JP2004143071A - Method for producing medicine-containing composite particle and medicine-containing composite particle - Google Patents

Method for producing medicine-containing composite particle and medicine-containing composite particle Download PDF

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Publication number
JP2004143071A
JP2004143071A JP2002308991A JP2002308991A JP2004143071A JP 2004143071 A JP2004143071 A JP 2004143071A JP 2002308991 A JP2002308991 A JP 2002308991A JP 2002308991 A JP2002308991 A JP 2002308991A JP 2004143071 A JP2004143071 A JP 2004143071A
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Japan
Prior art keywords
drug
powder
particles
containing
containing composite
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Pending
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JP2002308991A
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Japanese (ja)
Inventor
Naotoshi Kinoshita
Hiroyuki Tsujimoto
Toyokazu Yokoyama
木下 直俊
横山 豊和
辻本 広行
Original Assignee
Hosokawa Funtai Gijutsu Kenkyusho:Kk
株式会社ホソカワ粉体技術研究所
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Priority to JP2002308991A priority Critical patent/JP2004143071A/en
Publication of JP2004143071A publication Critical patent/JP2004143071A/en
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Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for combining a medicine with one or more kinds of raw material powder without using a liquid binder, in order to prevent the problem that the stabilization of the medicine is deteriorated by contact with a liquid. <P>SOLUTION: The method for producing medicine-containing composite particles is characterized by involving a process for adding a compression force and a shear force to medicine-containing particles containing the medicine and polymer powder to coat the surfaces of the medicine-containing particles with the polymer. The medicine is combined with the other raw material powder without using the liquid binder. Thereby, the highly functional medicine-containing composite particles combined with the medicine can be produced in a stable state as such. <P>COPYRIGHT: (C)2004,JPO

Description

[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a method for producing drug-containing composite particles, which is effective for improving the surface characteristics of a powder raw material and enhancing the function of drug-containing drug-containing particles, and to drug-containing composite particles.
[0002]
[Prior art]
Pharmaceutical preparations are required to have various properties such as, for example, ease of handling (handling properties) during production, masking of bitterness, control of solubility, and DDS (Drug Delivery System) properties. In order to impart properties, a plurality of raw materials are compounded to form composite particles. Examples of the composite particles in which a plurality of raw materials are composited include those in which the excipient and the drug are composited, and those in which the surface of the drug is covered with a lubricant or a coating agent.
[0003]
Here, the excipient improves the handleability of the drug, and plays a role in facilitating formulation into a desired form, and the lubricant plays a role in making the surface of the drug smooth and shiny. The coating agent plays a role of masking, for example, the bitter taste of the drug by covering the surface of the drug.
[0004]
In addition, many of the drug-containing particles containing a drug are granulated with various additives and then subjected to a functional coating treatment for masking bitterness, controlling elution, and compounding the particles. In these operations, a wet granulation technique such as a tumbling fluidized bed granulation method or a stirring granulation method is used, and the drug-containing particles as granules are coated with a liquid coating agent.
[0005]
Common problems with this type of wet coating method include the generation of agglomerated particles due to the formation of liquid cross-links between the drug-containing particles, the excessive addition of the liquid coating agent, the excessive increase in the hardness of the granules, or the granulation. Examples thereof include those caused by the interposition of a liquid substance such as a residual solvent in the body and a temporary dissolution phenomenon of the granules.
[0006]
In addition, there is also a problem that it becomes difficult to coat efficiently with the miniaturization of the particle diameter of drug-containing particles generally used.
[0007]
Conventional methods for producing composite particles include, for example, the production of spherical fine particles by introducing a binder solution into a mixture of an excipient powder and a drug powder having the property of retaining a solvent and subjecting the mixture to high-speed tumbling granulation. (See Patent Document 1).
[0008]
Further, as a conventional method for producing composite particles containing a sublimable drug, a method of subjecting ibuprofen, which is a sublimable drug, to undercoating of a saccharide followed by film coating (see Patent Document 2), a film substrate and polyethylene glycol (See Patent Document 3), a method of coating a water-insoluble compound on an ibuprofen-containing granule, and coating the surface with a sugar alcohol or a saccharide (see Patent Document 3). Patent Literature 4).
[0009]
[Patent Document 1]
JP-A-2000-128774 (published May 9, 2000)
[0010]
[Patent Document 2]
JP-A-2002-241275 (released on August 28, 2002)
[0011]
[Patent Document 3]
JP-A-11-5736 (published on January 12, 1999)
[0012]
[Patent Document 4]
JP-A-7-173057 (released on July 11, 1995)
[0013]
[Problems to be solved by the invention]
However, the methods for producing composite particles disclosed in Patent Documents 1 to 4 are all wet composite methods using a solution of a binder as a binder. For this reason, it is necessary to dry the binder after the compounding, it is necessary to adjust the temperature in the device used for the compounding, and furthermore, the device used for the wet compounding method is generally a device scale. However, there is a problem that adjustment takes a long time.
[0014]
In addition, the medicinal component of a drug is less stable than the solid state when dissolved in a liquid.Therefore, in a wet compounding method, the medicinal component dissolves in a binder during the compounding process and the stability is reduced. There is also a problem that the storage stability of the drug is reduced.
[0015]
For this reason, in the case of compounding a raw material containing a medicinal component in which it is particularly important to ensure stability, a compounding method that requires a short time for the compounding and does not cause a problem of a decrease in the stability of the medicinal component is desired. I have.
[0016]
The present invention has been made in order to solve the above problems, and an object of the present invention is, for example, to improve the surface characteristics of a powder and improve the handleability of the drug-containing composite. An object of the present invention is to provide a method for producing particles and a drug-containing composite particle.
[0017]
[Means for Solving the Problems]
The inventor of the present application has conducted intensive studies in order to solve the above-mentioned problems, and as a result of applying a compressive force and a shear force to a mixture of two or more powder raw materials to form a composite, a binder solution is used as a binder. They have found that drug-containing composite particles having good storage stability can be produced without using them, and have completed the present invention.
[0018]
That is, in order to solve the above-mentioned problems, the method for producing drug-containing particles of the present invention comprises applying a compressive force and a shearing force to the drug-containing particles and the polymer compound powder containing the drug, and Is characterized by including a coating step of coating the surface with a polymer compound.
[0019]
According to the above configuration, the surface of the drug-containing particles can be coated by spreading the polymer compound powder on the surface of the drug-containing particles without using a binder. Therefore, it is effective for controlling the dissolution rate of the drug, masking for stabilizing the drug for the purpose of preventing moisture, preventing oxidation, or removing bitterness, and the like. Therefore, the method for producing drug-containing composite particles of the present invention is very useful for designing drug formulation particles.
[0020]
For example, by adjusting the type and thickness of the polymer compound that coats the drug powder in accordance with the properties of the drug, the elution rate and elution site can be controlled. Specifically, the thickness of the polymer compound is adjusted depending on whether the site where the drug is to be absorbed is the stomach or intestine, and the drug can be exposed on the surface of the drug-containing composite particles at a desired site. .
[0021]
In addition, when a sublimable drug is used as the drug powder, the sublimation is prevented by the polymer compound film formed in the coating step, so that the storage stability of the drug-containing composite particles can be improved. .
[0022]
Before the coating step, the drug-containing composite particles of the present invention are subjected to a compounding step of applying a compressive force and a shearing force to a mixture of two or more kinds of powder raw materials including a drug powder to form compound-containing particles. May be further included.
[0023]
According to the above configuration, two or more kinds of powder raw materials including a drug powder can be compounded in a short time without deteriorating the stability of the drug powder, so that a drug containing a high function such as high operability is provided. Composite particles can be produced.
[0024]
Conventionally, in the compounding of a powder raw material including a drug powder, a liquid has been used as a binder having a function of bonding particles. For this reason, there has been a problem that a long time is required for adjusting the machine and drying the binder, and the stability of the drug is reduced by dissolving the drug in the binder at the time of compounding.
[0025]
On the other hand, the present invention provides a compounding step of applying a compressive force and a shearing force to a mixture composed of two or more kinds of powder raw materials including a drug powder to form a drug-containing particle, thereby using a drug powder without using a binder. It can be compounded with other powder raw materials.
[0026]
This eliminates the need for a preparation step of pre-adjusting the internal temperature of the apparatus during the compounding and a drying step of drying the binder. Can be compounded. In addition, since the drug powder is not dissolved in the binder at the time of compounding and the stability is not reduced, the compound is formed in a solid state with high stability.
[0027]
Further, in a conventional compounding method using a binder (hereinafter, referred to as a wet compounding method), it was not possible to compound a raw material which is altered by being dissolved in a liquid. On the other hand, since the method for producing the drug-containing composite particles of the present invention does not use a binder, it is possible to form a composite while securing the stability of a raw material that is altered by being dissolved in a liquid. it can. That is, as compared with the conventional method, the choices of the drug powder used for compounding and other powder materials are increased, and it is possible to produce more types of drug-containing composite particles.
[0028]
Therefore, two or more kinds of powder raw materials including the drug powder can be compounded in a short time without deteriorating the stability of the drug powder. That is, since the method for producing drug-containing particles of the present invention does not require a liquid binder, it has a feature that the material applicability is wide and the treatment process can be configured extremely simply. By such a compounding method using mechanical and chemical energy, that is, a compounding method not requiring a liquid binder (hereinafter, referred to as a dry compounding method), a function of another powder material is added to a specific powder material. Thus, highly functional drug-containing composite particles can be easily obtained. In the present invention, the term “composite” refers to a process in which a compressive force, a shearing force, a collision force, or the like is applied to a plurality of different powder raw materials to bond (bond) another raw material to the surface of the specific powder raw material. Say.
[0029]
In the method for producing a drug-containing composite particle of the present invention, the mixture may include a core particle. Thereby, in the compounding step, the drug powder can be spread on the surface of the core particle, and the surface of the core particle can be coated with the drug. For this reason, for example, even if the drug powder has a high cohesiveness, the solubility can be adjusted by preventing the agglomeration and adjusting the surface area within a desired range.
[0030]
Furthermore, by selecting the particle size and shape of the core particles, the particle size and shape of the drug-containing composite particles can be easily adjusted to desired ranges. Here, the shape of the drug-containing composite particles is also affected by the amount of the drug powder to be composited. Therefore, the shape of the drug-containing composite particles can be arbitrarily controlled by selecting the core particles and adjusting the amount of the drug powder to be composited. The bitterness can be masked by coating the drug in the coating step.
[0031]
For this reason, the present invention relates to the use of a rapidly disintegrating buccal tablet to be chewed in the mouth without water and having a particle size of 100 μm or less, and that bitterness is masked. It is particularly suitable as a method for producing orally rapidly disintegrating tablet granules required for improving the feeling. Preferably, the core particles are selected from the group consisting of celluloses and starches.
[0032]
The method for producing a drug-containing composite particle of the present invention is particularly preferably used when the stability of the above-mentioned drug in a state of being dissolved or dispersed in a solvent is inferior to the stability in a dry state. be able to.
[0033]
That is, as described above, the method for producing the drug-containing composite particles of the present invention is a dry composite method without using a binder. For this reason, the present invention can promote the decomposition of a drug that is promoted by dissolving or dispersing in a solvent, without promoting the decomposition, that is, a compound with good stability can be obtained. . The solvent includes, for example, water, alcohols such as ethanol and methanol, acetone, dichloromethane, and alkanes (eg, n-hexane).
[0034]
The method for producing a drug-containing composite particle of the present invention is a method for preparing a polymer compound powder by removing the dispersion medium from the polymer compound dispersion in which the polymer compound is dispersed in the dispersion medium before the coating step. The method may further include a step of coating the surface of the drug-containing particles with the polymer compound powder.
[0035]
With the above structure, a more uniform and high-density polymer compound film can be formed. Here, the polymer compound powder having a small particle diameter (particle diameter: about 0.01 μm to 100 μm) may be stored in a state of being dispersed in a dispersion medium in order to improve the handleability. Many. Then, the polymer compound having such a small particle diameter can be made into a powder by the powdering step. Therefore, in the coating step, the surface of the drug-containing particles is coated with the polymer compound powder having a small particle diameter, and a uniform and high-density film can be formed.
[0036]
The method for producing drug-containing composite particles of the present invention is useful when the drug powder is ibuprofen, that is, a method for producing drug-containing composite particles containing ibuprofen.
[0037]
Here, since ibuprofen is a sublimable drug, it is necessary to prevent sublimation in order to improve its storage stability.However, in the present invention, the ibuprofen has a high surface area of the drug-containing particles containing ibuprofen in the coating step. A film of a molecular compound can be formed. Therefore, sublimation of ibuprofen can be prevented by the polymer compound film, and the storage stability of the drug-containing composite particles can be improved.
[0038]
The drug-containing composite particles of the present invention, in order to solve the above-described problems, a core particle, a drug powder layer that covers the surface of the core particle, a drug powder layer containing a drug powder, And a molecular compound layer having an average particle diameter of 100 μm or less.
[0039]
As described above, the drug-containing composite particles of the present invention are obtained by covering the surface of the core particles with the drug powder layer by the polymer compound layer. Therefore, the bitterness of the drug powder can be masked by the polymer compound layer. Further, since the average particle size is 100 μm or less, the feeling of taking such as tongue is good, and it is suitable as a rapidly disintegrating tablet granule in the oral cavity. Here, the average particle diameter refers to a value obtained by calculating the particle diameter assuming that the particle is a true sphere based on the area of the projected image of the particle.
[0040]
Further, for example, when the drug powder is a sublimable drug having sublimability, the polymer compound layer can prevent sublimation and improve storage stability.
[0041]
The drug-containing composite particles of the present invention are characterized in that the drug powder is ibuprofen. Ibuprofen is one of drugs having a sublimation property, and the above polymer compound layer can prevent the sublimation and improve the storage stability. In addition, ibuprofen is a drug having strong cohesiveness, but by spreading ibuprofen on the surface of the above-mentioned core particles, the surface area is increased to prevent the dissolution efficiency at the time of administration from being reduced due to coagulation, and dissolution is prevented. You can also control it.
[0042]
BEST MODE FOR CARRYING OUT THE INVENTION
First, an embodiment of the present invention will be described below with reference to FIGS.
[0043]
The method for producing drug-containing composite particles of the present embodiment (hereinafter, simply referred to as a production method) is a method of applying a compressive force and a shearing force to a drug-containing particle containing a drug and a polymer compound powder, and A method for producing drug-containing composite particles, which comprises a coating step of coating the surface of the composite with a polymer compound.
[0044]
Here, the drug-containing particles, refers to particles comprising a drug, but is not particularly limited, by applying a compressive force and a shear force to a mixture of a powder raw material including a drug powder and core particles, Composite particles formed by spreading a drug powder on the surface of the core particles to form a composite can be suitably used. By using the core particles, the shape of the drug-containing composite particles can be easily controlled.
[0045]
The drug-containing particles only need to contain a drug, and are not limited to composite particles obtained by combining core particles and drug particles. The drug-containing particles may be, for example, those composed of drug particles alone, or those composed of powder particles other than the drug powder, such as lubricants, coating agents, ultraviolet scattering agents, and the like, and drug particles. It may be. By using a powder material other than the drug particles according to the properties required for the drug-containing composite particles, it is possible to impart necessary properties to the drug-containing composite particles.
[0046]
For example, by using a excipient as a powder raw material, the tableting characteristics and the like when formulating the drug-containing composite particles can be improved, and a very good product can be obtained. In addition, the use of an ultraviolet scattering agent can impart an ultraviolet protection function to the drug-containing composite particles. In addition, what is necessary is just to use the powder raw material other than a drug powder according to the property requested | required of a drug-containing composite particle, and it may be used by one type or several types.
[0047]
As the excipient, the same as the core particles described below can be used. Examples of the coating agent include hydroxypropyl cellulose, polyethylene glycol, lactose, sucrose, hydroxypropylmethyl, calcium carbonate, talc, titanium oxide, gum arabic, crystalline cellulose, carboxymethylethylcellulose, gelatin and the like.
[0048]
Examples of the ultraviolet scattering agent include fine particle titanium oxide and fine particle zinc oxide. Examples of the lubricant include lactose, sucrose, mannitol, sorbitol and the like.
[0049]
When using composite particles obtained by compounding core particles and drug particles as the drug-containing particles, the production method of the present embodiment comprises, before the coating step, two or more powder raw materials including a drug powder. The method further includes a compounding step of applying a compressive force and a shearing force to the mixture to compound the mixture into drug-containing particles.
[0050]
The drug powder is used as a powder and refers to a drug that can be micronized by applying mechanical energy. The average particle diameter of the drug powder is more preferably 0.01 μm or more and 10 μm or less, and still more preferably 0.01 μm or more and 1 μm or less.
[0051]
The compounding amount of the drug powder is preferably 0.01% by weight or more and 70% by weight or less, more preferably 10% by weight or more and 50% by weight or less of the drug-containing composite particles obtained by complexing. .
[0052]
The core particles preferably have an average particle size larger than that of the drug powder, and the average particle size is preferably in the range of 1 to 1000 times the average particle size of the drug powder. Further, the average particle diameter of the core particles is preferably 1 μm or more and 5000 μm or less, and the compounding amount thereof is preferably 90% by weight or less and 50% by weight or less of the drug-containing composite particles obtained by the complexation. Is more preferable.
[0053]
By setting the average particle diameter and the compounding amount of the drug powder and the core particles within the above ranges, the composite of the drug powder and the core particles can be made more reliable.
[0054]
Examples of the above-mentioned drugs include antipyretic analgesic anti-inflammatory agents, steroidal anti-inflammatory agents, antitumor agents, coronary vasodilators, peripheral vasodilators, antibiotics, synthetic antibacterial agents, antiviral agents, antitussives, antitussives, and sputum Agents, bronchodilators, inotropic agents, diuretics, muscle relaxants, cerebral metabolism improvers, minor tranquilizers, major tranquilizers, β-blockers, antiarrhythmic agents, gout treatments, anticoagulants, thrombolytics, for liver diseases Drugs, antiepileptic drugs, antihistamine drugs, antiemetic drugs, antihypertensive drugs, drugs for hyperlipidemia, sympathomimetics, oral antidiabetic drugs, oral anticancer drugs, alkaloid narcotics, vitamins, pollakiuria, angiotensin converting enzyme inhibitor Agents and the like are used.
[0055]
Examples of the antipyretic analgesic antiinflammatory include, for example, indomethacin, aspirin, diclofenac sodium, ketoprofen, ibuprofen, mefenamic acid, azulene, phenacetin, isopropylantipyrine, acetaminophen, benzadac, phenylbutazone, flufenamic acid, sodium salicylate, salicylamide, sazapyrin , Etodolac and the like. Examples of the steroid anti-inflammatory agent include dexamethasone, hydrocortisone, prednisolone, and triamcinolone. Examples of the antitumor agent include ecabet sodium, enprostil, sulpiride, cetraxate hydrochloride, gefarnate, irsogladine maleate, cimetidine, ranitidine hydrochloride, famotidine, nizatidine, roxatidine hydrochloride acetate and the like.
[0056]
Examples of the above coronary vasodilator include nifedipine, isosorbide dinitrate, diltiazem hydrochloride, trapidil, diviridamol, dilazep hydrochloride, verapamil, nicardipine hydrochloride, veraparimil hydrochloride and the like. Examples of the peripheral vasodilator include ifenprodyl tartrate, cinepaside maleate, cyclanderate, cinnarizine, pentoxifylline and the like. Examples of the antibiotic include ifenprodil tartrate, cinepaside maleate, cyclandate, cinnarizine, pentoxifylline and the like.
[0057]
Examples of the synthetic antibacterial agent include nalidixic acid, pyromidic acid, pipemidic acid trihydrate, enoxacin, sinoxacin, ofloxacin, norfloxacin, ciprofloxacin hydrochloride, and sulfamethoxazole / trimethoprim. Examples of the antiviral agent include acyclovir, ganciclovir and the like. Examples of the antiseptics include propantheline bromide, atropine sulfate, oxapium bromide, timepidium bromide, butyl scopolamine bromide, trospium chloride, butropium bromide, N-methylscopolamine methyl sulfate, methyloctalopine bromide and the like. No.
[0058]
Examples of the antitussive include tipepidine hibenzate, methylephedrine hydrochloride, codeine phosphate, tranilast, dextromethorphan hydrobromide, dimemorphane phosphate, clobutinol hydrochloride, hominoben hydrochloride, benproperin phosphate, epradinone hydrochloride, clofedanol hydrochloride , Ephedrine hydrochloride, noscapine, pentoxiverine citrate, oxerazine citrate, isoaminyl citrate and the like. Examples of the above-mentioned exfoliating agents include bromhexine hydrochloride, carbocisteine, ethylcysteine hydrochloride, methylcysteine hydrochloride and the like. As the bronchodilator, for example, theophylline, aminophylline, sodium cromoglycate, procaterol hydrochloride, trimethokinol hydrochloride, diprofylline, salbutamol sulfate, chlorprenaline hydrochloride, formoterol fumarate, orciprenaline sulfate, pirbuterol hydrochloride, hexoprenaline sulfate, bitolterol mesylate , Clenbuterol hydrochloride, terbutaline sulfate, mabuterol hydrochloride, fenoterol hydrobromide, methoxyphenamine hydrochloride and the like.
[0059]
Examples of the cardiotonic agents include dopamine hydrochloride, dobutamine hydrochloride, docarpamine, denopamine, caffeine, digoxin, digitoxin, ubidecarenone and the like. Examples of the diuretic include furosemide, acetazolamide, trichlormethiazide, methyclothiazide, hydrochlorothiazide, hydroflumethiazide, ethiazide, cyclopenthiazide, spironolactone, triamterene, fluorothiazide, piretanide, mefurside, ethacrynic acid, azosemide, and closemide. Can be Examples of the muscle relaxant include chlorphenesin carbamate, tolperisone hydrochloride, eperisone hydrochloride, tizanidine hydrochloride, mefenesin, chlorzoxazone, fenprobamate, methocarbamol, chlormezanone, pridinol mesylate, afloqualone, baclofen, dantrolene sodium and the like. Can be
[0060]
Examples of the above brain metabolism improving agent include nicergoline, meclofenoxate hydrochloride, taltirelin and the like. Examples of the minor tranquilizer include oxazolam, diazepam, clothiazepam, medazepam, temazepam, fludiazepam, meprobamate, nitrazepam, chlordiazepoxide and the like. Examples of the major tranquilizer include sulpiride, clocapramine hydrochloride, zotepine, chlorpromazine, haloperidol, and the like.
[0061]
Examples of the β-blocker include bisoprolol fumarate, pindolol, probranolol hydrochloride, carteolol hydrochloride, metoprolol tartrate, labetanol hydrochloride, acebutolol hydrochloride, bufetrol hydrochloride, alprenolol hydrochloride, arotinolol hydrochloride, oxprenolol hydrochloride, Nadolol, bucmorol hydrochloride, indenolol hydrochloride, timolol maleate, befnolol hydrochloride, bupranolol hydrochloride and the like. Examples of the above antiarrhythmic agents include procainamide hydrochloride, disopyramide phosphate, cibenzoline succinate, adimarin, quinidine sulfate, aplindine hydrochloride, propaphenone hydrochloride, mexiletine hydrochloride, azimilide hydrochloride and the like. Examples of the gout therapeutic agent include allopurinol, probenecid, colchicine, sulfinpyrazone, benzbromarone, bucolome and the like.
[0062]
Examples of the blood coagulation inhibitor include ticlopidine hydrochloride, dicoumarol, warfarin potassium, (2R, 3R) -3-acetoxy-5- [2- (dimethylamino) ethyl] -2,3-dihydro-8-methyl-2. -(4-methylphenyl) -1,5-benzothiazepine-4 (5H) -one maleate and the like. Examples of the thrombolytic agent include methyl (2E, 3Z) -3-benzylidene-4- (3,5-dimethoxy-α-methylbenzylidene) -N- (4-methylpiperazin-1-yl) succinate / hydrochloride And the like. Examples of the agent for liver disease include (±) r-5-hydroxymethyl-t-7- (3,4-dimethoxyphenyl) -4-oxo-4,5,6,7-tetrahydrobenzo [b] furan. -C-6-carboxylic acid lactone and the like.
[0063]
Examples of the antiepileptic agent include phenytoin, sodium valproate, metalpital, carbamazepine and the like. Examples of the antihistamine include chlorpheniramine maleate, clemastine fumarate, mequitazine, alimemazine tartrate, cyclohebutazine hydrochloride, bepotastine besylate, and the like. Examples of the above-mentioned antiemetic include diphenylidol hydrochloride, metoclopramide, domperidone, betahistine mesylate, trimebutine maleate and the like.
[0064]
Examples of the antihypertensive agent include dimethylaminoethyl reserpine hydrochloride, resinamine, methyldopa, pralozosine hydrochloride, bunazosin hydrochloride, clondin hydrochloride, budralazine, urapidil, N- [6- [2-[(5-bromo-2-pyrimidinyl) oxy] ] Ethoxy] -5- (4-methylphenyl) -4-pyrimidinyl] -4- (2-hydroxy-1,1-dimethylethyl) benzenesulfonamide sodium salt. Examples of the agent for hyperlipidemia include pravastatin sodium and fluvastatin sodium. Examples of the above sympathetic stimulants include dihydroergotamine mesylate, isoproterenol hydrochloride, and ethylephrine hydrochloride.
[0065]
Examples of the therapeutic agent for oral diabetes include glibenclamide, tolbutamide, sodium glymidine and the like. Examples of the oral anticancer agent include Marimastat. Examples of the alkaloid narcotics include morphine, codeine, cocaine and the like.
[0066]
Examples of the above-mentioned vitamin preparation include vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, folic acid and the like. Examples of the therapeutic agent for pollakiuria include flavoxate hydrochloride, oxybutynin hydrochloride, and terolidine hydrochloride. Examples of the angiotensin converting enzyme inhibitors include imidapril hydrochloride, enalapril maleate, alacepril, delapril hydrochloride and the like.
[0067]
It is preferable that the drug has a stability in a state of being dissolved or dispersed in a solvent, which is inferior to a stability in a dry state. Examples of such a drug include insulin, sodium cromoglycolic acid, etenzazamide, and sazapyrine. , Salicylamide, sodium salicylate, allylisopropylacetylurea, bromvalerylurea, acetaminophen, lactylphenesin, aspirin and its aluminum salts, alloclamide hydrochloride, cloperastine hydrochloride, dextromethorphan hydrobromide, tipetidine hippenate, phosphorus Acidine, dihydrocodeine phosphate, anhydrous caffeine, caffeine, aminoacetic acid, magnesium silicate, synthetic hydrotalcite, lysozyme chloride, diphenhydramine salicylate, carbinoxamile maleate , Dl-chlorpheniramine maleate, trimetoquinol Nord chloride, phenylpropanolamine hydrochloride, hydrochloric methoxyphenamine, dl-methylephedrine hydrochloride ephedrine hydrochloride, noscapine hydrochloride, aminophylline, theophylline, vitamin B 1 , Vitamin B 2 And various vitamins such as vitamin C.
[0068]
Examples of the core particles include microcrystalline cellulose, methylcellulose, carmellose sodium, carmellose calcium, celluloses such as low-substituted hydroxypropylcellulose, wheat starch, rice starch, corn starch, potato starch, hydroxypropyl starch, carboxy. Examples include starches such as sodium methyl starch, α-cyclodextrin, and β-cyclodextrin; and polymers such as polymethyl methacrylate (PMMA). Among those exemplified as the core particles, microcrystalline cellulose, corn starch, potato starch and polymethyl methacrylate are preferred. The core particles have an average particle diameter of preferably 1 μm or more and 1000 μm or less, more preferably 10 μm or more and 70 μm or less.
[0069]
The polymer compound powder used in the coating step of the manufacturing method of the present embodiment refers to a powdery polymer compound. Examples of the high molecular compound include acrylic polymers [eg, Eudragit (trade name; Degussa (Germany))] ethyl cellulose [eg, Aquacoat (trade name; Asahi Kasei Kogyo Co., Ltd.)], carboxymethyl cellulose, carmellose , Carmellose calcium, carmellose sodium, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose (eg, hydroxypropylmethylcellulose 2208, hydroxypropylmethylcellulose 2906, hydroxypropylmethylcellulose 2910, etc.), hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, Methyl cellulose etc. are mentioned.
[0070]
Among the polymer compounds exemplified above, Eudragit L100-55 (trade name), which is a spray-dried product of methacrylic acid copolymer-LD, and Aquacoat, which is an aqueous latex type dispersion based on ethylcellulose ( Trade name) is preferred.
[0071]
When the aqua coat is used as the polymer compound in the coating step in the production method of the present embodiment, water is removed from the dispersion obtained by dispersing the ethyl cellulose before the dispersing step, and ethyl cellulose powder (polymer compound (Powder) is required. This pulverization step can be performed by, for example, drying the aqua coat using a spray-drying type fluidized bed granulator (trade name: Agromaster AGM-2SD manufactured by Hosokawa Micron Corporation).
[0072]
By the above-mentioned powdering step, it is possible to produce ethylcellulose powder having a very small particle diameter, so that by using ethylcellulose powder in the above-mentioned coating step, it is possible to form a more uniform ethylcellulose film on the drug-containing particle surface. Becomes possible. Further, in this case, by adding and mixing a pore-forming agent before drying the aqua coat, pores can be formed in the polymer compound layer on the surface of the drug-containing particles. This makes it possible to release the drug in the drug-containing particles from the pores.By adjusting the amount of the pore-forming agent added and mixed, the sustained release of the drug from the drug-containing particles can be improved. Adjustment is also possible.
[0073]
The conditions such as the temperature, time, compressive force and shearing force in the coating step can be appropriately set according to the type and blending ratio of the drug-containing particles and the polymer compound powder.
[0074]
The powder processing apparatus used in the manufacturing method of the present embodiment may be any apparatus that can apply a strong compressive force and a strong shearing force to the powder raw material including the drug powder, 3 Pa or more 3 × 10 7 Compression force less than Pa and 1 × 10 3 Pa or more 1 × 10 7 What can give the shearing force of Pa or less is preferable. As the powder processing apparatus, for example, a mixer, a kneader, a ball mill, or the like having a strong stirring force can be used.
[0075]
(Powder processing equipment)
With reference to FIG. 1 and FIG. 2, the principle of a particle-compositing apparatus that can be used in the method for producing drug-containing composite particles of the present embodiment and an overview of the apparatus will be described.
[0076]
As shown in FIG. 1, the powder processing apparatus 1 generally includes a casing 2 that forms a substantially cylindrical closed space, and a cylindrical rotating section that is provided inside the casing 2 and that has a substantially cylindrical shape with a bottom. And a press head 4 disposed inside the cylindrical rotary member 3 to generate a compressive force and a shearing force on the inner peripheral surface of the cylindrical rotary member 3 to process the workpiece. .
[0077]
By rotating the cylindrical rotator 3, the receiving surface 5 formed on the inner peripheral surface of the cylindrical rotator 3 and the press head 4 are relatively rotated, and as shown in FIG. The compounding process is performed by applying a compressive force and a shearing force to the workpiece 7 existing in the pressing portion 6 formed as a gap between the press head 5 and the press head 4. Particles supplied as the processing target 7 are pressed against the receiving surface 5 of the inner wall of the container by centrifugal force, and receive a strong compressing / shearing force between the press head 4 and the receiving surface 5 to perform a particle composite process. Is made.
[0078]
As shown in FIG. 1, inside the casing 2, there is provided a cylindrical rotating body 3 having a substantially cylindrical shape and rotatable around a vertical rotation axis X. The cylindrical rotating body 3 includes a rotating shaft 12, a bottom 14 connected to the rotating shaft 12, and a cylindrical wall 15 connected to the bottom 14.
[0079]
In the powder processing apparatus 1 used in the present embodiment, the bottom portion 14 of the cylindrical rotating body 3 serves as a processing object removing means for actively circulating the processing object 7 with respect to the pressing section 6. Slits 8 penetrating the cylindrical wall 15 of the cylindrical rotating body 3 are formed at a plurality of locations in the vicinity. The slit 8 is for excluding a part of the processing target 7 held by the pressing portion 6 to the outside of the processing space 9 while the cylindrical rotating body 3 is being driven and rotated, which will be described later. As described above, all the objects 7 are sequentially circulated and supplied to the pressing portion 6. Since the mechanism for the sequential circulation supply is provided for the purpose of large-capacity processing, it can be omitted in a small-scale apparatus used in a laboratory.
[0080]
The casing 2 constituting the powder processing apparatus 1 is supported by a support member (not shown), and is mounted and fixed on a base (not shown). Inside the casing 2, a closed processing space 9 for processing the workpiece 7 is formed. The casing 2 has a workpiece inlet 10. At a part of the bottom peripheral edge of the casing 2 main body, there is provided a workpiece inlet 11 for taking out the workpiece 7 after the processing. With the above configuration, it is possible to continuously process the workpiece 7.
[0081]
The rotating shaft 12 is rotatably attached to a base (not shown) via a bearing (not shown). Then, a driving force is transmitted to a pulley (not shown) of the rotating shaft portion 12 by a motor attached to the base and a driving belt (not shown) connected to the motor, and 3 is driven to rotate. By rotating and driving the cylindrical rotator 3, a centrifugal force acts on the object 7, and the object 7 is pressed against the receiving surface 5 of the cylindrical rotator 3.
[0082]
The bottom portion 14 of the cylindrical rotator 3 has a function of connecting the rotary shaft portion 12 and the cylindrical wall portion 15 of the cylindrical rotator 3 and a function as a holding unit for holding the workpiece 7. . That is, the bottom portion 14 has a relationship in which the surfaces thereof are bent in relation to a cylindrical wall portion 15 described later, and when the cylindrical rotating body 3 rotates, the workpiece 7 is pressed without being sufficiently processed. It is prevented from escaping downward from the part 6.
[0083]
The inner peripheral surface of the cylindrical wall portion 15 serves as the receiving surface 5 of the object 7 to be moved outward under the centrifugal force. That is, the workpiece 7 is held on the pressing portion 6, and a compressive force and a shearing force are applied to the workpiece 7 in cooperation with the receiving surface 5 and the press head 4 to perform the compounding process.
[0084]
Here, in the coating step of the manufacturing method according to the present embodiment, a compressive force and a shearing force are applied to the mixture of the drug particles and the polymer compound powder as the object to be treated 7, so that the surface of the drug-containing particles has a high level. The molecular compound powder is spread and its surface is covered with a film of the polymer compound.
[0085]
In the compounding step of the present embodiment, a compressive force and a shearing force are applied to the mixture as the object to be treated 7, whereby the drug powder and other powder raw materials are compounded to form drug-containing particles. You. When the mixture contains core particles whose particle size is larger than that of the drug powder, the drug powder is spread on the surface of the core particles and is covered with a polymer compound film. It will be.
[0086]
Further, a plurality of slits 8 are formed near the bottom of the cylindrical wall 15 as shown in FIG. The slit 8 penetrates the receiving surface 5, that is, the cylindrical wall portion 15, and is provided, for example, at two positions symmetrically with respect to the rotation axis X of the cylindrical wall portion 15. The slit 8 is for discharging a part of the processing target 7 held by the pressing part 6 to the outside of the pressing part 6 and functions as a unit for discharging the processing target 7. The slit 8 is formed so that the ratio of the opening area on the lower side is larger than that on the upper side so that, for example, the processing target 7 held below the receiving surface 5 is discharged more.
[0087]
In the present embodiment, for example, the slit 8 is formed in a truncated semicircular shape. The workpiece 7 is pressed against the receiving surface 5 by the centrifugal force, and at the same time, is affected by gravity. For this reason, in the case of the cylindrical wall portion 15 shown in FIG. 1, the workpiece 7 tends to move vertically downward and accumulate near the boundary between the receiving surface 5 and the bottom portion 14. The workpiece 7 deposited on this portion increases the rotational load of the cylindrical rotating body 3 and inhibits the circulation of the workpiece 7 to the pressing portion 6. Therefore, the inconvenience is solved by positively discharging the processing object 7 deposited on the relevant portion through the slit 8, and the efficiency of the compounding process is improved.
[0088]
According to the above configuration, most of the processing object 7 existing in the pressing portion 6 is discharged out of the pressing portion 6 through the slit 8. Therefore, the object to be processed 7 is held in the pressing portion 6 for a certain period of time, and a compressive force and a shearing force are applied, so that the compounding process is reliably performed.
[0089]
A press head 4 is provided inside the cylindrical rotator 3 at a predetermined interval on the receiving surface 5. The press head 4 applies a compressive force and a shearing force to the workpiece 7 in cooperation with the receiving surface 5. Therefore, the horizontal cross-sectional shape of the press head 4 is, for example, a semicircular shape as shown in FIG. With the above-described configuration, the object 7 to be intruded between the press head 4 and the receiving surface 5 is compacted, and an advantageous effect can be obtained for compounding and spheroidizing the powder particles.
[0090]
When the horizontal cross-sectional shape of the press head 4 is a semicircular shape, the curvature is made larger than the curvature of the surface 5. As a result, the workpiece 7 fixed to the receiving surface 5 of the cylindrical rotator 3 receives a strong compressive / shearing force when passing through the pressing portion 6 due to the rotation of the cylindrical rotator 3. Here, when a plurality of types of mixtures are used as the object to be processed 7, the particles are subjected to strong compressive and shearing forces, and are thereby combined with the particles, the surface of the particles is modified, the shape of the particles is controlled, and the fine precision dispersion at the particle level is performed. Mixing (powder fusion) or the like occurs, and the particle characteristics can be controlled.
[0091]
Further, the press head 4 may be configured to be fixed similarly to the casing 2, or may be configured to be rotationally driven using some driving means and positively rotated relative to the receiving surface 5. That is, by appropriately setting the rotation direction or the rotation speed of the press head 4, the relative rotation speed between the press head 4 and the receiving surface 5 can be set more finely, and the optimum processing conditions according to the workpiece 7 can be set. Can be set. The temperature of the press head 4 may be controlled. For example, though not shown, if a heat medium passage is secured inside the press head 4, the temperature may be optimized according to the thermal characteristics of the workpiece 7. It becomes easy to set various processing conditions.
[0092]
A circulation blade 16 is provided below the outer periphery of the casing 2. A plurality of the circulation blades 16 are provided along the circumferential direction of the cylindrical rotating body 3, but the number is arbitrary. The circulation blade 16 is for recirculating the workpiece 7 discharged from the slit 8 to the outside of the cylindrical rotary member 3 to the pressing portion 6 again. The circulating blade 16 raises the workpiece 7 along the outer peripheral surface of the cylindrical wall portion 15, returns the workpiece 7 to the processing space 9 of the cylindrical rotating body 3 beyond the upper end of the cylindrical wall portion 15, and returns the pressure to the pressing portion. In order to smoothly and surely transport the casing 2 back to 6, the casing 2 is formed so as to conform to the inner surface shape of the casing 2.
[0093]
By processing the processing target 7 using the powder processing apparatus 1 having the above-described configuration, the processing target 7 is pressed against the receiving surface 5 of the cylindrical rotating body 3 by centrifugal force, and is subjected to an assembling operation to receive the receiving surface. In 5, a layer of the processing target 7 in a compacted state is generated. On the other hand, a part of the compacted workpiece 7 is discharged to the outside of the cylindrical rotary body 3 through the slit 8, and the workpiece 7 existing inside the cylindrical rotary body 3 is The press head 4 receives a certain amount of stirring action. Therefore, the composite processing of the processing target 7 can be promptly advanced.
[0094]
As described above, according to the powder processing apparatus 1, the processing object 7 is introduced into the processing space 9 through the processing object input port 10 of the casing 2, and the cylindrical rotating body 3 and the press head 4 are more powerful. Compounding is performed by receiving compression and shearing forces. Further, since the slit 8 is formed on the wall surface of the cylindrical rotator 3, the mixture is sent to the outside of the processing space 9 of the cylindrical rotator 3 through the slit 8 of the cylindrical rotator 3. Then, the processing object 7 sent to the outside is conveyed to the upper part of the cylindrical rotating body 3 by the circulation blade 16 as shown in FIG. It will again receive compressive and shearing forces. As described above, the object 7 is subjected to the strong compressive / shearing force repeatedly by the cylindrical rotary member 3 and the press head 4, whereby the compounding process is effectively performed.
[0095]
Note that the powder processing apparatus 1 may be capable of appropriately changing the atmosphere inside the casing 2, that is, the atmosphere in the processing space 9 according to the type of the workpiece 7 and the like. For example, various gases such as an inert gas and a heated gas are introduced into the inside of the casing 2 from the above-mentioned workpiece inlet 10, or the inside of the casing 2 is pressurized and depressurized using a pressurization / vacuum pump or the like. It may be configured. In this case, for example, by providing a seal member (not shown) between the casing 2 and the rotating shaft portion 12 of the cylindrical rotating body 3, the atmosphere inside the processing space 9 can be reliably adjusted.
[0096]
A jacket 13 for adjusting mainly the temperature of the processing space 9 is provided around the casing 2. A heating medium or a cooling medium from a separately provided tank (not shown) is circulated and supplied to the jacket 13 as needed. Thereby, the internal temperature of the casing 2 can be adjusted. For example, in the case of treating a drug that may be degraded by a change in temperature as the object to be processed 7, a heating medium or a cooling medium is circulated and supplied to the jacket 13 so that the temperature of the object to be processed 7 during processing is controlled. The temperature of the drug can prevent the deterioration of the drug.
[0097]
Although the case of using the powder processing apparatus 1 has been described, the powder processing apparatus that performs the method for producing drug-containing composite particles according to the present embodiment is not limited to this. For example, it is possible to apply a strong compressive force and a shear force to the powder raw material, a mixer or a stirrer having a strong stirring force, a ball mill, or the like, the drug-containing composite particles of the present embodiment, A manufacturing method can be implemented.
[0098]
Subsequently, other conditions when the manufacturing method of the present embodiment is performed will be described below.
[0099]
The method of introducing the mixture containing the drug powder and the polymer compound powder into a powder processing apparatus is not particularly limited, and, for example, the polymer compound powder may be charged in a state where the mixture is mixed in advance, or And these may be separately charged and mixed in a powder processing apparatus. The order of charging when both are charged separately is not particularly limited, and both may be charged simultaneously.
[0100]
When the mixture and the polymer compound powder are separately charged, the mixture may be divided into a plurality of times and then composited. By charging the polymer compound powder in a plurality of times, a number of layers corresponding to the number of times of charging are formed.
[0101]
Further, by further adding the powder raw material to the drug-containing composite particles obtained by compounding two or more kinds of powder raw materials to form a composite, a layer of the powder raw material is further formed on the surface of the drug-containing composite particles. The Rukoto. In this way, by charging the powder raw material in a plurality of times, it is possible to obtain drug-containing composite particles having a multilayered powder raw material layer formed on the surface.
[0102]
In addition, the powder raw materials to be charged in a plurality of times may be of the same type or different types. By supplying the same kind of powder raw material in a plurality of times, a plurality of layers are formed by the same kind of powder raw material, so that the surface of the powder raw material to be coated can be surely covered with the covering powder raw material. In addition, by dispensing different kinds of powder materials in plural times for each type, it is possible to obtain drug-containing composite particles in which a plurality of layers of different types of powder materials are formed on the surface of the powder material to be coated. Can be. Therefore, it is possible to obtain drug-containing composite particles in which layers of a plurality of types of drug powders are formed. For example, a drug-containing composite particle obtained by compounding a powder material to be coated and a drug powder that dissolves in the intestine to exhibit a function is further combined with a drug powder that dissolves in the stomach to exhibit a function. As a result, layers of a plurality of types of drug powders are formed, and after ingestion into the human body, drug-containing composite particles that sequentially exhibit different functions over time can be obtained. Thus, it becomes possible to provide a plurality of properties to the drug-containing composite particles.
[0103]
The temperature at the time of compounding is not particularly limited as long as it is within a temperature range in which the powder raw material does not deteriorate. In addition, when using a powder raw material having a property of being deteriorated by heat, the powder raw material or the powder processing apparatus is cooled while the powder raw material or the powder processing apparatus is cooled in order to prevent the powder raw material from being deteriorated due to a rise in temperature during the compounding. It shall be. Thereby, it is possible to prevent the powder raw material from being deteriorated during the compounding.
[0104]
In the coating step, the time for applying the compressive force and the shearing force may be appropriately determined depending on the size of the powder processing apparatus, the type and amount of the polymer compound to be coated, and is not particularly limited. Processing time can be in the range of 5 minutes to 60 minutes. The end point of the coating is determined by evaluating the product characteristics (the characteristics of the drug-containing composite particles obtained by changing the treatment time) by a test in which the treatment time is changed.
[0105]
In the compounding step, the time for applying the compressive force and the shearing force may be appropriately determined depending on the size of the powder processing apparatus, the type and amount of the powdery material to be compounded, and is not particularly limited. The processing time can be between 5 and 20 minutes. The end point of the above treatment is determined by evaluating the product characteristics (the characteristics of the drug-containing composite particles obtained by changing the treatment time) by a test in which the treatment time is changed.
[0106]
In addition, since the method for producing the drug-containing composite particles of the present embodiment is a method that does not use a binder, it is not necessary to adjust the temperature of the inside of the powder processing apparatus to a temperature suitable for this, and the binder is not used. No need to dry. For this reason, the drug-containing composite particles can be obtained in a shorter time than in the conventional composite method using a binder.
[0107]
In order to apply a compressive force and a shearing force to a mixture comprising two or more kinds of powder raw materials including a drug powder, the rotation speed of the powder processing device depends on the size of the powder processing device, the type and amount of the powder raw material, etc. The rotation speed may be determined as appropriate, but is preferably 50 rpm (revolutions per minute) or more and 5000 rpm or less, more preferably 1000 rpm or more and 3000 rpm or less.
[0108]
(Drug-containing composite particles)
As shown in FIG. 3, the drug-containing composite particles 30 obtained by the production method of the present embodiment include carrier particles (core particles) 31 and a drug that covers the surface of the carrier particles 31 and includes a drug powder. It comprises a powder layer 32 and a polymer compound layer 33 covering the drug powder layer.
[0109]
As described above, in the drug-containing composite particles 30 of the present embodiment, the drug powder layer 32 formed by spreading a large number of drug powders on the surface of one carrier particle 31 is formed. On the surface, a polymer compound layer 33 formed by further spreading a polymer compound powder is formed.
[0110]
Since the carrier particles 31 located in the innermost layer of the drug-containing composite particles 30 are composed of one particle, the drug-containing composite particles can be easily controlled by controlling the particle diameter and shape of the carrier particles 31. The particle diameter and shape of the particles 30 can be made desired.
[0111]
Further, since the drug powder layer 32 is formed on the surface of the carrier particles 31, even if the drug constituting the drug powder layer 32 is a substance such as ibuprofen having high cohesiveness, it contributes to wetting. Since the obtained effective surface area per unit weight can be increased, the elution rate of the drug can be improved.
[0112]
Further, on the surface of the drug powder layer 32, a polymer compound layer 33 is further formed. For this reason, for example, when the drug powder layer 32 is a sublimable drug, the storage stability of the drug-containing composite particles 30 is improved by suppressing the sublimation, or the bitterness of the drug in the drug powder layer 32 is masked. Or you can.
[0113]
Further, by changing the type and thickness of the polymer compound according to the function required of the polymer compound layer 33, the necessary function can be imparted to the drug-containing composite particles 30. For example, by adjusting the permeability and thickness of the polymer compound constituting the polymer compound layer 33, it is also possible to adjust the release speed (slow release) of the drug contained in the drug powder layer 32. It is.
[0114]
For example, the drug-containing composite particles 30 are formed on the surface of the carrier particles 31 by a drug powder layer 32 made of a drug powder to be caused to act on the intestine, By configuring with. The drug powder layer 32 is prevented from dissolving in the stomach, and the drug powder can be dissolved in the intestine. Thus, the drug can work effectively by ensuring that the drug reaches the organ to be acted on.
[0115]
The carrier particles 31 are those exemplified as the core particles, the drugs constituting the drug powder layer 32 are those exemplified above as the drugs, and the polymer compound layers 33 are those exemplified as the above polymers. , Respectively.
[0116]
In order to spread the drug powder on the surface of the carrier particles 31 and cover the drug powder with the drug powder layer 32, the shape of the carrier particles 31 is preferably spherical, and the particle diameter of the carrier particles 31 and the drug powder layer 32 Those having a large difference from the particle size of the drug powder are preferably used. Further, the particle diameter of the carrier particles 31 is preferably at least three times the particle diameter of the drug powder layer 32, and more preferably at most 1,000 times.
[0117]
In order to spread and cover the polymer powder on the surface of the drug powder layer 32, the particle diameter of the polymer compound powder is larger than the particle diameter of the drug-containing particles composed of the carrier particles 31 and the drug powder layer 32. Is also preferably small.
[0118]
As described above, the drug-containing composite particles 30 of the present embodiment are obtained by mixing and processing two types of host particles (large particles) and guest particles (small particles) having different particle diameters at a fixed ratio. High energy is efficiently applied to the particle group, and the guest particle group receives a strong spreading action on the surface of the host particle to form a coating layer, and both particles are composited.
[0119]
As described above, by masking the surface of the drug-containing particles containing the drug powder with the polymer compound, the masking of the bitterness of the drug, the handleability of the drug, tableting properties, solubility, DDS properties, etc. are adjusted. The obtained drug-containing composite particles can be obtained.
[0120]
【Example】
An example in which drug-containing composite particles that are high-performance composite particles are produced by the method for producing drug-containing composite particles of the present invention will be described below. However, the present invention is not limited to the following examples.
[0121]
(Particle composite equipment)
In the following examples, the powder processing apparatus 1 described in the above embodiment with reference to FIGS. 1 and 2 was used as an experimental particle composite apparatus (dry particle composite apparatus). In addition, the powder processing apparatus 1 can replace the casing 2 according to the processing amount. Hereinafter, the case where the casing 2 corresponding to the processing amount of about 50 cc is mounted is referred to as AM-Mini, about 600 cc to 800 cc. AMS-Lab equipped with the casing 2 corresponding to the throughput is referred to as AMS-Lab.
[0122]
(Drug-containing particles)
In the method for producing the drug-containing composite particles of the present invention, the drug-containing particles coated with the polymer compound will be described below with reference to FIGS.
[0123]
In the formulation of poorly soluble drugs, it is required to improve the solubility and absorbability of the drug. Drug powders (drug particles) are refined by mechanical pulverization or crystallization to increase the specific surface area and improve solubility. However, fine particles are bulky and have strong particle adhesion. It cannot be used as it is.
[0124]
Therefore, a high-performance preparation was obtained by compounding a drug powder and carrier particles (core particles) into drug-containing particles (composite particles, composite particles). Specifically, by changing the processing speed of AM-mini, microcrystalline cellulose as carrier particles (average particle diameter: 100 μm (trade name; Selfia CP-102, manufactured by Asahi Kasei Corporation)) and melting point of 76 ° C. And ibuprofen (average particle size: 30 μm) as a drug powder having high cohesiveness was compounded.
[0125]
In the compounding treatment (composite step), 8 parts by weight of microcrystalline cellulose and 2 parts by weight of ibuprofen (hereinafter, parts by weight are simply referred to as "parts") are added to AM-mini at a time, and the particle temperature is reduced to 40C or lower. The rotation speed of the rotating shaft portion 12 was 1750 (rpm) to 2250 (rpm), and the processing time was 10 minutes. FIGS. 4A to 4E show scanning electron microscope (SEM) photographs of the ibuprofen-containing particles thus obtained.
[0126]
As the number of rotations of the rotating shaft portion 12 increases to 1750 rpm, 2000 rpm, and 2250 rpm, the specific surface area of the ibuprofen-containing particles becomes 0.216 (m 2 / G), 0.186 (m 2 / G), 0.117 (m 2 / G). The critical areas of the ibuprofen powder and microcrystalline cellulose before the complexing treatment were 0.501 (m 2 / G) and 0.0572 (m 2 / G).
[0127]
That is, the specific surface area of the ibuprofen-containing particles tends to decrease as the rotation speed of the rotation shaft portion 12 increases. This can be confirmed also from the images of the SEM photographs in FIGS.
[0128]
As is clear from the comparison between FIGS. 4A and 4B and FIGS. 4C to 4E, the morphology of the surface of the ibuprofen-containing particles, that is, the morphology, is the raw material particles due to the composite treatment. It is different from ibuprofen and microcrystalline cellulose. That is, it is observed that a dense and strong drug powder layer (coating layer) made of ibuprofen is formed on the surface of microcrystalline cellulose by the complexing treatment.
[0129]
Also, referring to FIG. 5, which shows the effect of the complexing treatment intensity and treatment time on the specific surface area of the complexed ibuprofen-containing particles, not only the bonding energy (complexing treatment strength) increases, but also the continuation of treatment, It was observed that the specific surface area of the ibuprofen-containing particles tended to decrease even when the treatment time was extended. Note that the processing strength in FIG. 5 is defined by the number of rotations of the rotating shaft portion 12 or the same rotating power. In addition, “processing intensity: small” shown by using a solid line and “processing intensity: large” shown by using a broken line in the same drawing are the rotation speeds of 1500 rpm and 2500 rpm, respectively, as the processing intensity. Shows the case.
[0130]
As described above, in order to form a drug powder layer (coating layer), it is necessary to apply a strong mechanical energy to the particles to exert a compressive / shearing action. Therefore, there is a concern that drug stability may be affected by generation of undesired reactants or loss of crystals (amorphization) due to a reaction between particles.
[0131]
However, it has already been confirmed that powder raw materials such as drug powders are not affected by the above-mentioned complexing treatment. Specifically, UV measurement, FT-IR measurement, X-ray diffraction (XRD) measurement, thermal analysis (DSC) measurement, inductively coupled plasma emission analysis (ICP-AES: quantitative analysis of metal contamination Fe, Cr / impurity element) For example, in the processing of a powder processing apparatus (AM-Mini, AMS-Lab), the degree of denaturation and contamination (contamination of impurity elements) of drug powder and other powder raw materials as raw materials must be below the detection limit. Have confirmed.
[0132]
As an example of the above measurement results, an ibuprofen-containing compound obtained by compounding microcrystalline cellulose [average particle size: 150 μm (trade name; Selfia CP-203, manufactured by Asahi Kasei Corporation)] and ibuprofen (average particle size: 30 μm) FIG. 6 shows the measurement results of the ultraviolet absorption spectrum of the particles, and FIG. 7 shows the measurement results of the X-ray diffraction.
[0133]
As shown in FIG. 6, the UV spectrum shows the measurement result of ibuprofen as a raw material (a) The measurement result of untreated and the measurement result of ibuprofen present in the ibuprofen-containing particles as a composite (b) (26 ° C.) and no significant difference was observed. Further, as shown in FIG. 7, no difference was confirmed between the simple mixed product obtained by simply mixing ibuprofen and microcrystalline cellulose and the ibuprofen-containing particles obtained by the composite treatment, from the X-ray diffraction spectrum. Was.
[0134]
An advantage of such a complexing process is that drug elution can be controlled. FIG. 8 is a graph showing the results of measuring the effect of complexation on the dissolution rate of ibuprofen in water. In addition, the elution rate means that at room temperature (25 ° C.), ibuprofen-containing particles were placed in 1 liter of water, and the proportion of ibuprofen in the ibuprofen-containing particles that had been dissolved in water was measured using a spectrophotometer. It was determined by measuring the absorbance, and the dissolution test was a Japanese Pharmacopoeia dissolution test (Paddle method, JP).
[0135]
The figure shows that the drug powder alone (ibuprofen only), the drug particles and the carrier particles are mixed with Nautamixer (trade name, manufactured by Hosokawa Micron), and the drug powder is mixed with the carrier particles. It is shown that the ibuprofen-containing particles (complexed at 26 ° C.) have different ibuprofen elution rates. Specifically, it is shown that the dissolution rate of ibuprofen from the ibuprofen-containing particles is much higher than that of ibuprofen alone and the simple mixture.
[0136]
This is considered to be the result of spreading the highly cohesive ibuprofen on the surface of the carrier particles, thereby increasing the effective specific surface area of the particles that can contribute to elution.
[0137]
[Example 1]
One embodiment of the present invention is described below with reference to FIG. In the present example, the above-described AM-Mini was used for the compounding process (compositing step) and the coating process (coating step). It has been confirmed that similar results can be obtained by using AMS-Lab instead of AM-Mini.
[0138]
Ibuprofen is a drug with a large dose, and its content in the drug-containing composite particles is preferably as large as possible. Therefore, in this example, a drug-containing particle having a higher ratio of ibuprofen than the above-described ibuprofen-containing particle was prepared, and the surface of the drug-containing particle was coated with a polymer compound to form a drug-containing composite particle. Ibuprofen-containing composite particles were produced.
[0139]
In this example, carrier particles (core particles) having a smaller particle diameter than the above-described ibuprofen-containing particles were used. Specifically, microcrystalline cellulose particles having a particle diameter of 80 μm or less, obtained by sieving microcrystalline cellulose (trade name; Selfia SCP-100) having an average particle diameter of 100 μm as carrier particles, were used.
[0140]
50 parts of the microcrystalline cellulose particles and 50 parts of ibuprofen (average particle diameter: 30 μm) as a drug powder are put into the AM-Mini at a time and cooled by a jacket (water-cooled jacket) on the outer peripheral part of the AM-Mini. The particle temperature was set to 40 ° C. or less, and the rotation speed of the rotating shaft portion 12 was set to 2500 (rpm).
[0141]
9 (a) and 9 (b) are scanning electron microscope (SEM) photographs of microcrystalline cellulose before composite, and FIGS. 9 (c) and 9 (d) are composites of microcrystalline cellulose and ibuprofen. It is an image of the SEM photograph of the ibuprofen-containing particles after performing.
[0142]
FIG. 9A shows an SEM photograph of microcrystalline cellulose having a particle diameter larger than 100 μm. As shown in FIG. 9B, the microcrystalline cellulose used as carrier particles in this example is Particles having a distribution of particle diameters and having a particle diameter of 80 μm or less were actually used as described above.
[0143]
As shown in FIGS. 9C and 9D, in this example, the carrier particles having a particle diameter of 80 μm or less were used, and the particle diameter of the ibuprofen-containing particles could be reduced to about 100 μm. For this reason, the ibuprofen-containing particles of the present embodiment have a good tongue even when taken as they are without water, and are very suitable as intraorally rapidly disintegrating tablet granules used for intraorally rapidly disintegrating tablets.
[0144]
While keeping the particle temperature at 40 ° C. or less and keeping the number of revolutions of the rotating shaft 12 at 2500 (rpm), the methacrylic acid copolymer LD (Eudragit L30D-55: trade name Degussa) is added to the ibuprofen-containing particles obtained as described above. The treatment was continued while gradually adding Eudragit L100-55 (trade name of Degussa), which is a spray-dried powder of Co., Ltd., until the final addition amount was reached (coating step). Thus, drug-containing composite particles in which the surface of the ibuprofen-containing particles was coated with Eudragit as a polymer compound were produced.
[0145]
The amount of Eudragit L100-55 to be added is adjusted according to the function required for the polymer compound film formed in the coating step. The treatment time may be a time sufficient for gradually adding the polymer compound, and is usually about 5 to 20 minutes.
[0146]
As described above, after compounding microcrystalline cellulose and ibuprofen, Eudragit L100-55 was added, and Eudragit L100-55 was bonded to the surface to form a film, so that the bitterness unique to ibuprofen was reduced. Because of the masking, it became more suitable as an orally rapidly disintegrating tablet granule. Furthermore, by increasing the bonding amount of Eudragit L100-55, acid resistance can be imparted and enteric-coated drug-containing composite particles can be obtained.
[0147]
Hereinafter, formulation examples of the drug-containing composite particles according to the functions required for the polymer compound film will be described.
[0148]
Formula 1 (moisture-proof coating)
Microcrystalline cellulose 46-47 parts
Ibuprofen 46-47 parts
Eudragit 6-8 copies
Formula 2 (bitter masking)
Microcrystalline cellulose 44-46 parts
Ibuprofen 44-46 parts
Eudragit 8-12 parts
Formulation 3 (enteric solubility treatment)
Microcrystalline cellulose 40 parts
Ibuprofen 40 parts
Eudragit 20 parts.
[0149]
As described above, the compound particles contained in the present example can control the elution of ibuprofen by spreading the highly cohesive drug ibuprofen on the surface of the carrier particles. Furthermore, since ibuprofen is a sublimable drug having a strong sublimation property, Eudragit, which is an acrylic polymer, was formed into a film on the surface of the ibuprofen-containing particles by the coating process, thereby preventing sticking. Specifically, even after being stored in a plastic container in a sealed state at 60 ° C. for 4 weeks, the fluidity was good and the preservability was good.
[0150]
Further, the drug-containing composite particles of this example have an average particle size of 100 μm or less, and a polymer compound film is formed on the surface thereof, so that the particle size is small and the bitterness is masked. I have. For this reason, it can be used very suitably as a rapidly disintegrating tablet in the oral cavity required for improving the feeling of taking such as tongue.
[0151]
[Example 2]
Another embodiment of the present invention will be described below with reference to FIGS. In this example, the AM-Mini was used for the compounding process (compositing step) and the coating process (coating step), as in the above example. It has been confirmed that similar results can be obtained by using AMS-Lab instead of AM-Mini.
[0152]
Example 1 In this example, a method for producing multi-layered drug-containing composite particles for the purpose of controlling the sustained release of a drug powder on the surface of carrier particles (core particles) will be described. The drug-containing composite particles of the present example were prepared by coating microcrystalline cellulose (average particle size: 150 μm (trade name; Selfia CP-102, manufactured by Asahi Kasei Corporation)) as a carrier particle on ethenzamid (an antipyretic analgesic, (Average particle diameter: 7 μm, melting point: 133 ° C.), and by bonding ethylcellulose fine particles to the surface of the ethenzamide layer of the ethenzamide-containing particles, a drug powder layer is formed by coating with a film of ethylcellulose as a polymer compound. Was sealed.
[0153]
In the complexation, 40 parts of microcrystalline cellulose and 6 parts of ethenzamide are collectively charged into the AM-Mini, the particle temperature is 30 ° C., the number of rotations of the rotating shaft 12 is 2,000, and the processing time is 15 minutes. did. Subsequently, 10 parts of ethylcellulose powder as a polymer compound was added to AM-mini over 10 minutes to prepare etensamide-containing composite particles (multilayer composite particles) as drug-containing composite particles.
[0154]
FIGS. 10A to 10G show images of scanning electron micrographs of the multilayer composite particles thus produced. The multilayer composite particles (ethenzamide-containing composite particles) shown in FIGS. 9 (d) and 9 (e) are obtained by compounding the microcrystalline cellulose shown in FIG. 9 (a) with the ethenamide shown in FIG. This is obtained by adding ethylcellulose microparticles to the thus-formed ethenzamide-containing particles of FIG. 3C and performing a complexing treatment (coating treatment) at a low temperature (30 ° C.). By comparing FIG. 10 (d) and FIG. 10 (e), as the amount of ethylcellulose fine particles (prepared by drying aqua coat) increases, the state of spreading of ethylcellulose on the entire surface of the multilayer composite particles increases. Is improved.
[0155]
On the other hand, FIG. 10 (g) shows ethenzamide-containing composite particles (multilayer composite particles) that have been subjected to a composite treatment and a coating treatment at a particle temperature (apparatus temperature) of 70 ° C. FIG. 10 (g) shows that ethenzamide-containing particles (FIG. 10 (f)) obtained by performing a complexing treatment at a particle temperature (apparatus temperature) of 70 ° C. were treated with ethyl cellulose fine particles at a particle temperature of 70 ° C. To cover the surface.
[0156]
From the image of FIG. 10 (g), it can be seen that the spreading and fixing state of ethyl cellulose is further improved by performing the complexing treatment and the coating treatment at the particle temperature of 70 ° C. as compared with the case of processing at the particle temperature of 30 ° C. I understand. As described above, the complexing process which can be considered to be difficult to obtain complex particles of the same quality as the conventional wet fluidized bed coating method (wet complexing method) is a dry method (dry complexing method). ) Is also possible.
[0157]
In this example, ethylcellulose fine particles (ethylcellulose particle group) used as the polymer compound powder were obtained by spray coating an aqua coat (trade name: Aquacoat ECD, manufactured by Asahi Kasei Kogyo Co., Ltd.), which is frequently used as a wet coating agent. It was dried using a granulator (trade name: Agromaster AGM-2SD manufactured by Hosokawa Micron Corporation). A method for drying the aqua coat to obtain ethyl cellulose fine particles will be described below.
[0158]
(Preparation method of aquacoat dry powder as a moisture-proof and bitter masking base)
In order to dry-treat Aquacoat (a water-based latex based on ethylcellulose) as a moisture-proof capsule base, a 30% weight loss was carried out using Agromaster AGM-2SD (trade name), a spray-drying fluidized-bed granulator made by Hosokawa Micron. Aquacoat, which is an aqueous latex of solid content, was dried as follows to obtain ethylcellulose fine particles.
[0159]
Supply liquid: Aquacoat only
Operating conditions
Aquacoat spray nozzle spray speed: 20 g / min
Spray air volume: 30L
Agromaster dry air volume: 1m 3 / Min
Agromaster dry air temperature: 100 ℃
Product temperature: 50 ° C
The ethylcellulose fine particles produced as described above can be suitably used when it is necessary to mask the bitter taste of a drug. The bitterness can be masked by bonding the ethyl cellulose fine particles (aqua coat fine particles) to the surface of the drug.
[0160]
(Preparation method of aquacoat dry powder as sustained release base)
In order to dry-process the aqua coat as a sustained-release base, the aqueous latex having a solid content of 30% by weight was dried with a spray-drying type fluidized bed granulator Agromaster AGM-2SD (trade name) manufactured by Hosokawa Micron. Ethyl cellulose fine particles capable of forming pores were produced.
[0161]
Here, the ethylcellulose fine particles capable of forming pores refer to fine particles in which a water-soluble hydroxypropylmethylcellulose forms a matrix inside the ethylcellulose fine particles. Since the water-soluble portion dissolves in the body and pores are formed in ethyl cellulose, the sustained release of the drug can be adjusted by adjusting the amount of the water-soluble matrix.
[0162]
Supply liquid: 95.9 parts of aquacoat (base), 2.7 parts of triethyl citrate (plasticizer, Tokyo Chemical Industry), and 1.4 parts of hydroxypropylmethylcellulose (pore former, Shin-Etsu Chemical) Mixed solution
Operating conditions
Spraying speed of the mixed solution with a spray nozzle of 20 g / min
Spray air volume: 30L
Agromaster dry air volume: 1m 3 / Min
Agromaster dry air temperature: 100 ℃
Product temperature: 50 ° C
The ethylcellulose fine particles produced as described above can be suitably used when it is necessary to release the drug gradually after taking the drug (sustained release). By bonding the ethylcellulose fine particles (aquacoat fine particles) to the surface of the drug, the sustained release of the drug can be controlled.
[0163]
Into the AM-mini, 40 parts of microcrystalline cellulose and 6 parts of ethenzamide were charged at a time, the particle temperature was set to 30 ° C., the number of rotations of the rotating shaft part 12 was set to 2,000, and the processing time was set to 15 minutes to produce ethenzamide-containing particles. did. Aqua-coated microparticles as a sustained-release base as polymer compound powder were added to AM-mini over 15 minutes to the ethenzamide-containing microparticles, and the resulting mixture was mixed with ethenzamide-containing composite particles (multi-layer composite particles) as drug-containing composite particles. ) Was prepared.
[0164]
Ethenzamide-containing composite particles were prepared by setting the amount of the sustained-release base as the polymer compound powder to 0% by weight, 5% by weight, 10% by weight, and 15% by weight with respect to the etenzamide-containing composite particles, The dissolution rate was measured for each. The result is shown in FIG. In this example, the dissolution rate was also measured by the above-mentioned paddle method of the Japanese Pharmacopoeia.
[0165]
FIG. 11 shows that by bonding aquacoat microparticles as a sustained release base, it is possible to suppress the elution of etenzamide and release it gradually, that is, to release etenzamide slowly.
[0166]
In the above-described examples, the compounding treatment of the drug powder and other powder materials by the method for producing the drug-containing composite particles of the present invention was examined. Carrier particles are combined with drug powder on the surface, and other drug powders and polymer compounds as elution control bases are combined on the surface.Composite treatment is performed by scanning electron microscope observation and dissolution test. It was clear that was done. In addition, macroscopic damage to the drug due to the injection of the bonding energy of the processed product was not detected by X-ray crystal diffraction measurement, thermal analysis, or the like.
[0167]
In addition, since the method for producing the drug-containing composite particles of the present invention is a dry method that does not use a liquid as a binder, even if the drug becomes unstable when wet with a liquid such as water, the stability may be impaired. And can be easily compounded. As another application, for example, by bonding a fine additive to the surface of lactose particles and smoothing it, it can be used as carrier particles for inhalation preparations.
[0168]
As described above, the method for producing a drug-containing composite particle of the present invention is very useful for a unique particle design based on a new viewpoint of a drug particle group containing a drug.
[0169]
【The invention's effect】
As described above, the method for producing drug-containing particles of the present invention comprises applying a compressive force and a shearing force to the drug-containing particles comprising a drug and the polymer compound powder to cause the surface of the drug-containing particles to be a polymer compound. And a coating step of coating with.
[0170]
Therefore, the surface of the drug-containing particles can be coated by spreading the polymer compound powder on the surface of the drug-containing particles without using a binder. Thereby, it is possible to control the elution rate of the drug, to prevent moisture, to prevent oxidation, and to mask the bitter taste, without causing a decrease in the stability of the drug due to the binder.
[0171]
Further, before the coating step, the method further includes a compounding step of applying a compressive force and a shearing force to a mixture of two or more kinds of powder raw materials including the drug powder to form a compound into drug-containing particles. Is also good.
[0172]
As a result, the compound can be compounded in a short time without deteriorating the stability of the drug powder, so that it is possible to produce stable drug-containing particles with high functions.
[0173]
Further, the mixture may contain core particles. Thereby, for example, even if the drug powder has a high cohesiveness, the effect is obtained that the coagulation can be prevented and the solubility can be adjusted.
[0174]
In addition, it is preferable that the stability of the above-mentioned drug in a state of being dissolved or dispersed in a solvent is inferior to that of a dry state.
[0175]
Further, the method for producing the drug-containing composite particles of the present invention, before the coating step, to remove the dispersion medium from the polymer compound dispersion in which the polymer compound is dispersed in the dispersion medium to obtain a polymer compound powder It may further include a powdering step.
[0176]
Thereby, there is an effect that a more uniform and high-density polymer compound film can be formed.
[0177]
The drug-containing composite particles of the present invention are composed of a polymer compound layer covering the drug powder layer, and have an average particle diameter of 100 μm or less.
[0178]
Therefore, the bitterness of the drug powder can be masked by the polymer compound layer. Further, since the average particle diameter is 100 μm or less, the feeling of taking such as the tongue feel is good. Therefore, there is an effect that drug-containing composite particles suitable as rapidly disintegrating tablets in the oral cavity can be provided.
[Brief description of the drawings]
FIG. 1 is a cross-sectional view showing one configuration example of a powder processing apparatus used for carrying out the method for producing a drug-containing composite particle of the present invention.
FIG. 2 is a cross-sectional view illustrating an operation when applying a compressive force and a shearing force to an object to be processed by the powder processing apparatus shown in FIG.
FIG. 3 is a cross-sectional view showing one embodiment of the drug-containing composite particle of the present invention.
FIGS. 4A and 4B are images of a scanning electron micrograph explaining the complexation of microcrystalline cellulose and ibuprofen, (a) showing an image of ibuprofen, (b) showing an image of microcrystalline cellulose, and (c) showing an image of microcrystalline cellulose. 1B shows an image of the ibuprofen-containing particles composited at 1750 rpm, (d) shows an image of the ibuprofen-containing particles composited at a rotation speed of 2,000 rpm, and (e) shows an image of the ibuprofen-containing particles composited at a rotation speed of 2250 rpm. An image is shown.
FIG. 5 is a graph showing the effect of the treatment intensity and treatment time of the composite of microcrystalline cellulose and ibuprofen on the specific surface area of the composite ibuprofen-containing particles.
FIG. 6 is a spectrum showing a measurement result of an ultraviolet absorption spectrum of ibuprofen before and after complexation.
FIG. 7 is a spectrum showing measurement results of X-ray diffraction of ibuprofen before and after complexation.
FIG. 8 is a graph showing the results of measuring the effect of the complexation on the dissolution rate of ibuprofen in water.
9 (a) and 9 (b) are scanning electron micrograph images of microcrystalline cellulose before complexation, and FIGS. 9 (c) and 9 (d) are ibuprofen-containing composites after microcrystalline cellulose and ibuprofen are complexed. It is a scanning electron micrograph image of a particle.
FIG. 10 is an image of a scanning electron microscope photograph for explaining a process of sequentially forming a layer of ethenzamide and a layer of ethyl cellulose on the surface of microcrystalline cellulose to form multilayer composite particles. (B) shows an image of ethenzamide, (c) shows particles containing ethenzamide composited at a processing temperature of 30 ° C., and (d) and (e) show composites at a processing temperature of 30 ° C. (F) shows ethenzamide-containing composite particles composited at a processing temperature of 70 ° C., and (g) · shows ethenzamide-containing composite particles composited at a processing temperature of 70 ° C. .
FIG. 11 is a graph showing the results of measuring the effect of complexation on the dissolution rate of etenzamide in water.
[Explanation of symbols]
30 Drug-containing composite particles
31 Carrier particles (nuclear particles)
32 Drug powder layer
33 High molecular compound layer

Claims (8)

  1. A drug-containing composite particle comprising a coating step of applying a compressive force and a shearing force to a drug-containing particle comprising a drug and a polymer compound powder to coat the surface of the drug-containing particle with a polymer compound. Manufacturing method.
  2. The method according to claim 1, further comprising, before the coating step, a compounding step of applying a compressive force and a shearing force to a mixture comprising two or more kinds of powder raw materials including the drug powder to form a compound into drug-containing particles. Item 10. A method for producing a drug-containing composite particle according to Item 1.
  3. The method for producing drug-containing composite particles according to claim 2, wherein the mixture contains core particles.
  4. 4. The drug-containing composite particle according to claim 1, wherein the drug has a lower stability in a state of being dissolved or dispersed in a solvent than a stability in a dry state. Method.
  5. Prior to the coating step, further comprising a powdering step of removing the dispersion medium from the polymer compound dispersion in which the polymer compound is dispersed in the dispersion medium to obtain a polymer compound powder,
    The method for producing a drug-containing composite particle according to any one of claims 1 to 4, wherein the coating step covers the surface of the drug-containing particle with the polymer compound powder.
  6. The method for producing drug-containing composite particles according to any one of claims 1 to 5, wherein the drug powder is ibuprofen.
  7. Nuclear particles,
    A drug powder layer covering the surface of the core particles, comprising a drug powder,
    And a polymer compound layer covering the drug powder layer,
    A drug-containing composite particle having an average particle diameter of 100 μm or less.
  8. The drug-containing composite particle according to claim 7, wherein the drug powder is ibuprofen.
JP2002308991A 2002-10-23 2002-10-23 Method for producing medicine-containing composite particle and medicine-containing composite particle Pending JP2004143071A (en)

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JP2006521287A (en) * 2002-12-20 2006-09-21 エスティ.ジェイムス アソシエイト エルエルシー/フェイバー リサーチ シリーズ High pressure compression for pharmaceutical formulations
WO2008018371A1 (en) * 2006-08-08 2008-02-14 Kissei Pharmaceutical Co., Ltd. Oral disintegrating tablet having masked bitter taste and method for production thereof
JP2009007295A (en) * 2007-06-28 2009-01-15 Kowa Co Solid preparation suppressing ibuprofen sublimation
JP2009114148A (en) * 2007-11-09 2009-05-28 Tokyo Printing Ink Mfg Co Ltd Microparticle dry coating preparation
WO2009110056A1 (en) * 2008-03-03 2009-09-11 エナックス株式会社 Powder treating apparatus
JP2013151565A (en) * 2013-05-13 2013-08-08 Kowa Co Solid preparation in which sublimation of ibuprofen is controlled
JP2013155124A (en) * 2012-01-30 2013-08-15 Moriroku Chemicals Co Ltd Bulk powder of medicine and method of producing the same
JP2016034922A (en) * 2014-08-02 2016-03-17 敏幸 丹羽 Production method for composite particles of pharmaceutical bulk powders and pharmaceutical additives, and composite particles produced by method thereof
JP2017500297A (en) * 2013-11-26 2017-01-05 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング Preparation of powdered pharmaceutical composition by cryomilling
US10201502B2 (en) 2011-07-29 2019-02-12 Gruenenthal Gmbh Tamper-resistant tablet providing immediate drug release
US20190083628A1 (en) * 2016-02-23 2019-03-21 Nipro Corporation Pharmaceutical composition particles and orally disintegrating preparation including the same
US10300141B2 (en) 2010-09-02 2019-05-28 Grünenthal GmbH Tamper resistant dosage form comprising inorganic salt
US10335373B2 (en) 2012-04-18 2019-07-02 Grunenthal Gmbh Tamper resistant and dose-dumping resistant pharmaceutical dosage form
US10369109B2 (en) 2002-06-17 2019-08-06 Grünenthal GmbH Abuse-proofed dosage form
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US10369109B2 (en) 2002-06-17 2019-08-06 Grünenthal GmbH Abuse-proofed dosage form
JP2006521287A (en) * 2002-12-20 2006-09-21 エスティ.ジェイムス アソシエイト エルエルシー/フェイバー リサーチ シリーズ High pressure compression for pharmaceutical formulations
WO2008018371A1 (en) * 2006-08-08 2008-02-14 Kissei Pharmaceutical Co., Ltd. Oral disintegrating tablet having masked bitter taste and method for production thereof
JP2009007295A (en) * 2007-06-28 2009-01-15 Kowa Co Solid preparation suppressing ibuprofen sublimation
JP2009114148A (en) * 2007-11-09 2009-05-28 Tokyo Printing Ink Mfg Co Ltd Microparticle dry coating preparation
WO2009110056A1 (en) * 2008-03-03 2009-09-11 エナックス株式会社 Powder treating apparatus
CN102083516A (en) * 2008-03-03 2011-06-01 英耐时有限公司 Powder treating apparatus
US8876368B2 (en) 2008-03-03 2014-11-04 Enax, Inc. Powder treating apparatus
CN102083516B (en) * 2008-03-03 2013-10-09 英耐时有限公司 Powder treating apparatus
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US10493033B2 (en) 2009-07-22 2019-12-03 Grünenthal GmbH Oxidation-stabilized tamper-resistant dosage form
US10300141B2 (en) 2010-09-02 2019-05-28 Grünenthal GmbH Tamper resistant dosage form comprising inorganic salt
US10201502B2 (en) 2011-07-29 2019-02-12 Gruenenthal Gmbh Tamper-resistant tablet providing immediate drug release
JP2013155124A (en) * 2012-01-30 2013-08-15 Moriroku Chemicals Co Ltd Bulk powder of medicine and method of producing the same
US10335373B2 (en) 2012-04-18 2019-07-02 Grunenthal Gmbh Tamper resistant and dose-dumping resistant pharmaceutical dosage form
JP2013151565A (en) * 2013-05-13 2013-08-08 Kowa Co Solid preparation in which sublimation of ibuprofen is controlled
JP2017500297A (en) * 2013-11-26 2017-01-05 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング Preparation of powdered pharmaceutical composition by cryomilling
US10449547B2 (en) 2013-11-26 2019-10-22 Grünenthal GmbH Preparation of a powdery pharmaceutical composition by means of cryo-milling
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