JP2009120476A - Spherical particle comprising calcium hydrogen phosphate - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To satisfy a need for spherical particles used as nucleator in the production of granules such as pharmaceuticals, cosmetics, and foods, being hardly solvent-soluble, nonhygroscopic, and very lowly reactive, and having a particle diameter of 50-300 μm and high particle strength and high sphericity. <P>SOLUTION: The spherical particles is provided which have a higher particle strength, a lower surface irregularity, and a higher sphericity than conventional spherical calcium hydrogen phosphate of an average particle diameter of about 100 μm by grinding and disintegrating agglomerates of scale-like primary particles of calcium hydrogen phosphate into fine primary particles and spraying the resultant primary particles. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to spherical particles made of calcium hydrogen phosphate having high sphericity and particle strength, a method for producing the same, and pharmaceuticals, cosmetics, foods and the like using the spherical particles.

  As a means for controlling the release of sustained-release pharmaceuticals, enteric dissolution, improving the stability of medicinal ingredients or masking tastes, pharmaceuticals use granules having a multi-layered structure centering on nucleating agents. When producing granules having a multilayer structure, it is preferable to use spherical particles having a uniform particle diameter and high sphericity as a nucleating agent in order to increase the lamination rate and to uniformly laminate the thickness of each layer. Furthermore, the properties required of the nucleating agent are required to be strength that does not break from the load applied during granulation, absorbability to absorb the spray solution, and stability that does not react with the drug.

  So far, spherical particles used as a nucleating agent are known as spherical particles of crystalline cellulose (Patent Document 1), and purified sucrose spheres used as core particles in the production of granulated particles comprising an active ingredient and its coating layer. (Patent Document 2). These particles have a low sphericity of the particle shape, and the smaller the particle size, the lower the sphericity and the distorted shape. When producing small granules, a uniform drug layer or coating layer is formed on the surface of the nucleating agent. It was unsuitable for formation.

Calcium hydrogen phosphate is used in pharmaceuticals, foods, cosmetics, and the like as a calcium component, a source of reinforcing phosphoric acid components, an anti-caking agent, an abrasive for toothpaste, and an excipient. In particular, it is hardly soluble in water, is non-hygroscopic and has little reaction with the active ingredient, so it is used as a pharmaceutical excipient. However, calcium hydrogen phosphate has good properties as an excipient that it is not hygroscopic, inactive, does not react with drugs, and does not color the dosage form. There was a fault that it was in the form of the above crystal particles and was inferior in bondability. In order to improve this, the applicant has a specific surface area of 20 to 60 m ² / g, a static bulk specific volume of 5 ml / g or more, an oil absorption of 1.0 ml / g or more, and primary particles measured with an electron microscope. Was proposed by spray-drying and granulating scaly calcium hydrogen phosphate having an average particle diameter of 0.1 to 5 μm and an aggregated secondary particle diameter of 2 to 10 μm (patent) Reference 3). This is marketed as Fujicalin SG [product name, manufactured by Fuji Chemical Industry Co., Ltd.].

  Spherical calcium hydrogen phosphate, which is spherical to some extent, contains spherical dibasic calcium phosphate obtained by reacting a calcium compound with a phosphate compound in the presence of a phosphate condensate, abrasive, fluorescent agent carrier, excipient, fluid It is known to be used as a property improving agent (Patent Document 4). Further, agglomerated spherical calcium hydrogen phosphate obtained by reacting slaked lime having a particle diameter of 0.5 to 5 mm with phosphoric acid at 50 ° C. or higher and stirring for 8 hours or longer is known (Patent Document 5).

The calcium hydrogen phosphate, which is said to be spherical, has a low sphericity and is not a beautiful spherical shape. The surface is uneven and smooth, and the strength is not sufficiently high. Spherical calcium hydrogen phosphate with extremely high sphericity, smooth surface, sufficient strength for production, and moderate water absorption capacity is not known, and is used for pharmaceuticals, cosmetics, foods, etc. It is not known to be useful as a nucleating agent in the production of granules.
JP-A-7-173050 Japanese Patent Laid-Open No. 2003-104882 JP 7-118055 A JP 59-223204 A JP 2005-289663 A

  Slightly soluble in water, non-hygroscopic, has little reaction with the active ingredient, has moderate water absorption capacity and sufficient strength for granule production, used as a nucleating agent for granule production of pharmaceuticals, cosmetics, foods, etc. However, there is a demand for spherical particles with few irregularities and extremely high sphericity.

  The present inventors found that spherical calcium hydrogen phosphate obtained by finely pulverizing calcium hydrogen phosphate and then performing wet granulation has surface irregularities despite having a smaller average particle size than conventional nucleating agents. We found that the sphericity is very low.

  The spherical calcium hydrogen phosphate of the present invention is insoluble in water, and has an extremely good sphericity and smooth surface even with an average particle size smaller than that of a conventional nucleating agent. The granular composition used and granulated can have good lamination properties. In addition, the granulated composition obtained by laminating using this spherical calcium hydrogen phosphate and granulating such as coating has a uniform layered structure, and thus has good sustained release properties and bitterness masking properties of drugs. .

The spherical calcium hydrogen phosphate of the present invention has an average particle diameter of primary particles of 0.01 to 5 μm, and the following formula (I)
CaHPO ₄ · mH ₂ O (I)
(In the formula, m represents a number in the range of 0 ≦ m ≦ 0.5)
It is calcium hydrogenphosphate shown by.

  The primary particles of calcium hydrogen phosphate used for the spherical calcium hydrogen phosphate of the present invention can be obtained by adjusting the particle size by grinding the calcium hydrogen phosphate during the synthesis of the primary particles of calcium hydrogen phosphate. . In view of the ease of controlling the particle diameter and sphericity of the spherical calcium hydrogen phosphate of the present invention, the primary particle of calcium hydrogen phosphate is better as the average particle diameter is smaller, and the SEM of the primary particle of calcium hydrogen phosphate is better. The average particle diameter observed in the photograph is 0.01 to 5 μm, preferably 0.01 to 3 μm, and more preferably 0.01 to 1 μm. Moreover, as the shape of the primary particles of calcium hydrogen phosphate, any shape such as a scale shape, a flake shape, a columnar shape, or a plate shape can be used. Scale-like or flaky calcium hydrogen phosphate is preferred.

The scaly calcium hydrogen phosphate of the primary particles used here may be any of dry powder, spray-dried spherical particles, and wet powder. Since the scale-like calcium hydrogen phosphate used in the present invention is pulverized in the production of the spherical calcium hydrogen phosphate of the present invention to adjust the average particle diameter, it is disclosed in JP-A-7-118055 and JP-A-10-120408. Physical property values (specific surface area of 20 to 60 m ² / g, static bulk specific volume of 5 ml / g or more, water absorption of 1.0 ml / g or more, and primary particles measured by an electron microscope are 0.1 ˜5 μm, the average particle diameter of the aggregated secondary particles need not satisfy 2-10 μm).

  The spherical calcium hydrogen phosphate of the present invention has an average particle size of 10 to 500 μm, preferably 20 to 300 μm, more preferably 30 to 200 μm. If the average particle size is less than 10 μm, it is not preferable because it is difficult to laminate the drugs and the particles tend to aggregate. In addition, when the average particle size exceeds 500 μm, the particle size of the laminated granule becomes large. Therefore, when applied to orally disintegrating tablets, it is easy to feel roughness, the dosing properties deteriorate, and it is applied to granule-containing tablets. This is not preferable because it leads to variation in the content of.

Spherical particles of the present invention is particle strength is 60 g / mm ² or more, preferably 60~300g / mm ^2, more preferably 100 to 200 g / mm ^2. When the particle hardness is lower than 60 g / mm ² , cracks and chipping occur during the production of granules described later, which is inappropriate. For example, powdering and chipping do not occur under the conditions of the Japanese Pharmacopoeia friability test.

  The spherical calcium hydrogen phosphate of the present invention has a sphericity of 0.85 to 1, preferably 0.90 to 1, and most preferably 0.95 to 1. When the sphericity is less than 0.85, the thickness of each layer is non-uniform during the production of the drug layer or the coating layer, the release property is non-uniform, and the coating is difficult to be performed completely, which is not preferable for the formation of granules. Here, the sphericity is a value obtained by dividing the minor axis of the sphere by the major axis. Another feature is that there are few irregularities on the surface.

The BET specific surface area of the spherical calcium hydrogen phosphate of the present invention should be large to some extent from the adsorption capacity on the particle surface, and the BET specific surface area is ² to 100 m ² / g, preferably 5 to 60 m ² / g, more preferably 5 ˜40 m ² / g. When the specific surface area exceeds 100 m ² / g, the particles are likely to be worn away, which leads to agglomeration of the particles and the particle size distribution of the granules becomes wide and non-uniform. Further, if the specific surface area is less than 2 m ² / g, the adhesion force of the solid or liquid to the surface is weakened, which is not preferable.

  The static bulk specific volume of the spherical calcium hydrogen phosphate of the present invention is 1 to 5 ml / g, preferably 1 to 3 ml / g, more preferably 1 to 2 ml / g. When it is less than 1 ml / g, it is heavy, so mixing with the fine powder laminated on the spherical particles hardly occurs, and when it exceeds 5 ml / g, it is light and fluidized bed granulation or rolling layer granulation itself. It is difficult to carry out the granulation process. Further, the greater the degree of pulverization, that is, the smaller the particle size of the primary particles, the smaller the static bulk specific volume. However, when the spherical calcium hydrogen phosphate is granulated by a method in which the contact time with the solvent component is relatively long, for example, kneading granulation such as a biaxial extruder, the static bulk specific volume should be slightly higher. -4 ml / g, preferably 2-3 ml / g.

  The water absorption of the spherical calcium hydrogen phosphate of the present invention requires an appropriate amount of solvent or fine powder to adhere to the surface, so the water absorption is 0.3-2.0 ml / g, preferably 0.4-1. 5 ml / g. Here, the amount of water absorption is a value indicating absorption of liquids such as organic solvents and oils and fats in addition to water, and there is a possibility that these liquid absorption amounts may deviate from the water absorption amount. Such errors are also within the scope of the present invention.

  The strength of the spherical calcium hydrogen phosphate of the present invention is sufficient if it has sufficient strength for the production of granules such as pharmaceuticals and foods. The spherical calcium hydrogen phosphate of the present invention is also characterized by low friability because the primary particles are densely aggregated. Specifically, the chip friability test method listed in the 14th revised Japanese Pharmacopoeia does not cause chipping or weathering.

  The angle of repose of the spherical calcium hydrogen phosphate of the present invention is 20 to 45 °, preferably 20 to 35 °. By having such an angle of repose, excellent fluidity can be exhibited, and excellent granulation properties can be exhibited in the granule production process. The angle of repose can be measured according to a normal method using a powder tester (manufactured by Hosokawa Micron).

The method for producing the spherical calcium hydrogen phosphate of the present invention will be described below.
A calcium hydrogen phosphate hydrate is suspended in water, a polyvalent organic acid is added, and hydrothermal treatment is performed at 60 ° C. or higher to form scale-like calcium hydrogen phosphate. The spherical calcium hydrogen phosphate of the present invention can be obtained by pulverizing and spray-drying the scaly calcium hydrogen phosphate.
Here, the calcium hydrogen phosphate used for pulverization is not limited to a scaly shape, and any shape such as a flake shape, a columnar shape, or a plate shape can be used, and the average particle diameter of primary particles of calcium hydrogen phosphate is The smaller the density, the higher the cohesiveness, and 0.01 to 20 μm, preferably 0.05 to 10 μm.

  The method for producing the scale-like calcium hydrogen phosphate can be produced by the methods described in JP-A-7-118055 and JP-A-10-120408. The scaly calcium hydrogen phosphate may be hydrothermally treated or may be spray-dried spherical particles.

The following method is mentioned as another manufacturing method of the spherical calcium hydrogen phosphate of this invention.
(1) Phosphoric acid and lime are reacted in water in the presence of an organic acid to form columnar calcium hydrogen phosphate, pulverized, hydrothermally treated at 60 ° C. or higher, and spray-dried.
(2) After suspending calcium hydrogen phosphate hydrate in water, hydrothermal treatment is performed at 60 ° C. or higher to form scaly calcium hydrogen phosphate, which is pulverized and spray-dried.
(3) Phosphoric acid and lime are reacted in water to form plate-like calcium hydrogen phosphate, and then citric acid is added and hydrothermally treated at 60 ° C. or higher, followed by spray drying.
(4) After pulverizing calcium hydrogen phosphate hydrate and suspending in water, an organic acid is added and hydrothermal treatment is performed at 60 ° C. or higher to form scaly calcium hydrogen phosphate, which is spray-dried.
(5) Calcium hydrogen phosphate hydrate is pulverized, suspended in water, hydrothermally treated at 60 ° C. or higher, and spray-dried.
(6) The calcium hydrogen phosphate is pulverized, suspended in water, and spray-dried.

  The step of pulverizing can be performed either before or after the hydrothermal treatment, or both, but is preferably performed after the hydrothermal treatment and before spray drying. As the pulverization method, either wet pulverization or dry pulverization may be used. As the wet pulverization, Nanomizer (product name, manufactured by SGS Engineering Co., Ltd.), Starburst (product name, manufactured by Sugino Machine Co., Ltd.), Ultimateizer (product) Name, high-pressure homogenizers such as Sugino Machine Co., Ltd., Kawasawa Fine Co., Ltd.), microfluidizer (product name, manufactured by Mizuho Industry Co., Ltd.), bead mill, disk mill, homomixer, etc. A high-pressure homogenizer, a bead mill, a cutter mill, and a hammer mill, and a high-pressure homogenizer is most preferable because of easy handling of the slurry.

  By this pulverization, the calcium hydrogen phosphate forming the aggregated particles is pulverized to primary particles, and those having large primary particles are adjusted to a desired average particle size. The average particle size in the pulverization is 0.01 to 5 μm, preferably 0.01 to 3 μm, more preferably 0.01 to 1 μm. By setting this average particle size, the aggregated particles are crushed to primary particles, and the primary particles are reduced and dispersed, improving the agglomeration property during drying, and spherical hydrogen phosphate with high sphericity. Can be calcium.

  The ground calcium hydrogen phosphate is suspended in water and spray-dried. The concentration of the suspension may be in a range that can be spray-dried, that is, the solid content is 1 to 40% by weight, preferably 5 to 30% by weight. When components other than calcium hydrogen phosphate such as drugs are added, they are blended at the time of preparing the suspension and simultaneously spray-dried.

  The conditions for spray drying are not particularly limited, but it is preferable to use a disk-type or nozzle-type spray dryer as the spray dryer. And as temperature in the case of spray-drying, inlet temperature is about 120-400 degreeC, and outlet temperature is about 80-300 degreeC.

  The spherical calcium hydrogen phosphate of the present invention has a higher sphericity and lower static bulk density than the scale-like calcium hydrogen phosphate spray-dried without performing the grinding step. Aggregated particles are crushed into primary particles, dispersed into primary particles, and re-aggregated by spray drying, so that the interparticle voids between the primary particles become denser during reaggregation, and the intermolecular force is strong. To work. For this reason, it has higher strength than the conventional spherical spherical calcium hydrogen phosphate.

A granular composition using the spherical calcium hydrogen phosphate of the present invention and a method for producing the granular composition will be described.
The granular composition of the present invention comprises an active ingredient layer centered on spherical calcium hydrogen phosphate. If necessary, a coating layer can be formed outside the active ingredient layer. The granular composition consists of 0.01 to 500 parts by weight, preferably 0.1 to 200 parts by weight of the active ingredient with respect to 100 parts by weight of spherical calcium hydrogen phosphate. In addition to the active ingredient, a binder, an excipient, a surfactant, a coating agent, and the like can be blended in the active ingredient layer. The active ingredient may be supported on an excipient and granulated with a binder. The amount of the coating component is 0.01 to 100 parts by weight with respect to 100 parts by weight of the spherical calcium hydrogen phosphate.

  The active ingredient is not particularly limited, and drugs for central nerves such as agents for peripheral nerves, antipyretic analgesic / anti-inflammatory agents, hypnotic sedatives, and agents for peripheral nerves; drugs for peripheral nerves such as skeletal muscle relaxants and autonomic nerve agents; Cardiovascular agents such as cardiotonic agents, arrhythmic agents, diuretics, vasodilators; respiratory organ agents such as bronchodilators and antitussives; gastrointestinal agents such as digestives, intestines, antacids; hormones, antihistamines, vitamins Metabolic drugs such as drugs; anti-ulcer agents; antibiotics; chemotherapeutic agents; herbal extracts;

  The active ingredient for cold medicine, the active ingredient for rhinitis, etc. can be mentioned. Examples of the active ingredient for cold medicine include antipyretic analgesic / anti-inflammatory agents, bronchodilators, antihistamines, antitussives, antiseptics, antiseptic antiseptics, vitamins, and herbal medicine extracts. Examples of the active ingredient for rhinitis include sympathomimetic agents, parasympathetic nerve blockers, antiallergic agents and antiinflammatory agents, and the like. Antipyretic analgesic and anti-inflammatory agents include, for example, pranlukast hydrate, acetaminophen, phenacetin, refractamine hydrochloride and other aniline derivatives, etenzamide, sazapyrine, methyl salicylate, phenyl salicylate, sodium salicylate, choline salicylate, aspirin, aspirin aluminum, etc. Salicylic acid derivatives, etc., pyrazolo derivatives such as isopropylantipyrine, sulpyrine, phenylbutazone, ketophenylbutazone, antipyrine, aminopyridine, propionic acid derivatives such as ibuprofen, ketoprofen, oxacyprozin, naproxen, fenoprofen calcium, thiaprofenic acid, etc. , Phenbufen, diclofenac sodium, amphenac sodium and other phenylacetic acid derivatives, indomethacin, indomethacin Insole acetic acid derivatives such as Nesyl, Progouritacin maleate, Tolmethine sodium, Anthranilacetic acid derivatives such as Mefenamic acid, Flufenamic acid, Tolfenamic acid, Oxicic derivatives such as Piroxicam, Ampiroxicam, Tenoxicam, Benzydamine hydrochloride, Epirizole (Mepyrizole), Examples thereof include tinolidine hydrochloride, tiaramid hydrochloride, anti-inflammatory enzyme agents, serrapeptidase (trade name), lysozyme chloride and the like. These antipyretic analgesic / anti-inflammatory agents can be used alone or in combination of two or more.

  Examples of bronchodilators include ephedrine hydrochloride, dl-methylephedrine hydrochloride, dl-methylephedrine saccharinate hydrochloride, isoprenaline hydrochloride, isoproterenol sulfate, methoxyphenamine hydrochloride, orciprenaline sulfate, chlorprenalin hydrochloride, trimethoxy hydrochloride. Ol, salbutamol sulfate, terbutaline sulfate, hexoprenaline sulfate, formoterol fumarate, fenoterol hydrobromide, procaterol hydrochloride, pluterol hydrochloride, clenpterol hydrochloride, mabuterol hydrochloride, aminophylline, theophylline, dibrophyrin, proxyphylline, xanthine derivatives, odor And anticholinergic agents such as flutropium iodide and oxitropium bromide. Antihistamines include, for example, ethanolamine antihistamines such as diphenhydramine, propylamine antihistamines such as dl-chlorpheniramine maleate and chlorpheniramine maleate, alimemazine tartrate, isothipentyl hydrochloride, promethazine hydrochloride, and phenothiazine hydrochloride. Examples include antihistamines, diphenylpyralin, carbinoxamine maleate, clemastine fumarate, iproheptin hydrochloride, homochlorcyclidine hydrochloride, cyproheptadine hydrochloride, dimethindene maleate, triprolidine hydrochloride, olopatadine hydrochloride, and the like.

  Antitussives include, for example, codeines such as codeine phosphate, dihydrocodeine phosphate, dextromethorphan hydrobromide, cloperastine, noscapine dimethylmorphane, oxerazine, pentoxyberine citrate, eprazinone hydrochloride, clobutinol hydrochloride, citric acid Examples include isoaminyl, fominoben hydrochloride, clofedanol hydrochloride, benproperin phosphate, hydrocotarnine, dibutate sodium and the like.

  Examples of the desquamating agent include potassium guaiacol sulfonate, carbocysteine, L-ethylcysteine hydrochloride, L-methylcysteine hydrochloride, cysteine derivatives such as acetylcysteine, bromhexine, ambroxol hydrochloride, and the like. Examples of antitussive removers include guaifenesin, tipipedin, oxymethebanol, aroclamide hydrochloride, carbetapentane phenate, trimethquinol hydrochloride, methoxyphenamine hydrochloride, and the like. In addition, the medicinal component exemplified as the antitussive agent, the antifouling agent, and the antitussive antifouling agent may sometimes exhibit an antitussive action and / or an antifouling action.

  Examples of psychotropic drugs include chlorpromazine, reserpine and the like. Examples of the anxiolytic drugs include tofisopam, zolpidem tartrate, alprazolam, chlordiazepoxide, diazepam and the like. Examples of the antidepressant include maprotiline hydrochloride, imipramine, amphetamine, metafetan and the like. Examples of the hypnotic sedative include estazolam, nitrazepam, diazepam, perlapine, phenobarbital sodium and the like. Examples of antispasmodic agents include scopolamine hydrobromide, papaverine hydrochloride, diphenhydramine hydrochloride, and the like. Examples of central nervous system drugs include citicoline. Examples of the antiepileptic agent include phenytoin and carbamazepine. Examples of the sympathomimetic agent include isoproterenol hydrochloride. Examples of peripheral neuropathy agents include epalrestat and mecobalamin.

  The gastrointestinal drugs include, for example, gastrointestinal agents such as diastase, sugar-containing pepsin, funnel extract, cellulase AP3, lipase AP, cinnamon oil, etc., berberine chloride, resistant lactic acid bacteria, bifidobacteria and the like. Examples of the antacid include magnesium carbonate, sodium bicarbonate, magnesium aluminate metasilicate, magnesium aluminate silicate, synthetic hydrotalcite, precipitated calcium carbonate, magnesium oxide and the like. Examples of the anti-ulcer agent include teprenone, famotidine, lansoprazole, omeprazole, rabeprazole, cimetidine, ranitidine hydrochloride and the like. Examples of digestive organ drugs include mosapride citrate.

Examples of antihypertensive agents include carvedilol, olmesartan medoxomil, benidipine hydrochloride, telmisartan, amlodipine besylate, delapril, captopril, hydralazine hydrochloride, labetalol hydrochloride, manidipine hydrochloride, candesartan cilexetil, methyldopa, perindopril erbumine, etc. It is done. Examples of the vasoconstrictor include phenylephrine hydrochloride. Examples of the vasodilator include nicorandil, carbochromene hydrochloride, molsidomine, perapamil hydrochloride, cinnarizine and the like. Examples of the arrhythmic agent include procainamide hydrochloride, propranolol hydrochloride, pindolol and the like. Examples of the cardiotonic agent include caffeine and digoxin.
Examples of the diuretic include isosorbide, furosemide, hydrochlorothiazide and the like.
Examples of the hyperlipidemia agent include ethyl icosapentate, cerivastatin sodium, simvastatin, pravastatin sodium, atorvastatin calcium hydrate and the like.

Antibiotics include, for example, vancomycin hydrochloride, cefdinir, itraconazole, clarithromycin, cefcapene pivoxil hydrochloride, cephalexin, cefaclor, amoxicillin, pipmecillinam hydrochloride, cefotiam hexetyl, cefadroxyl, cefixime, cefditoren pivoxil, cefterampyr And cephem compounds such as cefpodoximiproxetil, synthetic antibacterial agents such as ampicillin, cyclacin, nalidixic acid, levofloxacin, enoxacin, monobactams such as carmonam sodium, penems and carbapenem antibiotics.
Examples of the chemotherapeutic agent include sulfamethizole.

Examples of the agent for diabetes include tolbutamide, voglibose, pioglitazone hydrochloride, glibenclamide, troglidazone and the like.
Examples of antispasmodic agents include meclizine hydrochloride and dimenhydrinate.
Antirheumatic drugs include methotrexate, bucillamine and the like.
Examples of hormone agents include liothyronine sodium, dexamethasone sodium phosphate, prednisolone, oxendron, leuprorelin acetate, and the like.
Alkaloid narcotics include opium, morphine hydrochloride, throne, oxycodone hydrochloride, opium alkaloid hydrochloride, cocaine hydrochloride, and the like.
Examples of the sulfa drugs include sulfisomidine and sulfamethizole.
Examples of anti-gout drugs include allopurinol and colchicine.
Examples of the blood coagulation inhibitor include dicumarol.
Examples of the antineoplastic agent include 5-fluorouracil, uracil, mitomycin, manidipine hydrochloride, voglibose, candesartan cilexetil, pioglitazone hydrochloride and the like.

  Other active ingredients include, for example, tamsulosin hydrochloride, donepezil hydrochloride, oseltamivir, limaprost alphadex, loxoprofen sodium, sarpogrelate hydrochloride, ursodeoxycholic acid, alacepril, brotizolam, berberine hydrochloride or tannate, loperamide hydrochloride, ebastine, etc. Is mentioned.

Nutritional ingredients include proteins, carbohydrates, lipids, vitamins, minerals and other beneficial ingredients.
As vitamins, for example, carotenoids such as astaxanthin, vitamin A, β-carotene, lutein, zeaxanthin, fursultiamine, fursultiamine hydrochloride, prosultiamine, octothiamine, thiamine disulfide, bisbutyamine, bisbuthiamine Vitamin B1 such as bisibutiamine, benfotiamine, cetotiamine hydrochloride or a derivative thereof, or a salt thereof, riboflavin, sodium riboflavin phosphate, sodium flavin adenine dinucleotide, a riboflavin vitamin B2 or a derivative thereof, or a salt thereof, Vitamin C derivatives such as ascorbic acid, ascorbic acid glucoside, L-ascorbyl palmitate, L-ascorbic acid phosphate, tocopherol, tocopherol acetate, co Click tocopherol, tocopherol nicotinate, vitamin E such as tocotrienol or the like.

  Other useful ingredients include, for example, deoxyribonucleic acid and its salts, adenylic acid derivatives such as adenosine triphosphate, adenosine monophosphate and their salts, ribonucleic acid and its salts, guanine, xanthine and their derivatives and their derivatives. Nucleic acid-related substances such as salt; Serum deproteinized extract, spleen extract, placenta extract, chicken crown extract, royal jelly extract, etc .; yeast extract, lactic acid bacteria extract, bifidobacteria extract, ganoderma extract Extracts from microorganisms such as foods; extracts from plants such as carrot extract, assembly extract, rosemary extract, buckwheat extract, garlic extract, hinokitiol, cephalanthin; α- or γ-linolenic acid, Eicosapentaenoic acid and derivatives thereof, succinic acid and derivatives thereof, and salts thereof, estradiol And derivatives thereof and salts thereof, glycolic acid, lactic acid, malic acid, citric acid, salicylic acid and other α-hydroxy acids and their derivatives and their salts, glycyrrhizic acid, glycyrrhetinic acid, mefenamic acid, phenylbutazone, indomethacin, Ibuprofen, ketoprofen, allantoin, guaiazulene and derivatives thereof and salts thereof, ε-aminocaproic acid, zinc oxide, diclofenac sodium, hyaluronic acid, chondroitin, collagen, aloe extract, salvia extract, arnica extract, chamomile extract, Birch extract, Hypericum extract, Eucalyptus extract and Mukuroji extract, tyrosinase activity inhibitor is cysteine and its derivatives and salts thereof, Sempokka extract, Caiquet extract, Sunpens extract , Sakuhakuhi extract, Toki extract, Ibukitorano extract, Clara extract, Hawthorn extract, Shirayuri extract, Hop extract, Neubara extract and Yokuinin extract, Hyaluronic acid, Chondroitin sulfate, Dermatan sulfate, Heparan sulfate, Heparin and keratan sulfate and salts thereof, collagen, elastin, keratin and derivatives thereof, and salts thereof, deep sea water, loofah extract, gypsum extract, papaya powder, zinc, ginseng extract, bulberry extract, DHA, One or more kinds can be selected from the group consisting of ginkgo biloba leaf extract, glutathione, flavonoid, tannin, ellagic acid, nucleic acids, herbal medicines, seaweeds, inorganic substances and the like, and mixtures thereof.

  A binder, a coating agent, an excipient and the like can be blended in the active ingredient layer and / or the coating layer. In addition, a water-soluble substance, a plasticizer, a stabilizer, a colorant, a surfactant, a fluidizing agent, etc. for adjusting the dissolution rate may be added as necessary.

  Excipients include lactose, corn starch, crystalline cellulose, sucrose, D-mannitol, pregelatinized starch, partially pregelatinized starch, silicic anhydride, magnesium aluminate metasilicate, magnesium aluminate silicate, hydrtalcite, etc. Can be mentioned.

  Examples of binders include water-soluble polysaccharides such as gelatin, pullulan, carrageenan, locust bean gum, agar, konjac mannan, xanthan gum, tamarind gum, pectin, sodium alginate, gum arabic, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, etc. Examples thereof include celluloses, starches such as pregelatinized starch and starch paste, and synthetic polymers such as polyvinylpyrrolidone, carboxyvinyl polymer and polyvinyl alcohol.

  As coating agents, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, starch paste, pregelatinized starch, polyvinylpyrrolidone, gum arabic, sugar syrup, sodium carboxymethylcellulose, pullulan, polyvinyl alcohol, polyethylene glycol, ethylcellulose, acrylic copolymer Examples include coalescence, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, carboxymethylethylcellulose, cellulose acetate, hydroxypropylmethylcellulose acetate succinate, shellac, and silicone resin.

Examples of the surfactant include phospholipid, glycerin fatty acid ester, polyethylene glycol fatty acid ester, sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, and the like.
Examples of the fluidizing agent include hydrous silicon dioxide and light anhydrous silicic acid.

  The granular composition using the spherical calcium hydrogen phosphate of the present invention, the spherical calcium hydrogen phosphate of the present invention as a nucleating agent, fluidized bed granulation, stirring granulation, rolling bed granulation, spray drying granulation, It can carry out by well-known wet granulation methods, such as extrusion granulation, These conditions can be performed by a conventional method.

While rolling the spherical calcium hydrogen phosphate of the present invention in a wet granulator, the binder-containing solution is continuously sprayed, and at the same time, a powder comprising the active ingredient and, if necessary, an excipient is supplied, Spherical calcium hydrogen phosphate is coated with powder and dried to form granules. Alternatively, while the spherical calcium hydrogen phosphate is fluidized in a wet granulator, the liquid in which the drug is dissolved or suspended in the binder-containing solution is sprayed, and the powder containing the drug is coated on the spherical calcium hydrogen phosphate. Dry into granules. Subsequently, the coating solution or coating suspension is sprayed while the granules are flowing, and dried to form a film layer for the purpose of moisture proofing, bitterness masking, enteric properties, sustained release, sustainability, etc. Granules. Further, when the powder containing the drug is coated, a coating-containing solution or a coating suspension may be sprayed simultaneously. The order of granulation can be appropriately selected according to the type of drug.
The solvent of the above solution may be any pharmaceutically acceptable solvent without affecting these physical properties, and examples thereof include water, ethanol, methanol and the like.

The pharmaceutical preparation of the present invention can be in the form of a solid dosage form such as a tablet, a rapidly disintegrating tablet in the oral cavity, a capsule, a granule or a fine granule, or a liquid preparation of a suspension.
In the tablet production method, the granular composition is mixed with an additive component that can be blended with a pharmaceutical product by a method such as dry mixing or wet mixing, and then compression-molded. At this time, by adding a disintegrant such as F-MELT (trademark manufactured by Fuji Chemical Industry Co., Ltd.), crospovidone, low-substituted hydroxypropylcellulose, sodium carboxymethyl starch, croscarmellose sodium, starch, etc. It can be a fast disintegrant.

  As an additional component that can be blended in the pharmaceutical preparation of the present invention, a binder (for example, carmellose, hydroxypropylcellulose, alginic acid, gelatin, partially pregelatinized starch, popidone, gum arabic, pullulan, dextrin, etc.), excipient (for example, (Corn starch, potato starch, rice starch, powdered sugar, lactose, D-mannitol, trehalose, crystalline cellulose, crystalline cellulose / carmellose sodium, magnesium metasilicate magnesium phosphate, calcium hydrogen phosphate, hydrotalcite, silicic anhydride, etc.) , Surfactants (eg polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, sorbitan fatty acid ester, polysorbate, fatty acid glycerin ester, sodium lauryl sulfate), lubricants (sucrose fatty acid ester) , Magnesium stearate, talc, sodium stearyl fumarate, etc.), acidulants (eg, citric acid, tartaric acid, malic acid, ascorbic acid, etc.), foaming agents (eg, sodium bicarbonate, sodium carbonate, etc.), sweeteners (sodium saccharin, Glycyrrhizin dipotassium, aspartame, stevia, thaumatin, etc.), perfume (eg lemon oil, orange oil, menthol, etc.), colorant (eg edible red No. 2, edible blue No. 2, edible yellow No. 5, edible lake pigment, edible sesquioxide Iron, etc.), stabilizers (eg sodium edetate, tocopherol, cyclodextrin, etc.), flavoring agents, flavoring agents and the like.

  The spherical calcium hydrogen phosphate and the granular composition using the spherical calcium hydrogen phosphate of the present invention can be used for foods, cosmetics and the like in addition to pharmaceuticals. In particular, it is suitable for controlling the absorbability of functional food in the body.

  Other uses of the spherical calcium hydrogen phosphate of the present invention include a high degree of sphericity, so that it is a dental abrasive, a raw material and filler for artificial joints and artificial teeth, a column chromatography filler, a release agent for films, etc. It can be used as an anti-sticking agent for paints, a matting material, and an adsorption carrier.

EXAMPLES The present invention will be described below with reference to examples, but these examples do not limit the scope of the present invention.
[Particle size measurement method]
The average particle size of the particles in the suspension was measured with a wet particle size distribution analyzer (SALD-2000J, manufactured by Shimadzu Corporation) under the condition of a refractive index of 1.7-0.20i.
The average particle size of the dry powder was measured with a dry particle size distribution analyzer (LA-920, manufactured by Horiba, Ltd.).
[Particle strength]
It measured using the particle hardness measuring apparatus (Grano, Okada Seiko Co., Ltd. product).
[SEM (scanning microscope) photograph]
An SEM photograph was taken using S-3000N of Hitachi, Ltd.
[Sphericity]
From the image taken using a microscope (VHX-100, manufactured by Keyence Corporation), the minor axis and major axis of each particle were measured, and a numerical value was derived from the ratio of minor axis / major axis.
[Water absorption]
The amount of water absorption was based on JISK5101, using water instead of linseed oil.
[Static volume ratio]
The static specific volume is when the glass tube is inserted into a 100 ml measuring cylinder, the sample is put into the glass tube with a funnel so that the volume is 90 to 100 ml, the glass tube is gently pulled out, and the surface of the sample is flattened. The volume (Vml) and the weight (Wg) of the sample were determined by V / W.

[Reference Example 1]
Calcium hydrogen phosphate was produced by the method described in JP-A-10-120408. While stirring 102 L of water, 10.2 kg of quick lime (CaO purity 96%) was added and stirred for 30 minutes to obtain lime milk, which was sieved with 100 mesh to remove coarse particles. While stirring at room temperature to 40 ° C., 35.6 kg of 50% strength aqueous phosphoric acid solution and lime milk prepared by the above procedure were simultaneously added to this solution for 30 minutes. Subsequently, stirring was continued for 30 minutes to complete the reaction. 72 g of citric acid monohydrate was added and heated to 95 ° C., held for 30 minutes, and then filtered and washed. Water was added and suspended to obtain a suspension of flaky calcium hydrogen phosphate (solid content 16%).

[Example 1]
Using a high-pressure homogenizer [Starburst Large Machine HJP-25080, manufactured by Sugino Machine Co., Ltd.], 70 L of the suspension of scale-like calcium hydrogen phosphate of Reference Example 1 was passed 10 times under the condition of a flow rate of 7 L / min. And crushed. The average particle size in the suspension was 1.5 μm. This turbid liquid was spray-dried using a centrifugal atomizer under conditions of a heat input temperature of 320 ° C. and an outlet temperature of 220 ° C. to obtain spherical calcium hydrogen phosphate. The angle of repose was 28 °. FIG. 1 shows a microscope photograph, and FIGS. 2 and 3 show SEM photographs. It can be seen that the sphere has a very high sphericity, and the scaly primary particles are densely aggregated.

[Example 2]
Using a high-pressure homogenizer [Starburst Large Machine HJP-25080, manufactured by Sugino Machine Co., Ltd.], 70 L of the suspension of scale-like calcium hydrogen phosphate of Reference Example 1 was passed 20 times under the condition of a flow rate of 7 L / min. And crushed. This turbid liquid was spray-dried using a centrifugal atomizer under conditions of a heat input temperature of 320 ° C. and an outlet temperature of 220 ° C. to obtain spherical calcium hydrogen phosphate.

[Comparative Example 1]
Water is added to the suspension of flaky calcium hydrogen phosphate of Reference Example 1 to obtain a suspension having a solid content of 25%, and sprayed using a flow centrifugal atomizer at a heat input temperature of 320 ° C. and an outlet temperature of 200 ° C. Dried to obtain slightly spherical calcium hydrogen phosphate. FIG. 4 shows a microscope photograph. It can be seen that the surface is uneven and the degree of sphericalness is low.

[Table 1] Analysis values
Inability to measure indicates that the intensity is low and no peak can be detected.

  The spherical calcium hydrogen phosphate of the present invention has a sphericity of 0.99, which is very close to a sphere, compared with the calcium hydrogen phosphate of Comparative Example 1, and has a small static bulk density, an appropriate water absorption capacity, and no friability. It can be seen that this is a spherical calcium hydrogen phosphate that has never before been obtained.

[Example 3] Manufacture of granules 100 g of spherical calcium hydrogen phosphate of Example 1 was charged into a fluidized granulator (Freund Sangyo Co., Ltd., Flow Coater Mini FL), and 8.3 g of hydroxypropylcellulose and 367 g of purified water containing 41.7 g of pulverized acetaminophen (200 mesh sieve product) was sprayed at a spray rate of 1 to 4 mL / min, and granules were obtained through granulation and drying processes. The average particle size was 142 μm. FIG. 5 shows an SEM photograph. A layer of hydroxypropyl cellulose and acetaminophen is uniformly wrapped around the spherical calcium hydrogen phosphate of the present invention to form beautiful granules.

[Example 4] Manufacture of tablets 300 g of the granules of Example 3 were mixed with 200 g of excipient F-MELT [trademark, manufactured by Fuji Chemical Industry Co., Ltd.] for intraoral quick disintegrating agent, 5 g of magnesium stearate, and 5 g of aspartame. Using a rotary tableting machine (HT-AP18SS-II, manufactured by Hata Iron Works Co., Ltd.), a tablet having a weight of 200 mg, a diameter of 8 mm, and 9R was tableted with a set hardness of 50 N to obtain an orally rapidly disintegrating tablet. It was possible to tablet well without capping or peeling. The disintegration time in the pharmacopoeia disintegration test was 15 seconds. The bitterness of acetaminophen was not felt.

2 is a microscopic photograph of spherical calcium hydrogen phosphate of Example 1 (1 memory: 100 μm). 2 is an SEM photograph (1 memory: 5 μm) of spherical calcium hydrogen phosphate of Example 1. 2 is an SEM photograph (1 memory 1 μm) of spherical calcium hydrogen phosphate of Example 1. 2 is a slightly spherical calcium hydrogen phosphate microscope photograph (1 memory: 100 μm) of Comparative Example 1. It is a SEM photograph (1 memory 10 micrometers) of the granule of Example 3.

Claims (8)

The following formula (I) in which the average particle diameter of the primary particles is 0.01 to 5 μm
CaHPO ₄ · mH ₂ O (I)
(In the formula, m represents a number in the range of 0 ≦ m ≦ 0.5)
The average particle size is 10 to 500 μm, the sphericity is 0.85 to 1, the particle strength is 60 to 300 g / mm ² , and the water absorption is 0.4 to 1.5 ml / g. Spherical particles characterized in that Spherical particles having an average particle diameter of 20 to 300 μm, a sphericity of 0.9 to 1, a particle strength of 80 to 200 g / mm ² , and a water absorption of 0.6 to 1.2 ml / g. The spherical particle according to any one of claims 1 to 2, wherein the BET specific surface area is 20 to 100 m ² / g and the static bulk specific volume is 1 to 5 ml / g. The spherical particle according to any one of claims 1 to 2, wherein the BET specific surface area is 20 to 60 m ² / g and the static bulk specific volume is 1 to 3 ml / g. The spherical particles according to any one of claims 1 to 4, wherein the shape of the primary particles of calcium hydrogen phosphate is scaly. The spherical particles according to any one of claims 1 to 8, which are obtained by pulverizing calcium hydrogen phosphate so as to have an average particle diameter of 0.01 to 5 µm and spraying it in an air stream. Manufacturing method. A granular composition comprising the spherical particles of claims 1 to 5 having a drug layer and optionally a coating layer thereon. A pharmaceutical composition comprising the spherical particles of claims 1 to 5 and the granular composition of claim 6.