] of particles constituting agglomerated granules and the number [b] of single isolated particles are counted visually. The agglomeration ratio is calculated in accordance with the following equation. The number of particles observed is 1000 (=a+b). Agglomeration ratio [%] = {a/(a+b)}x100 [0033] [Example 1] (Preparation of layering liquid) While stirring 74.4 g of water in a rotary disperser ("T. K. Homomixer Mark II f model", product of Tokushu Kika Kogyo Co., Ltd.) at 5000 rpm, 15 g of povidone ("K-30", product of ISP Tec. Inc.) was added. The resulting mixture was stirred further until completely dissolved. Then, 0.1 g of a polyoxyethylene hydrogenated castor oil ("HCO-60", product of Nikko Chemicals Co., Ltd.) as an emulsifier was dispersed in the resulting solution until dissolved. 10 g of Ethenzamide ("Type A", product of API Corporation) was added in the resulting solution as a hardly water-soluble drug and then, 0.5 g of microcrystalline cellulose-carmellose sodium ("CEOLUS" RC-A591NF, product of Asahi Kasei Chemicals Corporation) was added as a micronized microcrystalline cellulose, followed by dispersion for 30 minutes to prepare a layering liquid. The resulting layering liquid was free from separation of the drug and foaming after completion of the dispersion and had considerably high suspension stability compared with that obtained in Comparative Example 1, which will be described later. (Layering) In a Wurster coating apparatus ("Multiplex" MP-01, equipped with a Wurster column, product of Powrex Corporation) was charged 0.3 kg of spherical core particles composed of 100% of microcrystalline cellulose ("Celphere" CP-203, product of Asahi Kasei Chemicals Corporation, sphericity: 0.9, tapped bulk density: 0.98 g/cm3, average short diameter: 165 µm) and the spherical core particles were layered until the layering amount reached 12.8 % by mass (5.0 % by mass in terms of the drug) under the conditions of a spray air pressure of 0.16 MPa, a spray air flow rate of 40 L/min, an inlet-air temperature of from 65 to 70°C, an outlet-air temperature of 40°C, an air flow rate of 40 m3/h, and a layering liquid spray rate of 3 g/min. The layering liquid was stirred with propeller constantly at 150 rpm. After the spraying of the layering liquid was terminated, drying was performed without changing the conditions until the outlet-air temperature increased to 42°C. A heater for inlet-air was then turned off and cooling was performed until the inlet-air temperature became 40°C. Few powdered drug that did not attach to the spherical core particles were observed and almost all the amount of the granules was recovered . In addition, the granules thus obtained were almost free from agglomeration. The results are shown in Table 1. [0034] [Example 2] (Layering) In a tumbling fluidized-bed coating apparatus ("Multiplex MP-01", product of Powrex Corporation) was charged 0.6 kg of spherical core particles which was the same as that used in Example 1 and they were layered with the layering liquid prepared in Example 1 until the layering amount became 12.8 % by mass (5.0 % by mass in terms of the drug) of the spherical core particles by using a tangential bottom spray under the conditions of a spray air pressure of 0.16 MPa, a spray air flow rate of 40 L/min, an inlet-air temperature of from 75°C, an outlet-air temperature of 41 °C, an air flow rate of 35 m3/h, a rotation speed of a rotor of 400 rpm, and a layering liquid spray rate of 5.0 g/min. The iayering liquid was stirred with propeller constantly at 150 rpm. After spraying of the layering liquid was terminated, the rotation speed of a rotor was decreased to 200 rpm and drying was performed until the outlet-air temperature reached 42°C. A heater for inlet-air was then turned off and cooling was performed until the inlet-air temperature became 40°C. Few powdered drug that did not attached to the spherical core particles were observed. The resulting spherical base granules showed good results with a recovery ratio of 94.6% and an agglomeration ratio of 1.2%. The results are shown in Table 1. [0035] [Comparative Example 1] (Preparation of layering liquid) While stirring 75.0 g of water in a rotary disperser ("T. K. Homomixer Mark II f model", product of Tokushu Kika Kogyo Co., Ltd.) at 5000 rpm, 15 g of povidone was added. The resulting mixture was stirred further until completely dissolved. Then, 10 g of ethenzamide was added and the resulting mixture was dispersed for 30 minutes to prepare a layering liquid. The resulting layering liquid foamed severely and foams did not disappear even after the passage of time. Five minutes after completion of the preparation, precipitation of the drug occurred and the layering liquid had only poor suspension stability. (Layering) In the same manner as Example 1 except that the inlet-air temperature was raised to from 70 to 78°C and layering liquid was stirred with propeller at 300 rpm, layering was performed. A recovery ratio of the spherical base granules decreased because the drug did not attach to the spherical core particles and the powdered drug attached to a bug filter at the upper portion of the apparatus. Moreover, the spherical base granules thus obtained contained many agglomerated particles. The results are shown in Table 1. [0037] The spherical base granules obtained in Examples 1 and 2 by using the layering liquid comprising both a micronized microcrystalline cellulose and an emulsifier did not contain many agglomerated granules and showed a high recovery ratio. In contrast, the spherical base granules obtained in Comparative Example 1 by using the layering liquid comprising neither a micronized microcrystalline cellulose nor an emulsifier, agglomerated due to foaming of the layering liquid and showed a low recovery ratio. [0038] [Referential Example] While stirring 89.4 g of water in a rotary disperser at 5000 rpm, 0.1 g of polyoxyethylene hydrogenated castor oil was added. The resulting mixture was stirred until completely dissolved. To the resulting solution were added successively 10 g of ethenzamide and 0.5 g of microcrystalline cellulose- carmellose sodium which is the same as that employed in Example 1. The resulting mixture was dispersed for 30 minutes to prepare a layering liquid. The layering liquid thus obtained was a uniform and highly clouded suspension free from foaming and precipitation of drug particles. The appearance of it is shown in-JFIG. 1. The observation results of the appearance are shown in Table 2. [0039] [Referential Comparative Example 1] While stirring 88.0 g of water in a rotary disperser at 5000 rpm, 2 g of povidone was added. The resulting mixture was stirred further until completely dissolved. In the resulting solution was added 10 g of ethenzamide, followed by dispersing for 30 minutes to prepare a layering liquid. The resulting layering liquid showed an uneven state with a foamy drug separated in the upper 53% portion of the liquid. The appearance of the layering liquid is shown in FIG. 2. The observation results of the appearance are shown in Table 2. [0040] [Referential Comparative Example 2] In the same manner as Referential Comparative Example 1 except that the amount of povidone was 15 g, a layering liquid was prepared. The separation state of the liquid was observed. Although the drug amount present in the lower layer increased compared with that in Referential Comparative Example 1, the foamy drug layer in the upper portion was still present without decreasing. The appearance of the layering liquid is shown in FIG. 3. The observation results of the appearance are shown in Table 2. [0041] [Referential Comparative Example 3] While stirring 89.5 g of water in a rotary disperser at 5000 rpm, 0.1 g of polyoxyethylene hydrogenated castor oil was added. The resulting mixture was stirred further until completely dissolved. In the resulting solution was added 10 g of ethenzamide, followed by dispersion for 30 minutes to obtain a layering liquid. The resulting layering liquid was separated into three layers. The upper 23% layer contained foams, while the lower 23% layer contained a drug precipitation layer. The appearance of the liquid is shown in FIG. 4. The observation results of the appearance are shown in Table 2. [0042] [Referential Comparative Example 4] In the same manner as Referential Comparative Example 3 except that 0.3 g of polyoxyethylene hydrogenated castor oil was added to 89.7 g of water, a layering liquid was prepared. The lower 11 % layer was a drug precipitation layer, showing a little improvement compared with Referential Comparative Example 3 but a problem of three-layer separation does not resolved. The observation results of the appearance are shown in Table 2. [0043] [Referential Comparative Example 5] While stirring 89.4 g of water in a rotary disperser at 5000 rpm, 0.5 g of microcrystalline cellulose-carmellose sodium was added. The resulting mixture was dispersed for 30 minutes. In the resulting dispersion was added 10 g of ethenzamide, followed by dispersion for 30 minutes to prepare a layering liquid. The layering liquid thus obtained showed an uneven state with a foamy drug layer in the upper 52% portion of the liquid as in Referential Comparative Example 1. The observation results of the appearance are shown in Table 2. [0044] [Referential Comparative Example 6] In the same manner as Referential Comparative Example 5 except that 2.2 g of microcrystalline cellulose-carmellose sodium which is the same as that used in Example 1 was added to 87.8 g of water, a layering liquid was prepared. The layering liquid thus obtained showed a uniform state without separation, but it became a gel due to the addition of a large amount of microcrystalline cellulose-carmellose sodium. The resulting gel was so tacky and it was difficult to transfer the layering liquid via a tube pump. The appearance is shown in FIG. 5. The observation results of the appearance are shown in Table 2. [0046] The layering liquid obtained in Referential Example by using micronized microcrystalline cellulose and an emulsifier in combination was a uniform suspension. In contrast, the layering liquids comprising neither micronized microcrystalline cellulose nor emulsifier separated into two layers (Referential Comparative Examples 1 and 2). The layering liquids comprising the emulsifier but not comprising the micronized microcrystalline cellulose foamed severely and separated into three layers (Referential Comparative Examples 3 and 4). The layering liquid comprising the micronized microcrystalline cellulose but not comprising the emulsifier did not foam and the layer separation was partially resolved (Referential Comparative Example 5). In order to completely resolve the problem of separation, however, it was necessary to increase the amount of micronized microcrystalline cellulose to the extent that it made the layering liquid into gel and thus made it unsatisfactory as a layering liquid (Referential Comparative Example 6). From the above results, it has been confirmed that the layering liquid comprising a hardly water-soluble drug has improved suspension stability when both micronized microcrystalline cellulose and an emulsifier are added in combination to the liquid. Industrial Applicability [0047] The production method of the present invention is suited in the field of the production of film-coated pharmaceutical granules. Brief Description of the Accompanying Drawings [0048] [FIG. 1] The appearance of the layering liquid prepared in Referential Example. [FIG. 2] The appearance of the layering liquid prepared in Referential Comparative Example 1. [FIG. 3] The appearance of the layering liquid prepared in Referential Comparative Example 2. [FIG. 4] The appearance of the layering liquid prepared in Referential Comparative Example 3. [FIG. 5] The appearance of the layering liquid prepared in Referential Comparative Example 6. WE CLAIM: 1. A production method of spherical base granules comprising a hardly water-soluble drug, comprising spraying a layering liquid to pharmaceutically inert spherical core particles and coating the particles with a drug-containing layer, wherein: the layering liquid comprises: (1) from 0.01 to 50 mass% of hardly water-soluble drug particles having a maximum long diameter and a maximum short diameter of from 17% to 30% and of from 3% to 12%, respectively, of an average short diameter of the spherical core particles; (2) from 0.1 to 2 mass% of a micronized microcrystalline cellulose; and (3) from 0.01 to 1 mass% of an emulsifier. 2. The production method of spherical base granules comprising a hardly water-soluble drug as claimed in claim 1, wherein the maximum long diameter and the maximum short diameter of the hardly water-soluble drug particles are not greater than 20% and not greater than 10% of the average short diameter of the spherical core particles, respectively. 3. The production method of spherical base granules comprising a hardly water-soluble drug as claimed in claim 1 or 2, wherein the layering liquid comprises from 1 to 30 mass% of the hardly water-soluble drug particles. 4. The production method of spherical base granules comprising a hardly water-soluble drug as claimed in claim 1 or 2, wherein the layering liquid comprised from 5 to 20 mass% of the hardly water-soluble drug particles. 5. The production method of spherical base granules comprising a hardly water-soluble drug as claimed in any one of claims 1 to 4, wherein the layering liquid comprises from 0.2 to 1 mass% of the micronized macrocrystalline cellulose. 6. The production method of spherical base granules comprising a hardly water-soluble drug as claimed in any one of claims 1 to 5, wherein the layering liquid comprises from 0.3 to 0.8 mass% of the micronized microcrystalline cellulose. 7. The production method of spherical base granules comprising a hardly water-soluble drug as claimed in any one of claims 1 to 6, wherein the layering liquid comprises from 0.05 to 0.8 mass% of the emulsifier. 8. The production method of spherical base granules comprising a hardly water-soluble drug as claimed in any one of claims 1 to 7, wherein the emulsifier is polyoxyethylene hydrogenated castor oil 60. 9. The production method of spherical base granules comprising a hardly water-soluble drug as claimed in any one of claims 1 to 8, wherein the micronized microcrystalline cellulose has an average particle size of 9 \|Jm or less. 10. The production method of spherical base granules comprising a hardly water-soluble drug as claimed in any one of claims 1 to 9, wherein the spherical core particles have a microcrystalline cellulose content of 70 mass% or greater. 11. The production method of spherical base granules comprising a hardly water-soluble drug as claimed in any one of claims 1 to 10, wherein the spherical core particles have a bulk density of from 0.5 to 1.0 g/cm3 . ABSTRACT Title: A production method of spherical base granules A production method of spherical base granules comprising a hardly water-soluble drug, comprising spraying a layering liquid to pharmaceutically inert spherical core particles and coating the particles with a drug-containing layer, wherein: the layering liquid comprises: from 0.01 to 50 mass% of hardly water-soluble drug particles having a maximum long diameter and a maximum short diameter of from 17% to 30% and of from 3% to 12%, respectively, of an average short diameter of the spherical core particles; from 0.1 to 2 mass% of a micronized microcrystalline cellulose; and from 0.01 to 1 mass% of an emulsifier.

Full Text

DESCRIPTION
METHOD FOR PRODUCING SPHERICAL BASE GRANULES COMPRISING
HARDLY WATER-SOLUBLE DRUG
Technical Field
[0001]
The present invention relates to a production method of spherical
base granules comprising a hardly water-soluble drug.
Background Art
[0002]
Pharmaceutical solid preparations sometimes have sustained release,
enteric, or bitterness-masking film coating with a view to reducing side effects
of a drug comprising in them, reducing the administration frequency, improving
the effect of the drug, suppressing a bitter taste, stabilizing the drug, or the like.
Drug-containing spherical granules having a dosage form suited for film
coating thereon are called spherical base granules.
[0003]
As a production method of spherical base granules, a method of
carrying out extrusion granulation using a drug and an excipient as raw
materials and then spheronizing the resulting granule product (extrusion-
spheronization method), a method of coating the surface of spherical core
particles with a drug (layering method) (refer to, for example, Patent Document
1), and the like are known.
[0004]
In the layering method, granules are produced by spraying a layering
liquid comprising a drug, a binder, and the like to spherical core particles to

coat them with a coating layer. Specific examples of it include a method of
simultaneously supplying drug powders and an aqueous solution of a binder
and coating spherical core particles with them; a method of supplying a
suspension of drug particles and coating the spherical core particles therewith;
and a method of supplying an aqueous solution of a drug and coating the
spherical core particles therewith.
[0005]
The layering method is suited as a method for producing spherical
base granules to be film-coated, because spherical base granules having a
high sphericity and a narrow particle size distribution can be obtained using
spherical core particles having a high sphericity and a narrow particle size
distribution.
[0006]
However, when a drug that is contained in the layering liquid has low
water solubility (hardly water-soluble drug), dispersion in an apparatus having
a high shear force is necessary to obtain a uniform suspension. Therefore,
when such a layering liquid is prepared, vigorous foaming occurs, and foam
breaking is sometimes necessary. In addition, in a layering liquid having a
practical drug concentration, the drug particles precipitate with the passage of
time. The layering liquid therefore must be stirred/mixed constantly to keep
the suspension uniform. Even if the layering liquid is stirred/mixed constantly,
there is a risk of a tube or spray nozzle being clogged with
precipitated/agglomerated particles during a transfer of the layering liquid from
a tank to the spray nozzle. When the drug has a large particle size, the above
risk increases further, which leads to deterioration in adhesion to spherical
core particles, a reduction in a recovery ratio, and an increase in
agglomeration ratio due to inhibition of smooth tumbling. A reduction in the

size of the drug particles improves suspension stability of the layering liquid
and a recovery ratio, but it need's an extra pulverization (or grinding) treatment
step of the drug particles.
[0007]
It is known to add various additives to the layering liquid for the
purpose of preventing detachment of the coated drug, controlling a dissolution
rate of the drug, or stabilizing the layering liquid (refer to, for example, Patent
Documents 2, 3, and 4). These prior arts however fail to improve the
suspensibility of a hardly water-soluble drug. Patent Documents 2 to 4
include no description on the use of both micronized microcrystalline cellulose
and an emulsifier in combination
Patent Document 5 discloses a technology of coating spherical core
particles with a hardly water-soluble drug, an emulsifier, and the like in
accordance with the layering method, but the technology specifically disclosed
herein is a layering method in which drug powders and an aqueous solution of
a binder are supplied simultaneously to coat therewith the particles. Patent
Document 5 includes no description on the improvement of suspensibility
during addition of a hardly water-soluble drug to a layering liquid.
[0008]
Patent Document 1: Japanese Patent Application Laid-Open No. 63-301816
Patent Document 2: Japanese Patent Application Laid-Open No. 9-165329
Patent Document 3: Japanese Patent Application Laid-Open No. 9-67247
Patent Document 4: Published Japanese translation of PCT international
publication No.2005-536527
Patent Document 5: International Publication No. 2005/044240
Disclosure of the Invention

Problems to be solved by the Invention
[0009]
An object of the present invention is to provide a method of producing,
with an improved production efficiency, spherical base granules comprising a
hardly water-soluble drug by using a layering liquid comprising the hardly
water-soluble drug, having good suspension stability, and controlled to
minimize foaming.
Means for Solving the Problem
[0010]
The present inventors have carried out an extensive investigation with
a view to overcoming the above-described problem. As a result, it has been
found that by adding micronized microcrystalline cellulose and an emulsifier in
a layering liquid, suspension stability of the layering liquid is improved and
foaming is suppressed without extra pulverization treatment of a drug, leading
to the completion of the present invention. The following is the details of the
present invention.
A production method of spherical base granules comprising a hardly
water-soluble drug, which comprises spraying a layering liquid to
pharmaceutically inert spherical core particles and coating the particles with a
drug-containing layer, wherein the layering liquid comprises:
(1) from 0.01 to 50 % by mass of hardly water-soluble drug particles
having a maximum long diameter and a maximum short diameter of not
greater than 30% and not greater than 12% of an average short diameter of
the spherical core particles, respectively;
(2) from 0.1 to 2 % by mass of micronized microcrystalline cellulose;
and

(3) from 0.01 to 1 % by mass of an emulsifier.
Advantage of the Invention
[0011]
The method according to the present invention enables stable
production of spherical base granules comprising a hardly water-soluble drug
with high productivity.
Best Mode for Carrying out the Invention
[0012]
The present invention will hereinafter be described specifically.
The spherical core particles to be used in the present invention are
pharmaceutically inert. This means that the core particles do not comprise a
drug.
The term "drug" as used herein means what is used for treatment,
prevention, or diagnosis of human or animal diseases but what is not an
instrument/machine.
[0013]
The spherical core particles may contain one or more pharmaceutical
additive. Examples of such a pharmaceutical additive include excipients such
as lactose, sucrose, D-mannitol, corn starch, powder cellulose, calcium
hydrogen phosphate, and calcium carbonate; disintegrants such as low-
substituted hydroxypropyl cellulose, carmellose calcium, pregelatinized starch ,
croscarmellose sodium, crospovidone, and carboxymethyl starch; binders such
as hydroxypropyl cellulose, povidone (polyvinylpyrrolidone), and xanthan gum;
coating agents such as hypromelose (hydroxypropylmethyl cellulose),
methacrylic acid copolymer LD, and ethylcellulose aqueous dispersion;

emulsifiers such as sucrose fatty acid ester, glycerin fatty acid ester, sodium
lauryl sulfate, and polysorbate 60; and other additives such as talc, magnesium
stearate, magnesium aluminometasilicate, titanium oxide, light silicic anhydride,
microcrystalline cellulose carmellose sodium.
[0014]
Preferred examples of a formulation include spherical core particles
composed only of sucrose, those composed of 70 % by mass of sucrose and
30 % by mass of corn starch, those composed of 30 % by mass or more of
microcrystalline cellulose and another pharmaceutical additive, those
composed only of microcrystalline cellulose, and those composed only of
mannitol. Spherical core particles comprising 30 % by mass or more of
microcrystalline cellulose are preferred because of having high strength and
high water absorption capacity. Those comprising 70 % by mass or more of
microcrystalline cellulose are more preferred, with spherical core particles
composed only of crystalline cellulose being still more preferred. Spherical
core particles composed only of microcrystalline cellulose are most preferred.
[0015]
The term "spherical" of spherical core particles means that the
particles have a sphericity (= short diameter/long diameter) of 0.7 or greater.
Particles which are not spherical are not preferred because they deteriorate
uniformity of film coating. The spherical core particles having a sphericity of
0.9 or greater are preferred.
As the spherical core particles, those having an average particle size
of from about 50 to 1000 µm can be used. The particle size distribution is
preferably sharp. The bulk density is preferably from about 0.5 to 2.0 g/cm3.
The spherical core particles composed only of microcrystalline cellulose have
generally a bulk density of from about 0.5 to 1.0 g/cm3. The mechanical

strength is preferably higher.
[0016]
The layering liquid to be used in the present invention will next be
described.
First, hardly water-soluble drug particles to be incorporated in the
layering liquid of the present invention will be described.
The term "hardly water-soluble" as used herein means that the
particles do not dissolve in water readily and they have solubility, in 1 cm3 of
water at 20°C, of 0.001 g or less.
Examples of the hardly water-soluble drug include amcinonide,
ibuprofen, indomethacin, ethenzamide, erythromycin, cefotiam hexetil
hydrochloride, nicardipine hydrochloride, omeprazole, prednisolone valerate
acetate, diflucortolone valerate, dexamethasone valerate, betamethasone
valerate, clarithromycin, griseofulvin, clonazepam, chloramphenicol, synthetic
peptide compounds, cortisone acetate, diflorasone diacetate, dexamethasone
acetate, triamcinolone acetate, paramethasone acetate, hydrocortisone
acetate, fludrocortisone acetate, methylprednisolone acetate, diazepam,
digitoxin, digoxin, difluprednate, beclometasone dipropionate, betamethasone
dipropionate, sulpiride, sulfathiazole, cefuroxime axetil, dexamethasone,
triamcinolone, triamcinolone acetonide, nicardipine, nifedipine, nilvadipine,
noscapine, halcinonide, hydrocortisone, flumetasone pivalate, phenacetin,
phenitoin, budesonide, prazepam, fluocinonide, fluocinolone acetonide,
fluorometholone, fludroxycortide, prednisolone, alclometasone dipropionate,
clobetasol propionate, dexamethasone propionate, deprodone propionate,
betamethasone, migrenin, methylprednisolone, ubidecarenone, clobetasone
butyrate, hydrocortisone butyrate, hydrocortisone butyrate propionate,
riboflavin butyrate, lansoprazole, and riboflavin.

[0017]
The hardly water-soluble drug particles are preferably smaller. The
maximum long diameter of them is 30% or less of the average short diameter
of the spherical core particles and the maximum short diameter is 12% or less
of the average short diameter of the spherical core particles. When each of
the diameters exceeds the specified values, respectively, the drug particles are
likely to detach from the spherical base granules, and the recovery ratio of the
spherical base granules will decrease. In addition, presence of the drug
particles detached from the granules inhibits tumbling of the spherical core
particles, resulting in an increase in agglomeration of the spherical base
granules.
The maximum long diameter of the drug particles is preferably not
greater than 20% of the average short diameter of the spherical core particles
and the minimum short diameter of the drug particles is preferably not greater
than 10%.
[0018]
The hardly water-soluble particles are added to the layering liquid in
an amount of from 0.01 to 50 % by mass. When the amount is less than
0.01 % by mass, layering need to be performed for long hours to coat the
spherical core particles with a necessary amount of the drug. When it
exceeds 50 % by mass, on the other hand, the viscosity of the layering liquid
becomes too high and prevents smooth spraying. It is preferably from 1 to
30 % by mass, more preferably from 5 to 20 % by mass.
[0019]
The micronized microcrystalline cellulose to be incorporated in the
layering liquid of the present invention will hereinafter be described.
The term " micronized microcrystalline cellulose" to be incorporated in

the layering liquid in the present invention means microcrystalfine cellulose
having an average particle size of 12 µm or less as measured in water. It is
more preferably 9 urn or less.
The term "microcrystalline cellulose" as used herein means that
conforms to any of the standards "Microcrystalline cellulose" specified in the
Japanese Pharmacopoeia, Fifteenth Edition, "Microcrystalline cellulose"
specified in Japanese Standards of Food Additives, Seventh Edition, and
"Microcrystalline cellulose-carmellose sodium" specified in Japanese
Pharmaceutical Excipients 2003.
[0020]
The micronized microcrystalline cellulose is, for example, that
obtained by dry or wet grinding of typical microcrystalline cellulose or that
obtained by dispersing microcrystalline cellulose-carmellose sodium in water.
Microcrystalline cellulose-carmellose sodium is preferred because a layering
liquid comprising it can be prepared easily and at the same time, has high
suspension stability, and spherical base granules available using it have high
strength.
[0021]
The micronized microcrystalline cellulose is added to the layering
liquid in an amount of from 0.1 to 2 % by mass. When the amount is less
than 0.1 % by mass, a sufficient suspension stabilizing effect is not obtained.
When it exceeds 2 % by mass, on the other hand, the layering liquid has a too
high viscosity and cannot be sprayed smoothly. It is preferably from 0.2 to
1 % by mass, more preferably from 0.3 to 0.8 % by mass.
[0022]
Addition of the micronized microcrystalline cellulose to the layering
liquid improves suspension stability of the hardly water-soluble drug particles in

the layering liquid and solves the problem of clogging a tube and also a spray
nozzle therewith. Moreover, it improves the adhesion of the hardly water-
soluble drug particles to the spherical core particles so that it is also effective
for raising a recovery ratio and reducing an agglomeration ratio.
[0023]
An emulsifier that can be comprised in the layering liquid of the
present invention will next be described.
in the present invention, the term "emulsifier" that may be comprised
in the layering liquid means a substance having an emulsifying function to be
used for the preparation of pharmaceutical formulations.
Examples of the emulsifier include sucrose fatty acid esters, glycerin
fatty acid esters, sodium lauryl sulfate, polysorbates, polyoxyethylene
hydrogenated castor oils, carmellose sodium, and xanthan gum. The
emulsifier is adequately selected, depending on the physical properties of the
drug particles. Of these, polyoxyethylene hydrogenated castor oils are
preferred from the viewpoint of their high foaming suppressing effect, with
polyoxyethylene hydrogenated castor oil 60 being more preferred. The
polyoxyethylene hydrogenated castor oil 60 is a nonionic surfactant obtained
by addition polymerization of a hydrogenated castor oil with ethylene oxides
and having an average molar number of added ethylene oxide of about 60. It
has a CAS No. of 61788-85-0. The average molar number of ethylene oxide
added to polyoxyethylene hydrogenated castor oil 60 is preferably from 52 to
68, more preferably from 55 to 65.
[0024]
The emulsifier is added to the layering liquid in an amount of from
0.01 to 1 % by mass. Amounts less than 0.01 % by mass do not sufficiently
improve the affinity of the drug particles with water. Although there is no

upper limit for the additive amount of emulsifier, the effect is not enhanced as
much as expected when the additive amount exceeds 1 % by mass or greater.
The amount is more preferably from 0.05 to 0.8 % by mass.
[0025]
Addition of the emulsifier to the layering liquid raises affinity of the
drug particles with water, thereby suppressing foaming. Due to a synergetic
effect of the emulsifier and micronized microcrystalline cellulose, the layering
liquid becomes a stable suspension. Only slight stirring or, in some cases, no
stirring is therefore necessary for maintaining the suspension state of the
layering liquid.
To a suspension such as a suspension syrup or dry syrup comprising
sucrose at a concentration of 20 % by mass or a concentration as high as
about 5 % by mass or greater, microcrystalline cellulose carmellose sodium
and an emulsifier such as polysorbate have been sometimes added in
combination in order to improve suspension stability. However, a problem of
foaming does not originally happen in such a suspension, as it contains
sucrose at a high concentration. Therefore, for those skilled in the art, it is
unexpected that combination use of an emulsifier and micronized
microcrystalline cellulose in the layering liquid that dose not comprise sucrose
at high concentration produces not only a suspension stabilization effect but
also an excellent foaming suppressing effect.
[0026]
Another pharmaceutical additive may be added to the layering liquid
as needed, in particular, addition of a binder is especially preferred because
it improves the strength of the drug-containing layer. Examples of the binder
include hydroxypropyl cellulose, povidone, and hypromelose
(hydroxypropylmethyl cellulose).

[0027]
A process of coating the spherical core particles with a layer
comprising the hardly water-soluble drug by layering will next be described.
Fluidized-bed coating apparatuses can be used for coating the
spherical core particles with the layer comprising a hardly water-soluble drug.
Examples of the fluidized-bed coating apparatus include, in addition to an
ordinary fluidized bed type, a spouted fluidized-bed type having, inside thereof,
a guide tube (Wurster column) and a tumbling fluidized-bed type equipped, on
the bottom thereof, a rotation mechanism.
Specific examples of such apparatuses include "Flow Coater" and
"Spiral Flow", products of Freund Corporation, "WST/WSG Series" and "GPCG
Series", products of Glatt GmbH, "New Marumerizer", product of Fuji Paudal
Co., Ltd., and "Multiplex", product of Powrex Corporation.
[0028]
The layering liquid can be supplied by a method suited for each of
apparatuses such as top spray, bottom spray, side spray, and tangential spray.
It may be sprayed to the spherical core particles continuously or intermittently.
After completion of spraying, the spherical base granules are dried. Drying of
the spherical base granules may be performed as are or after controlling an air
flow rate or temperature as needed, while not taking out the granules from the
apparatus.
[0029]
The coating amount of the drug-containing layer can be determined
based on the formulation design such as single dosage or size of the
preparation. For example, it is generally from about 0.5 to 200 % by mass
relative to the spherical core particles.
[0030]

Next, one example of a production method of the spherical base
granules will be described.
(a) Preparation of micronized microcrystalline cellulose: First,
microcrystalline cellulose is dispersed in water and the resulting aqueous
dispersion is micronized in a Manton-Gaulin Homogenizer. Micronization=
treatment is performed for necessary times at high pressure, for example, at
50 MPa and five passes. When micronized microcrystalline cellulose (for
example, "CEOLUS Cream" FP-03, product of Asahi Kasei Chemicals
Corporation, solid content: 10 % by mass, average particle size: about 4 µm)
or microcrystalline cellulose.carmellose sodium (for example, "CEOLUS" RC-
A591NF, product of Asahi Kasei Chemicals Corporation) is used, the
micronization step is not necessary.
(b) Preparation of layering liquid: A layering liquid is prepared by
adding a hardly water-soluble drug, the micronized microcrystalline cellulose,
an emulsifier, and necessary pharmaceutical additives to water and stirring the
mixture sufficiently until dissolved or suspended. During stirring, a rotary
disperser is preferably used to fully minimize the micronized microcrystalline
cellulose and mix it with the other components. Examples of the disperser
include "T.K. Homomixer", product of Tokushu Kika Kogyo Co., Ltd. and
"ULTRA TURRAX", product of IKA Company. A stirrer having a weak stirring
power such as propeller stirrer is not so preferred. In order to confirm
dissolution or dispersion, components may be dispersed sequentially.
(c) Heating of spherical core particles and fluidized-bed coating
apparatus: After spherical core particles are charged in a fluidized-bed coating
apparatus, the core particles are fluidized (when the fluidized-bed coating
apparatus is a tumbling fluidized-bed type is employed, the rotation portion of it
is turned simultaneously) by supplying hot air from the bottom portion of the

apparatus until an outlet-air temperature reaches a predetermined temperature.
(d) Coating with drug layer: The layering liquid is sprayed at a
predetermined spray rate continuously or intermittently or at a rate raised in a
stepwise fashion. The supply of the layering liquid is terminated when the
coating amount reaches a predetermined amount.
(e) Drying of spherical base granules: The spherical base granules
are dried while adjusting the amount of hot air and temperature (rotation speed
of the rotating portion when a tumbling fluidized-bed type is employed) if
necessary.
(f) Taking-out of spherical base granules: In the end, the resulting
spherical base granules are taken out from the apparatus.
[0031]
The spherical base granules obtained by the present invention can be
used as granules, capsules, tablets or the like after subjected to particle size
regulation and sustained release film coating, enteric film coating, or bitter-
taste masking film coating if necessary.
Example 1
[0032]
The present invention will next be described based on some
examples. First, measuring methods of physical properties are described
collectively.

The shape of a sample is photographed using a digital microscope
("VH-7000", product of KEYENCE CORPORATION) (with a 50x or 100x lens)
and a short diameter (D) and a long diameter (L) of 50 particles are measured
using an image analyzer ("Image Hyper", product of Inter Quest). The terms

"short diameter" and "long diameter" as used herein mean the length of a short
side and the length of a long side of the smallest (in area) rectangle that
circumscribes a boundary pixels of a particle, respectively. The sphericity is
an average of a short diameter/long diameter (D/L) ratio

The average short diameter is a value at which the cumulative
distribution of short diameter (D), which is determined in the same manner as
the measuring method of sphericity, reaches 50%.

A 100-cm3 graduated cylinder is filled with 30 g of a sample and a
tapped volume [cm3] after tapping about 30 times is measured. The bulk
density is calculated in accordance with the following equation. This
operation is performed three times and an average is adopted as a tapped bulk
density.
Apparent tapped density [g/cm3] = 30 [g]/tapped volume [cm3].

The layering liquid (30 cm3) is charged in a sample bottle having a
diameter of 40 mm and a height of 50 mm and the state after five minutes is
observed.

A sample is prepared by dropping the layering liquid onto a slide
glass and then, placing a cover glass thereon. The sample is photographed
using an optical microscope (use of a 40 × lens). Long diameter and short
diameter of each of 50 drug particles on the photograph are measured and the
maximum long diameter [µm] and maximum short diameter [urn] are
determined.

In the same manner as that employed for the preparation of the
layering liquid, micronized microcrystalline cellulose is dispersed in purified
water and a median diameter [urn] of the resulting dispersion is determined
using a laser diffraction/scattering particle-size distribution analyzer ("LA-910",
product of Horiba, Ltd.) while setting a specific refractive index at 1.20. The
above operation is performed twice and an average is used.

The recovery ratio is determined in accordance with the following
equation based on the recovery amount [g] of spherical base granules after
layering and the total amount [g] of raw materials employed.
Recovery ratio [% by mass] = {recovery amount [g]/total amount [g] of raw
materials} x 100

After dispersion of spherical base granules on paper, the number [a]
of particles constituting agglomerated granules and the number [b] of single
isolated particles are counted visually. The agglomeration ratio is calculated
in accordance with the following equation. The number of particles observed
is 1000 (=a+b).
Agglomeration ratio [%] = {a/(a+b)}x100
[0033] [Example 1]
(Preparation of layering liquid)
While stirring 74.4 g of water in a rotary disperser ("T. K. Homomixer
Mark II f model", product of Tokushu Kika Kogyo Co., Ltd.) at 5000 rpm, 15 g
of povidone ("K-30", product of ISP Tec. Inc.) was added. The resulting
mixture was stirred further until completely dissolved. Then, 0.1 g of a
polyoxyethylene hydrogenated castor oil ("HCO-60", product of Nikko
Chemicals Co., Ltd.) as an emulsifier was dispersed in the resulting solution

until dissolved. 10 g of Ethenzamide ("Type A", product of API Corporation)
was added in the resulting solution as a hardly water-soluble drug and then,
0.5 g of microcrystalline cellulose-carmellose sodium ("CEOLUS" RC-A591NF,
product of Asahi Kasei Chemicals Corporation) was added as a micronized
microcrystalline cellulose, followed by dispersion for 30 minutes to prepare a
layering liquid.
The resulting layering liquid was free from separation of the drug and
foaming after completion of the dispersion and had considerably high
suspension stability compared with that obtained in Comparative Example 1,
which will be described later.
(Layering)
In a Wurster coating apparatus ("Multiplex" MP-01, equipped with a
Wurster column, product of Powrex Corporation) was charged 0.3 kg of
spherical core particles composed of 100% of microcrystalline cellulose
("Celphere" CP-203, product of Asahi Kasei Chemicals Corporation, sphericity:
0.9, tapped bulk density: 0.98 g/cm3, average short diameter: 165 µm) and the
spherical core particles were layered until the layering amount reached 12.8 %
by mass (5.0 % by mass in terms of the drug) under the conditions of a spray
air pressure of 0.16 MPa, a spray air flow rate of 40 L/min, an inlet-air
temperature of from 65 to 70°C, an outlet-air temperature of 40°C, an air flow
rate of 40 m3/h, and a layering liquid spray rate of 3 g/min. The layering liquid
was stirred with propeller constantly at 150 rpm. After the spraying of the
layering liquid was terminated, drying was performed without changing the
conditions until the outlet-air temperature increased to 42°C. A heater for
inlet-air was then turned off and cooling was performed until the inlet-air
temperature became 40°C.
Few powdered drug that did not attach to the spherical core particles

were observed and almost all the amount of the granules was recovered . In
addition, the granules thus obtained were almost free from agglomeration.
The results are shown in Table 1.
[0034] [Example 2]
(Layering)
In a tumbling fluidized-bed coating apparatus ("Multiplex MP-01",
product of Powrex Corporation) was charged 0.6 kg of spherical core particles
which was the same as that used in Example 1 and they were layered with the
layering liquid prepared in Example 1 until the layering amount became 12.8 %
by mass (5.0 % by mass in terms of the drug) of the spherical core particles by
using a tangential bottom spray under the conditions of a spray air pressure of
0.16 MPa, a spray air flow rate of 40 L/min, an inlet-air temperature of from
75°C, an outlet-air temperature of 41 °C, an air flow rate of 35 m3/h, a rotation
speed of a rotor of 400 rpm, and a layering liquid spray rate of 5.0 g/min. The
iayering liquid was stirred with propeller constantly at 150 rpm. After spraying
of the layering liquid was terminated, the rotation speed of a rotor was
decreased to 200 rpm and drying was performed until the outlet-air
temperature reached 42°C. A heater for inlet-air was then turned off and
cooling was performed until the inlet-air temperature became 40°C.
Few powdered drug that did not attached to the spherical core
particles were observed. The resulting spherical base granules showed good
results with a recovery ratio of 94.6% and an agglomeration ratio of 1.2%.
The results are shown in Table 1.
[0035] [Comparative Example 1]
(Preparation of layering liquid)
While stirring 75.0 g of water in a rotary disperser ("T. K. Homomixer
Mark II f model", product of Tokushu Kika Kogyo Co., Ltd.) at 5000 rpm, 15 g

of povidone was added. The resulting mixture was stirred further until
completely dissolved. Then, 10 g of ethenzamide was added and the
resulting mixture was dispersed for 30 minutes to prepare a layering liquid.
The resulting layering liquid foamed severely and foams did not
disappear even after the passage of time. Five minutes after completion of
the preparation, precipitation of the drug occurred and the layering liquid had
only poor suspension stability.
(Layering)
In the same manner as Example 1 except that the inlet-air
temperature was raised to from 70 to 78°C and layering liquid was stirred with
propeller at 300 rpm, layering was performed.
A recovery ratio of the spherical base granules decreased because
the drug did not attach to the spherical core particles and the powdered drug
attached to a bug filter at the upper portion of the apparatus. Moreover, the
spherical base granules thus obtained contained many agglomerated particles.
The results are shown in Table 1.

[0037]
The spherical base granules obtained in Examples 1 and 2 by using
the layering liquid comprising both a micronized microcrystalline cellulose and
an emulsifier did not contain many agglomerated granules and showed a high
recovery ratio.
In contrast, the spherical base granules obtained in Comparative
Example 1 by using the layering liquid comprising neither a micronized
microcrystalline cellulose nor an emulsifier, agglomerated due to foaming of
the layering liquid and showed a low recovery ratio.
[0038] [Referential Example]
While stirring 89.4 g of water in a rotary disperser at 5000 rpm, 0.1 g
of polyoxyethylene hydrogenated castor oil was added. The resulting mixture
was stirred until completely dissolved. To the resulting solution were added
successively 10 g of ethenzamide and 0.5 g of microcrystalline cellulose-
carmellose sodium which is the same as that employed in Example 1. The
resulting mixture was dispersed for 30 minutes to prepare a layering liquid.
The layering liquid thus obtained was a uniform and highly clouded
suspension free from foaming and precipitation of drug particles. The
appearance of it is shown in-JFIG. 1. The observation results of the
appearance are shown in Table 2.
[0039] [Referential Comparative Example 1]
While stirring 88.0 g of water in a rotary disperser at 5000 rpm, 2 g of
povidone was added. The resulting mixture was stirred further until
completely dissolved. In the resulting solution was added 10 g of
ethenzamide, followed by dispersing for 30 minutes to prepare a layering liquid.
The resulting layering liquid showed an uneven state with a foamy drug
separated in the upper 53% portion of the liquid.

The appearance of the layering liquid is shown in FIG. 2. The
observation results of the appearance are shown in Table 2.
[0040] [Referential Comparative Example 2]
In the same manner as Referential Comparative Example 1 except
that the amount of povidone was 15 g, a layering liquid was prepared. The
separation state of the liquid was observed. Although the drug amount
present in the lower layer increased compared with that in Referential
Comparative Example 1, the foamy drug layer in the upper portion was still
present without decreasing.
The appearance of the layering liquid is shown in FIG. 3. The
observation results of the appearance are shown in Table 2.
[0041] [Referential Comparative Example 3]
While stirring 89.5 g of water in a rotary disperser at 5000 rpm, 0.1 g
of polyoxyethylene hydrogenated castor oil was added. The resulting mixture
was stirred further until completely dissolved. In the resulting solution was
added 10 g of ethenzamide, followed by dispersion for 30 minutes to obtain a
layering liquid.
The resulting layering liquid was separated into three layers. The
upper 23% layer contained foams, while the lower 23% layer contained a drug
precipitation layer. The appearance of the liquid is shown in FIG. 4. The
observation results of the appearance are shown in Table 2.
[0042] [Referential Comparative Example 4]
In the same manner as Referential Comparative Example 3 except
that 0.3 g of polyoxyethylene hydrogenated castor oil was added to 89.7 g of
water, a layering liquid was prepared.
The lower 11 % layer was a drug precipitation layer, showing a little
improvement compared with Referential Comparative Example 3 but a

problem of three-layer separation does not resolved. The observation results
of the appearance are shown in Table 2.
[0043] [Referential Comparative Example 5]
While stirring 89.4 g of water in a rotary disperser at 5000 rpm, 0.5 g
of microcrystalline cellulose-carmellose sodium was added. The resulting
mixture was dispersed for 30 minutes. In the resulting dispersion was added
10 g of ethenzamide, followed by dispersion for 30 minutes to prepare a
layering liquid.
The layering liquid thus obtained showed an uneven state with a
foamy drug layer in the upper 52% portion of the liquid as in Referential
Comparative Example 1. The observation results of the appearance are
shown in Table 2.
[0044] [Referential Comparative Example 6]
In the same manner as Referential Comparative Example 5 except
that 2.2 g of microcrystalline cellulose-carmellose sodium which is the same as
that used in Example 1 was added to 87.8 g of water, a layering liquid was
prepared.
The layering liquid thus obtained showed a uniform state without
separation, but it became a gel due to the addition of a large amount of
microcrystalline cellulose-carmellose sodium. The resulting gel was so tacky
and it was difficult to transfer the layering liquid via a tube pump. The
appearance is shown in FIG. 5. The observation results of the appearance
are shown in Table 2.

[0046]
The layering liquid obtained in Referential Example by using
micronized microcrystalline cellulose and an emulsifier in combination was a
uniform suspension.
In contrast, the layering liquids comprising neither micronized
microcrystalline cellulose nor emulsifier separated into two layers (Referential
Comparative Examples 1 and 2). The layering liquids comprising the
emulsifier but not comprising the micronized microcrystalline cellulose foamed
severely and separated into three layers (Referential Comparative Examples 3
and 4). The layering liquid comprising the micronized microcrystalline
cellulose but not comprising the emulsifier did not foam and the layer
separation was partially resolved (Referential Comparative Example 5). In
order to completely resolve the problem of separation, however, it was
necessary to increase the amount of micronized microcrystalline cellulose to
the extent that it made the layering liquid into gel and thus made it
unsatisfactory as a layering liquid (Referential Comparative Example 6).
From the above results, it has been confirmed that the layering liquid
comprising a hardly water-soluble drug has improved suspension stability
when both micronized microcrystalline cellulose and an emulsifier are added in
combination to the liquid.
Industrial Applicability
[0047]
The production method of the present invention is suited in the field of
the production of film-coated pharmaceutical granules.

Brief Description of the Accompanying Drawings
[0048]
[FIG. 1] The appearance of the layering liquid prepared in Referential
Example.
[FIG. 2] The appearance of the layering liquid prepared in Referential
Comparative Example 1.
[FIG. 3] The appearance of the layering liquid prepared in Referential
Comparative Example 2.
[FIG. 4] The appearance of the layering liquid prepared in Referential
Comparative Example 3.
[FIG. 5] The appearance of the layering liquid prepared in Referential
Comparative Example 6.

WE CLAIM:
1. A production method of spherical base granules comprising a hardly water-soluble
drug, comprising spraying a layering liquid to pharmaceutically inert spherical core
particles and coating the particles with a drug-containing layer, wherein:
the layering liquid comprises:
(1) from 0.01 to 50 mass% of hardly water-soluble drug particles having a
maximum long diameter and a maximum short diameter of from 17% to 30% and
of from 3% to 12%, respectively, of an average short diameter of the spherical core
particles;
(2) from 0.1 to 2 mass% of a micronized microcrystalline cellulose; and
(3) from 0.01 to 1 mass% of an emulsifier.
2. The production method of spherical base granules comprising a hardly water-soluble
drug as claimed in claim 1, wherein the maximum long diameter and the maximum short
diameter of the hardly water-soluble drug particles are not greater than 20% and not
greater than 10% of the average short diameter of the spherical core particles,
respectively.

3. The production method of spherical base granules comprising a hardly water-soluble
drug as claimed in claim 1 or 2, wherein the layering liquid comprises from 1 to 30
mass% of the hardly water-soluble drug particles.
4. The production method of spherical base granules comprising a hardly water-soluble
drug as claimed in claim 1 or 2, wherein the layering liquid comprised from 5 to 20
mass% of the hardly water-soluble drug particles.
5. The production method of spherical base granules comprising a hardly water-soluble
drug as claimed in any one of claims 1 to 4, wherein the layering liquid comprises from
0.2 to 1 mass% of the micronized macrocrystalline cellulose.
6. The production method of spherical base granules comprising a hardly water-soluble
drug as claimed in any one of claims 1 to 5, wherein the layering liquid comprises from
0.3 to 0.8 mass% of the micronized microcrystalline cellulose.
7. The production method of spherical base granules comprising a hardly water-soluble
drug as claimed in any one of claims 1 to 6, wherein the layering liquid comprises from
0.05 to 0.8 mass% of the emulsifier.
8. The production method of spherical base granules comprising a hardly water-soluble
drug as claimed in any one of claims 1 to 7, wherein the emulsifier is polyoxyethylene
hydrogenated castor oil 60.

9. The production method of spherical base granules comprising a hardly water-soluble
drug as claimed in any one of claims 1 to 8, wherein the micronized microcrystalline
cellulose has an average particle size of 9 |Jm or less.
10. The production method of spherical base granules comprising a hardly water-soluble
drug as claimed in any one of claims 1 to 9, wherein the spherical core particles have a
microcrystalline cellulose content of 70 mass% or greater.
11. The production method of spherical base granules comprising a hardly water-soluble
drug as claimed in any one of claims 1 to 10, wherein the spherical core particles have a
bulk density of from 0.5 to 1.0 g/cm3 .

ABSTRACT

Title: A production method of spherical base granules
A production method of spherical base granules comprising a hardly water-soluble drug,
comprising spraying a layering liquid to pharmaceutically inert spherical core particles
and coating the particles with a drug-containing layer, wherein:
the layering liquid comprises: from 0.01 to 50 mass% of hardly water-soluble drug
particles having a maximum long diameter and a maximum short diameter of from 17% to
30% and of from 3% to 12%, respectively, of an average short diameter of the spherical
core particles; from 0.1 to 2 mass% of a micronized microcrystalline cellulose; and from
0.01 to 1 mass% of an emulsifier.

A PRODUCTION METHOD OF SPHERICAL BASE GRANULES

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