JP5717424B2 - Coating particles - Google Patents

Description

  The present invention relates to coated particles. The present invention relates to a coating particle suitable for an orally disintegrating agent, a gastric solid preparation, an enteric solid preparation, a sustained release solid preparation, a bitterness-inhibiting solid preparation, and the like.

  Production of a bitterness mask in dry syrup or an oral disintegrant pursuing ease of use has been developed using coating particles obtained by coating core particles having a particle diameter of 100 μm or less with drug particles. Further, the use of core particles having a particle size of 100 μm or less as a drug delivery system such as oral preparations and injections has attracted attention.

  A binder is used in coating and granulating (layering) a drug on core particles having a particle diameter of 100 μm or less. However, the core particles having a particle diameter of 100 μm or less are very likely to aggregate due to the bonding between the particles formed by the coating agent containing the binder. As a result, the amount of drug particles adhering to the core particles (drug layering efficiency) decreases. As one means for suppressing the aggregation of the core particles, it is conceivable to use a coating agent having a low binding force. However, when a coating agent having a low binding force is used, the binding force between the core particles and the drug particles becomes small, and the drug particles covered with the core particles are easily peeled off, thereby reducing the drug layering efficiency.

  In Non-Patent Documents 1 and 2, by using a coating agent containing hydroxypropyl cellulose having a viscosity of 2.0 to 2.9 mPa · s in a 2% aqueous solution at 20 ° C. as a binder, the aggregation of core particles is suppressed to a certain extent. It is described that the drag layering efficiency can be increased.

Ichikawa H., Fukumori Y., Adeyeye C. M. Int. J. pharm., 156, 39-248 (1977) Ichikawa H., Aoyagi K., Fukumori Y., AAPS Journal, 7 (S2), 301 (2005)

However, a coating agent containing hydroxypropyl cellulose having a viscosity of 2.0 to 2.9 mPa · s in a 2% aqueous solution at 20 ° C. is used in the coating granulation (layering) of a drug on core particles having a particle diameter of 100 μm or less. Even if the core particles were coated and granulated, the aggregation of the core particles could not be completely suppressed, and the drug could not be completely attached to each core particle.
Then, this invention makes it a subject to provide the coating particle suitable for the manufacturing method of a coating particle, solid formulation, etc. in which the aggregation rate of a core particle is lower and drag layering efficiency is higher.

  As a result of intensive studies to solve the above problems, the present inventors sprayed a coating agent containing a hydroxyalkyl cellulose having a viscosity of 1.10 to 1.95 mPa · s in a 2% aqueous solution at 20 ° C. When the coating agent was made to adhere to the surface, the aggregation of the core particles compared to when using a coating agent containing hydroxypropyl cellulose having a viscosity of 2.0 to 2.9 mPa · s in a 2% aqueous solution at 20 ° C. We have found that the rate is lower and the drag layering efficiency is higher. The present invention has been completed by further studies based on this finding.

That is, the present invention includes the following aspects.
<1> Coated particles having core particles and a coating layer containing hydroxyalkyl cellulose having a viscosity of 1.10 to 1.95 mPa · s in a 2% aqueous solution at 20 ° C.
<2> The coating particle according to <1>, wherein the coating layer further includes drug particles.
<3> The coating particle according to <1> or <2>, wherein the core particle has a volume average primary particle diameter of 100 μm or less.

<4> Coating particles comprising spraying a coating agent containing hydroxyalkyl cellulose having a viscosity of 1.10 to 1.95 mPa · s in a 2% aqueous solution at 20 ° C. to adhere the coating agent to the surface of the core particles The manufacturing method.
<5> A coating agent containing hydroxyalkyl cellulose having a viscosity of 1.10 to 1.95 mPa · s in a 2% aqueous solution at 20 ° C. is placed in a fluidized bed type, spouted bed type or fluidized rolling type coating apparatus. A method for producing coated particles, comprising spraying to attach the coating agent to the surface of the core particles.

According to the coating particle manufacturing method of the present invention, the core particles, particularly the core particles having an average primary particle size of 100 μm or less, are almost completely aggregated and the drug particles are almost completely adhered and coated on each core particle (drug Increase layering efficiency).
The coated particles of the present invention can provide a solid preparation such as a tablet having sufficient tablet strength and good disintegration time.

The conceptual diagram which shows an example of a spouted layer type coating apparatus. The figure which showed the influence which it has on the yield of spray pressure. The figure which showed the influence which it has on the aggregation rate of spray pressure. The figure which showed the influence which it has on the drug layering efficiency of spraying pressure. The figure which showed the influence which it has on the spraying droplet diameter of spraying pressure.

(Coating particles)
The coating particle of the present invention has a core particle and a coating layer that covers the core particle. The coating layer includes hydroxyalkyl cellulose.

<Nuclear particles>
The core particles used in the present invention may be particles composed of an active ingredient itself (for example, a drug or an active ingredient for health foods if it is a pharmaceutical or agrochemical), or particles composed of a mixture of a carrier and an active ingredient. It may be a particle whose surface is covered with an active ingredient, or a particle consisting only of a carrier containing no active ingredient. The core particles can be used without any limitation as long as they do not lose shape during operation.

The upper limit of the volume average primary particle diameter of the core particles is preferably 1000 μm, more preferably 500 μm, and particularly preferably 100 μm. The lower limit of the volume average primary particle diameter of the core particles is usually 10 μm, preferably 20 μm. The volume average primary particle size was obtained by measuring using a laser diffraction particle size distribution measuring apparatus (for example, LDSA-2400; manufactured by East Japan Computer Co., Ltd.) under the conditions of air pressure 3.5 kgf / cm ² and focal length 100 mm. This is the value of the particle size D _{50 with} an integrated value of 50% in the particle size distribution. The particle shape can be observed with a scanning electron microscope (for example, JSM-7330; manufactured by JEOL Ltd.).

  Examples of the core particles include pills, granules, powders, drug single crystals, drug powder aggregates, lactose particles, hydroxyapatite, calcium carbonate particles; crystalline cellulose granules commercially available as coating core particles in the formulation area Sucrose spherical granules, mannitol spherical granules and the like can be used.

  The core particles may be controlled-release preparations such as immediate-release preparations and sustained-release preparations (sustained-release preparations). The core particles may contain conventional additives. Examples of the additive include an excipient, a disintegrant, a binder, a lubricant, a colorant, a pH adjuster, a pH buffer, a surfactant, a sustained release agent, a stabilizer, a sour agent, and a fragrance. , Fluidizing agents, cooling agents, sweeteners, umami ingredients, sweetness enhancers and the like. These additives are used in amounts conventionally used in the pharmaceutical field.

  Examples of drugs that are active pharmaceutical ingredients include analgesics, antipyretic analgesics, headache treatments, antitussives, expectorants, sedatives, antispasmodics, antihistamines, antiallergic agents, antiplasmin agents, bronchodilators, asthma Therapeutic agent, diabetes therapeutic agent, liver disease therapeutic agent, ulcer therapeutic agent, gastritis therapeutic agent, healthy stomach digestive agent, gastrointestinal motility activator, hypertension therapeutic agent, angina treatment agent, antihypertensive agent, hypotension therapeutic agent, Antihyperlipidemic agent, Hormone agent, Antibiotic agent, Antiviral agent, Sulfa agent, Anti-inflammatory agent, Psychiatry and nerve agent, Intraocular pressure-lowering agent, Antiemetic agent, Antidiarrheal agent, Gout agent, Arrhythmia agent, Vasoconstrictor , Digestive agent, sleep or hypnotic induction (induction) agent, sympatholytic agent, anemia treatment agent, antiepileptic agent, anti-vertigo agent, parallel injury treatment agent, tuberculosis treatment agent, vitamin deficiency treatment agent, dementia treatment agent, urinary incontinence Therapeutic agent, antidepressant, bactericidal agent, parasite Removing agents, vitamins, amino acids, such as minerals and the like. More specifically, for example, central nervous system drugs (acetaminophen, aspirin, indomethacin, ibuprofen, naproxen, diclofenac sodium, meclofenoxate hydrochloride, chlorpromazine, sodium tolmethine, milnacipran hydrochloride, phenobarbital, etc.) Peripheral nervous system drugs (etomidrine, tolperisone hydrochloride, ethyl pipetanate bromide, methylbenactidium bromide, furopropion, etc.), hemostatic drugs (sodium carbazochrome sulfonate, protamine sulfate, etc.), drugs for cardiovascular system (aminophylline, Such as ethylephrine hydrochloride, diltiazem hydrochloride, digitoxin, captopril), respiratory drugs (ephedrine hydrochloride, chlorprenalin hydrochloride, oxerazine citrate, cloperastine, sodium cromoglycate, etc.) Organ drugs (berberine chloride, loperamide hydrochloride, cimetidine, ranitidine hydrochloride, famotidine, etc.), coronary vasodilators (nifedipine, nicardipine, verapamil, etc.), vitamins (ascorbic acid, thiamine hydrochloride, calcium pantothenate, riboflavin, etc.), Metabolic preparations (camostat mesilate, mizoribine, lysozyme chloride, etc.), allergic drugs (cyproheptadine hydrochloride, diphenhydramine hydrochloride, alimemazine tartrate, suplatast tosylate, diphenhydramine maleate, etc.), chemotherapeutic agents (acyclovir, enoxacin, ofloxacin, pipemetic acid) Trihydrate, levofloxacin, etc.), antibiotics (erythromycin, cefcapene pivoxil hydrochloride, cefteram pivoxil, cefpodoxime proxetil, cefaclor) Cephalexin, clarithromycin, Rokitamycin) and the like.

Examples of drugs that are active ingredients of agricultural chemicals include antibacterial agents, antiviral agents, fungicides, acaricides, insecticides, nematicides, rodenticides, herbicides, plant growth regulators, fertilizers, safeners, etc. Is mentioned.
Among the above-mentioned compounds that are active ingredients of pharmaceuticals and agricultural chemicals, those having a salt-forming site include physiologically or pharmaceutically acceptable salts thereof (particularly, pharmaceutically or agriculturally acceptable salts). It is.

  The active ingredient for health food is an ingredient that is added for the purpose of health enhancement. For example, green juice powder, aglycone, agaricus, ashwagandha, astaxanthin, acerola, amino acids (valine, leucine, isoleucine, lysine, methionine, phenylalanine, threonine, tryptophan, histidine, cystine, tyrosine, arginine, alanine, aspartic acid, seaweed powder, Glutamine, glutamic acid, glycine, proline, serine, etc.), alginic acid, ginkgo biloba extract, sardine peptide, turmeric, uronic acid, echinacea, sorghum, oligosaccharide, oleic acid, nucleoprotein, katsuobushi peptide, catechin, potassium, calcium, carotenoid, Garcinia, L-carnitine, chitosan, conjugated linoleic acid, Kidachi aloe, Gymnema sylvestre extract, citric acid, cumistin, glyceride, glycenol, g Kagon, glutamine, glucosamine, L-glutamine, chlorella, cranberry extract, cat's claw, germanium, enzyme, ginseng extract, coenzyme QIO, collagen, collagen peptide, coleus forskolin, chondroitin, psyllium husk powder, hawthorn extract, saponin, lipid , L-cystine, perilla extract, citrimax, fatty acid, plant sterol, seed extract, spirulina, squalene, white willow, ceramide, selenium, St. John's wort extract, soybean infibon, soybean saponin, soybean peptide, soybean lecithin, simple sugar, protein Chestnut extract, iron, copper, docosahexaenoic acid, tocotrienol, natto kinase, natto fungus culture extract, niacin sodium, nicotinic acid, disaccharide, Acid bacteria, garlic, saw palmetto, germinated rice, pearl barley extract, herbal extract, valerian extract, pantothenic acid, hyaluronic acid, biotin, chromium picolinate, vitamin A, A2 vitamin B1, B2, B6, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K, hydroxytyrosol, bifidobacteria, brewer's yeast, fructooligosaccharides, flavonoids, butcher's bloom extract, black cohosh, blueberry, prune extract, proanthocyanidins, protein, propolis, bromelain, probiotics, phosphatidylcholine, phosphatidyl Serine, β-Carotene, Peptide, Safflower extract, Maitake extract, Maca extract, Magnesium, Maria thistle, Manganese, Mitochondria, Mineral, Muco , Melatonin, Phellinus linteus, melilot extract powder, molybdenum, vegetable powder, folic acid, lactose, lycopene, linoleic acid, lipoic acid, phosphorus (phosphorus), lutein, lecithin, rosmarinic acid, royal jelly, DHA, EPA, and the like.

  Examples of excipients include starches such as corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, and porous starch; lactose, fructose, glucose, D-mannitol, sorbitol, trehalose Sugars and sugar alcohols such as erythritol; anhydrous calcium phosphate, crystalline cellulose, precipitated calcium carbonate, calcium silicate, and the like.

  Examples of the disintegrant include carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch and the like.

Examples of the binder include crystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gum arabic powder and the like.
Examples of the lubricant include magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, sodium stearyl fumarate and the like.

Examples of the colorant include edible pigments such as edible yellow No. 5, edible red No. 2, and edible blue No. 2, edible lake pigments, and iron sesquioxide.
Examples of the pH adjuster include citrate, phosphate, carbonate, tartrate, fumarate, acetate, amino acid salt and the like.
Examples of the pH buffer include citric acid-sodium citrate buffer.
Examples of the surfactant include sodium lauryl sulfate, polysorbate, polyoxyethylene polyoxypropylene glycol and the like.
Examples of the stabilizer include tocopherol, tetrasodium edetate, nicotinamide, and cyclodextrins.

Examples of sour agents include ascorbic acid, citric acid, tartaric acid, malic acid and the like.
Examples of the fragrances include menthol, peppermint oil, lemon oil, and vanillin.
Examples of the fluidizing agent include light anhydrous silicic acid and hydrous silicon dioxide.
As a refreshing agent, in addition to terpene compounds such as camphor and borneol (monoterpene alcohol, etc.), essential oils, essences or powders containing the terpene compounds; essential oils such as peppermint, spearmint, cool mint, essences or powders (Powder): The above essential oil or essence adsorbed on a powder carrier (eg dextrin), essential oil or essence mixed with a shaping material (eg gum arabic) and a liquid base (water, alcohol etc.) And powdered ones.

Examples of the sweetener include non-sugar sweeteners, sugar alcohols and sugars. As the non-sugar sweetener, either a synthetic sweetener or a natural sweetener can be used.
As the umami component, an amino acid umami component (amino acid or a salt thereof such as glutamic acid, sodium glutamate, potassium glutamate, glutamic acid hydrochloride, sodium guanylate, inosinic acid, sodium inosinate, arginine-glutamate, aspartic acid, aspartic acid Sodium, glycine, alanine, etc.), peptide-based umami components (dipeptides such as L-glutamyl-L-glutamic acid, L-glutamyl-L-serine; tri-L-glutamic acid, L-glutamyl-L-glycyl-L-serine, etc.) And carboxylic acid-based umami components (such as carboxylates such as sodium succinate).
Furthermore, you may contain the sweet taste enhancer (or taste agent) which has a taste (salt taste). Examples of such sweetness enhancers include sodium chloride, potassium chloride, phosphates (such as potassium hydrogen phosphate and sodium hydrogen phosphate). Sweetness enhancers (or flavoring agents) are often neutral salts, such as salts that dissociate as sodium ions and / or chloride ions (chloride ions).

  Other components that can be contained in the core particles include antioxidants or antioxidants, dispersants, suspending agents, solubilizers, thickeners (carboxyvinyl polymer, polyvinyl alcohol, gelatin and other water-soluble components). Polymers; cellulose ethers such as carboxymethylcellulose), preservatives or preservatives (such as parabens such as methylparaben and butylparaben), bactericides or antibacterial agents (such as benzoic acids such as sodium benzoate), antistatic agents, Examples include flavoring agents or masking agents, flavoring agents, antifoaming agents, isotonic agents, and soothing agents. These additives can be used alone or in combination of two or more. The method for producing the core particles is not particularly limited, and a general granulation method can be adopted.

<Coating layer>
<Hydroxyalkyl cellulose>
The hydroxyalkyl cellulose used for the coating layer has a viscosity of 1.10 to 1.95 mPa · s, preferably 1.50 to 1.90 mPa · s in a 2% aqueous solution at 20 ° C. When the viscosity of the hydroxyalkyl cellulose becomes too low, the binding force tends to decrease. On the other hand, when the viscosity of the hydroxyalkyl cellulose is too high, the core particles are aggregated and the drag layering efficiency is lowered.

Hydroxyalkyl cellulose is obtained, for example, by allowing sodium hydroxide to act on raw material cellulose to obtain alkali cellulose, and then subjecting alkali cellulose and alkylene oxide to a substitution reaction. After the substitution reaction, an acid such as acetic acid or hydrochloric acid can be added to the reaction solution to neutralize sodium hydroxide, followed by purification. By this substitution reaction, a part or all of —OH groups in the glucose ring unit of cellulose are substituted with —O— (R—O) _m —H groups. Here, R represents a divalent alkyl group. m represents the number of repetitions of R—O in parentheses and is a natural number of 1 or more.

The hydroxyalkyl cellulose preferably has a hydroxyalkyl group (— (R—O) _m —H) content in the range of 40 to 80% by weight, and more preferably in the range of 53 to 78% by weight. In addition, content of a hydroxyalkyl group can be calculated | required by the method by USP24 (US Pharmacopoeia), etc.

  Examples of the alkylene oxide used for the substitution reaction include ethylene oxide and propylene oxide. Of these, propylene oxide is preferably used in the present invention. When a substitution reaction is performed using propylene oxide, hydroxypropyl cellulose is obtained.

  The method for producing the hydroxyalkyl cellulose used for the coating layer is not particularly limited. For example, a production method using low molecular weight cellulose as a raw material; a hydroxyalkyl cellulose obtained by a normal production method is dissolved in water, gelled and precipitated, a supernatant liquid is collected, and water is removed. And the like.

  The content of hydroxyalkyl cellulose in the coating layer is not particularly limited.

The coating layer preferably further includes drug particles.
Examples of the drug particles include the active ingredient particles listed in the description of the core particles.
The size of the drug particle is not particularly limited, but is usually smaller than the core particle. The volume average primary particle diameter of the drug particles is preferably 0.1 μm to 100 μm, more preferably 0.5 μm to 50 μm, and particularly preferably 1 μm to 10 μm.

  The coating layer may further contain a material having a function of increasing the binding force between the core particles and the drug particles (binding force improving agent). For example, organic fatty acids (such as lauric acid, palmitic acid, myristic acid, stearic acid), ester derivatives of organic fatty acids, higher alcohols (such as cetyl alcohol, stearyl alcohol), glycerin fatty acid esters (such as glyceryl monostearate), polyethylene glycols (Such as Macrogol 6000) and wax-like substances such as natural wax (carnauba wax, rice wax, etc.). Among these, at least one selected from the group consisting of polyalkylene glycol, polyalkylene glycol higher fatty acid ester, higher fatty acid, higher alcohol, higher alcohol ester and natural wax is preferable, and polyethylene glycol is particularly preferable. The binding power improver is preferably hydrophilic. Further, the binder improving agent preferably has a melting point of 40 to 70 ° C, particularly preferably 50 to 65 ° C. Although content in particular of the binding power improvement agent in a coating layer is not restrict | limited, It is preferable that it is 0.1-20 weight% in a coating particle, and it is more preferable that it is 0.5-15 weight%.

The coating layer may contain other coating base. The coating base preferably has a volume average particle size of 0.1 to 100 μm, more preferably 0.1 to 50 μm.
Other coating bases include polymer bases, inorganic powders, and the like. Moreover, the additive illustrated as what can be contained in a nuclear particle in the above can be used as another coating base.

Examples of the polymer base include synthetic polymers and natural polymers. Specific examples include acrylic polymers, biodegradable polymers, and polyvinyl polymers.
Examples of the acrylic polymer include aminoalkyl methacrylate copolymer E and methacrylic acid-methyl methacrylate copolymer. Examples of biodegradable polymers include L-lactic acid, D-lactic acid, DL-lactic acid, glycolic acid, ε-caprolactone, N-methylpyrrolidone, homopolymers, copolymers or mixtures of these polymers, polycaprolactam, Examples include chitin and chitosan. Examples of the polyvinyl polymer include polyvinyl acetal diethylaminoacetate and PVA copolymer.

  As the polymer base, an elution control base such as enteric coating base, gastric coating base, water-insoluble coating base, sustained-release coating base, water-soluble coating base, etc. can be preferably used. Among them, a water-insoluble coating base is preferable. These polymer bases can be used alone or in combination of two or more. For example, a combination of a water-insoluble coating base and an enteric coating base and a combination of a water-insoluble coating base and a water-soluble coating base are preferable.

  As the enteric coating base, a polymer that is substantially insoluble under an acidic liquid and soluble under an alkaline liquid can be used. For example, methacrylic acid copolymer LD (Eudragit L30D55; manufactured by Evonik), methacrylic acid copolymer L (Eudragit L100; manufactured by Evonik), methacrylic acid copolymer S (Eudragit S100; manufactured by Evonik), hydroxypropylmethylcellulose phthalate (HPMCCP) ), Hydroxypropylmethylcellulose acetate succinate (AQOAT), carboxymethylethylcellulose (CMEC), cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), cellulose acetate trimellitate (CAT), aquateric (CAP water dispersion) ) And zein.

As the water-insoluble coating base, those which are hardly soluble in water but can be dissolved or uniformly dispersed in an organic solvent such as methanol, ethanol, propanol, isopropanol, and acetone can be used. Examples thereof include water-insoluble natural resins such as ethyl cellulose; shellac and the like; water-insoluble acrylic polymers such as aminoalkyl methacrylate copolymer RS (Eudragit RS; manufactured by Evonik) and methacrylic acid copolymer RSPO (Eudragit RSPO; manufactured by Evonik). It is done. Of these, water-insoluble acrylic polymers are preferred.
Examples of the water-soluble coating base include methyl cellulose, sodium carboxymethyl cellulose, and polyvinyl pyrrolidone.

  Examples of the inorganic particles include talc, sodium chloride, sodium citrate, soft anhydrous silicic acid (silica), precipitated calcium carbonate, magnesium stearate, calcium stearate, titanium oxide and the like. Of these, silica is preferred. By blending inorganic particles, the fluidity of the solid preparation is increased.

The coated particles of the present invention can be obtained by coating the core particles with a coating layer using a known coating method.
Coating methods include granulation handbook (edited by Japan Powder Industry Technology Association, Ohm), formulation design for oral administration (Professor Mitsuru Hashida, Graduate School of Pharmaceutical Sciences, Kyoto University), particle design engineering (powder) The methods described in publications such as the Society of Body Engineering, Industrial Books), Particle Design and Formulation Technology (Powder Engineering Association Formulation and Particle Design Subcommittee Chairman Yoshiaki Kawashima, Yakuho Hokpo) In the present invention, the fluidized coating method is preferable, and the spouted layer coating method is particularly preferable.

  There are a fluidized bed type coating device, a spouted bed type coating device, and a fluidized rolling type coating device as an apparatus for performing fluidized coating. Of these, the spouted layer type coating apparatus is particularly preferable.

  The fluidized bed type coating apparatus is composed of a screen through which an air flow whose bottom is blown from below can pass. The particles supplied on the screen are suspended and fluidized in the apparatus by the air flow. The coating agent is sprayed on the flowing particle layer. Examples of the spraying method include a spraying method from the top (top spray), a spraying method from the bottom (bottom spray), and a spraying method from the side (tangential spray). Of these, the top spray method is common. Drying is done by a stream of air blowing from the bottom of the screen.

  The spouted bed type coating apparatus is provided with a cylindrical inner pipe (guide pipe) inside the fluidized bed type coating apparatus, and is configured such that the screen blows up only from the lower part of the guide pipe. The particles rise as a result of the air stream blowing from below at high speed in the guide tube, and a spout layer of particles is formed. The spouted particles fall outside the guide tube, slide to the bottom, and are again spouted by airflow. The spray nozzle is located at the center of the screen and is generally sprayed upward (bottom spray). Drying is performed by a stream of air blown from the bottom of the screen. FIG. 1 is a conceptual diagram showing an example of a spouted layer type coating apparatus.

  The fluid rolling type coating apparatus incorporates a rotating disk instead of a screen at the bottom of the fluidized bed type coating apparatus, and causes particles to flow with an air flow blown from the periphery of the rotating disk.

  In the solid preparation as the coated particles of the present invention, after coating, if necessary, another coating such as film coating, sugar coating, thin layer sugar coating, sugarless sugar coating, sugarless thin layer sugar coating can be applied. When coated granules, fine granules, and drug particles are obtained, they can be compressed into tablets with other excipients. Moreover, the coating particles can be filled into capsules to form capsules. Furthermore, it can be packaged and taken as it is as a granule or fine granule. Or it can also be set as a dissolution type preparation at the time of use, an intraoral quick disintegrating tablet, a sustained release preparation, a film sheet type preparation, a gummy preparation, and a jelly preparation.

  Next, an Example is shown and this invention is demonstrated more concretely. In addition, this invention is not limited by these Examples.

Production Example 1
Hydroxypropyl cellulose having a viscosity of 2.2 mPa · s in an aqueous solution at 20 ° C. and in a concentration of 2% was dissolved in water at a concentration of 15%. The aqueous solution was heated to about 62 ° C. A part of hydroxypropylcellulose was gelled and precipitated. The supernatant was collected. The supernatant was diluted with water to obtain a 2% strength hydroxypropylcellulose aqueous solution. The viscosity at 20 ° C. was 1.70 mPa · s. Water was removed from the supernatant to obtain hydroxypropylcellulose.

Production Example 2
A hydroxypropyl cellulose having a viscosity of 1.84 mPa · s in an aqueous solution at 20 ° C. and 2% concentration was obtained in the same manner as in Production Example 1 except that the heating temperature was changed to 58 ° C.

Production Example 3
A hydroxypropyl cellulose having a viscosity of 1.93 mPa · s in an aqueous solution at 20 ° C. and 2% concentration was obtained in the same manner as in Production Example 1 except that the heating temperature was changed to 55 ° C.

The coating particles were evaluated by the following method.
(Particle size distribution, aggregation rate)
The particle size distribution of the CCSS coating particles was measured using an electromagnetic vibration sieve (manufactured by Tsutsui Riken Kikai Co., Ltd., sample charge 1 g). When the particles of each fraction were observed with a digital microscope, aggregates were observed in the fraction above the inflection point in the log normal probability plot of the total sieving percentage. Therefore, the ratio of the amount of particles screened beyond the bending point to the total amount of particles was defined as the aggregation rate.

(Drag layering efficiency)
10 mg of CCSS coated particles were placed in a 100 ml volumetric flask, and purified water was poured into this. CCSS was dissolved and extracted. Then, the volume was made up to 100 ml with purified water. This solution was filtered through a 0.1 μm membrane filter. The absorbance of the filtrate at a measurement wavelength of 363 nm was measured using an ultraviolet-visible absorptiometer (UV-150-02, manufactured by Shimadzu Corporation). Based on the calibration curve prepared in advance, the content of CCSS was calculated from the measured absorbance. The drag layering efficiency was determined by multiplying the total mass of the coating particles obtained in the coating operation by the CCSS content calculated above and dividing the result by the total mass of CCSS charged in the coating operation.

(Spray droplet diameter)
The spray liquid was sprayed at a predetermined spray pressure in an open environment at room temperature. Spray droplets were measured at a position 40 mm from the tip of the spray gun using a laser light scattering particle size distribution analyzer (LDSA-2400A, manufactured by Tohnichi Computer Applications). Three measurements were taken and the average value was determined.

Example 1
1.5 parts by weight of hydroxypropyl cellulose having a viscosity of 1.70 mPa · s in an aqueous solution at 20 ° C. and 2% concentration obtained in Production Example 1 is dissolved in 80 parts by weight of distilled water, and sodium carbazochrome sulfonate (CCSS) is dissolved in this solution. 4 parts by weight of an average particle diameter of 4 μm, manufactured by Sanwa Chemical Co., Ltd.) was dispersed to obtain a spray liquid (SL).
50 parts by weight of lactose having a primary particle size of 63 to 75 μm is charged into a spouted bed coating apparatus (guide tube length 170 mm, exhaust blower frequency 12 Hz) shown in FIG. 1, and air at a temperature of 65 ° C. (Air) is 0.15 m ^3. The spray liquid (SL) was sprayed at a predetermined spray pressure from the bottom of the apparatus at 1.4 ml / min. The exhaust temperature was 26-30 ° C.
CCSS coating particles were obtained by the above coating operation. The evaluation results are shown in FIGS.

Comparative Example 1
Example 1 except that hydroxypropyl cellulose having a viscosity of 2.68 mPa · s in an aqueous solution at 20 ° C. and 2% concentration was used instead of hydroxypropyl cellulose having a viscosity of 1.70 mPa · s in a 2% concentration aqueous solution at 20 ° C. CCSS coated particles were obtained in the same manner as above. The evaluation results are shown in FIGS.

Comparative Example 2
Except for using high-viscosity polyvinylpyrrolidone (PVP-40T, manufactured by Sigma-Aldrich) having a weight average molecular weight of about 40,000 instead of hydroxypropylcellulose having a viscosity of 1.70 mPa · s in a 2% concentration aqueous solution at 20 ° C. CCSS coated particles were obtained in the same manner as in Example 1. The evaluation results are shown in FIGS.

Comparative Example 3
Example except that low-viscosity polyvinylpyrrolidone (PVP-10, manufactured by Sigma-Aldrich) having a weight average molecular weight of about 10000 was used in place of hydroxypropylcellulose having a viscosity of 1.70 mPa · s in a 2% concentration aqueous solution at 20 ° C. CCSS coated particles were obtained in the same manner as in Example 1. The evaluation results are shown in FIGS.

  FIG. 2 is a diagram showing the yield of coating particles. In both Example 1 and Comparative Examples 1 to 3, the yield was approximately 90% or more. Product loss is thought to be due to leakage outside the chamber and passage through the bag filter. In Comparative Example 2, product loss due to adhesion to the guide tube occurred at a spray pressure of 0.19 MPa. This is because the core particles are blown up excessively by the jet stream generated under the high-pressure sprayer, the amount of the core particles flowing in the guide tube is insufficient, and the spray droplets that should have come into contact with the core particles are guided. This is probably due to excessive adhesion to the tube.

  FIG. 3 is a diagram showing the aggregation rate of particles. As the spray pressure increased, the aggregation rate tended to decrease. At any spray pressure, the coating particles of Example 1 were less aggregated than the coating particles of Comparative Examples 1-3. FIG. 5 is a diagram showing the spray droplet diameter. It can be seen that the droplet diameter decreases as the spray pressure increases. When FIG. 3 and FIG. 5 are compared, it can be seen that there is a correlation between the droplet diameter and the aggregation rate. That is, the smaller the droplet diameter, the smaller the aggregation rate. Under a constant concentration, the larger the droplet diameter, the greater the amount of binder contained therein. For this reason, it is considered that the cross-linking of the particles easily proceeds and aggregation is promoted.

FIG. 4 is a diagram showing drag layering efficiency. In the comparison between Comparative Example 2 and Comparative Example 3, the drug layering efficiency was higher when the high viscosity polyvinyl pyrrolidone was used than when the low viscosity polyvinyl pyrrolidone was used.
However, in comparison between Example 1 and Comparative Example 1, the drug layering efficiency was higher when the low-viscosity hydroxypropylcellulose according to the present invention was used than when the high-viscosity hydroxypropylcellulose was used.

  From the results of Example 1 and Comparative Examples 1 to 3, it can be seen that the coating particles obtained using the hydroxyalkyl cellulose of the present invention have a low aggregation rate and a high drug layering efficiency.

1: Nuclear particle 2: Guide tube 3: Jet fluidized bed 4: Nozzle SL: Spray liquid Air: Air

Claims (4)

Core particles having a volume average primary particle diameter of 100 μm or less ;
Coated particles having a coating layer containing hydroxypropyl cellulose having a viscosity of 1.10 to 1.95 mPa · s in a 2% aqueous solution at 20 ° C. and a hydroxypropyl group content of 40 to 80% by weight .   The coated particle according to claim 1, wherein the coating layer further comprises drug particles. Volume average primary particles are sprayed with a coating agent containing hydroxypropylcellulose having a viscosity of 1.10 to 1.95 mPa · s in a 2% aqueous solution at 20 ° C. and a hydroxypropyl group content of 40 to 80% by weight. A method for producing a coating particle, comprising attaching the coating agent to the surface of a core particle having a diameter of 100 μm or less . Core particles having a volume average primary particle diameter of 100 μm or less are put into a fluidized bed type, spouted bed type or fluidized rolling type coating apparatus , and the viscosity in a 2% aqueous solution at 20 ° C. is 1.10 to 1.95 mPa · s , and A method for producing coated particles, comprising spraying a coating agent containing hydroxypropyl cellulose having a hydroxypropyl group content of 40 to 80% by weight to attach the coating agent to the surface of the core particles.

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