JP2003012504A - Method for producing medicine-containing compounded particle - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce compounded particles containing a medicine as a stable state in a short time. SOLUTION: This method for producing compounded particles containing the medicine is provided by applying a strong compressive force and shearing force on a mixture consisting of >=2 kinds of powdery raw materials including the medicine powder, while passing it through a compressing part 6 of a press head 4 and a receiving surface 5 of a cylindrical rotary body 3 so as to compound the medicine powder with the other powdery raw materials.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing drug-containing composite particles, which is effective for modifying the surface characteristics of a powder raw material and highly functionalizing the drug-containing composite particles.

[0002]

2. Description of the Related Art Pharmaceutical preparations are required to have various characteristics such as ease of handling (handling) during production, masking of bitterness, control of solubility, and DDS (Drug Delivery System) characteristics. Conventionally, a plurality of raw materials have been compounded in order to impart required properties. Examples of the composite of a plurality of raw materials include a composite of a excipient and a drug, and a surface of the drug covered with a lubricant or a coating agent. Here, the above-mentioned excipient improves the handling property of the drug and plays a role of facilitating formulation into a desired form, and the lubricant plays a role of making the surface of the drug smooth and glossy. The coating agent plays a role of masking the bitterness of the drug, for example, by covering the surface of the drug.

As a method of compounding, for example, Japanese Patent Application Laid-Open No. 2
Japanese Patent Publication No. 000-128774 discloses a method for producing spherical fine particles by adding a solution of a binder to a mixture of an excipient powder having a property of retaining a solvent and a drug powder, and performing high speed rolling granulation. ing.

[0004]

However, the composite method disclosed in the above publication is a wet composite method using a solution of a binder as a binder. For this reason, it is necessary to dry the binder after compounding, and it is also necessary to adjust the temperature in the device used for compounding. Furthermore, the device used for the wet compounding method generally has a device scale. However, there is a problem in that adjustment takes a long time.

Further, since the medicinal component of a drug is less stable when dissolved in a liquid than in the solid state, in the wet compounding method, the medicinal component is dissolved in the binder during the compounding treatment and the stability is deteriorated. However, there is also a problem that the storage stability of the drug is deteriorated.

[0006] Therefore, in complexing raw materials containing a medicinal component in which stability is particularly important, there is a complexing method in which the complexing time is short and the stability of the medicinal component is not deteriorated. Is desired.

The present invention has been made to solve the above problems, and its purpose is, for example, useful for modifying the surface characteristics of powder to improve its handleability. It is to provide a method for producing composite particles containing a drug.

[0008]

In order to solve the above problems, the method for producing drug-containing composite particles of the present invention applies a compressive force and a shearing force to a mixture of two or more powder raw materials containing a drug powder. In addition, it is characterized by compounding.

With the above structure, two or more kinds of powder raw materials containing the drug powder can be compounded in a short time without impairing the stability of the drug powder, and thus high functionality such as high operability is imparted. It is possible to produce drug-containing composite particles.

Conventionally, in the composite of powder raw materials containing drug powder, a liquid has been used as a binder having a function of adhering particles. Therefore, there is a problem that it takes a long time to adjust the machine and dry the binder, and the drug is dissolved in the binder at the time of complexing, so that the stability of the drug is lowered.

On the other hand, the present invention includes a drug powder containing 2
This is a method of applying a compressive force and a shearing force to a mixture composed of one or more kinds of powders to form a composite. That is, by applying compressive force and shearing force, the drug powder can be combined with other powder raw materials without using a binder.

As a result, there is no need for a preparatory step for adjusting the temperature inside the apparatus at the time of compounding, and there is no need for a binder drying step. Therefore, as compared with compounding using a conventional binder. Therefore, it can be composited in a short time. Further, during the complexing, the drug powder is not dissolved in the binder and the stability is not lowered, and the complex is formed in the solid state with high stability.

Further, in the conventional conjugation method using a binder, it was not possible to conjugate a raw material which is deteriorated by being dissolved in a liquid. However, the method for producing drug-containing composite particles of the present invention uses a binder. Not the way. For this reason, it is possible to form a composite material while ensuring its stability even with respect to a raw material that is altered by being dissolved in a liquid. That is, compared with the conventional method, the drug powder used for conjugation and other raw material options are increased, and more types of drug-containing composite particles can be produced.

Therefore, the drug-containing composite particles can be produced by complexing two or more powder raw materials containing the drug powder in a short time without lowering the stability of the drug powder. In the present invention, the term "compositing" means that a plurality of different powder raw materials are subjected to mechanical energy such as compressive force, shearing force, or collision force to bond other raw materials to the surface of the specific powder raw material. , To be integrated. According to this compounding method using mechanical energy, a chemical reaction between powder raw materials does not occur, and the function of another powder raw material is added to a specific powder raw material, thereby achieving high-performance composite Particles can be obtained.

Further, the above mixture may contain a excipient powder. Thus, by compounding the drug powder and the excipient powder, for example, drug-containing composite particles having good handleability during formulation can be obtained.

In the method for producing drug-containing composite particles of the present invention, the excipient powder is preferably selected from the group consisting of celluloses and starches.

In the method for producing drug-containing composite particles of the present invention, it is preferable that the average particle size of the excipient powder is 1 to 10,000 times the average particle size of the drug powder. Thereby, since the compounding of the excipient powder and the drug powder can be performed more reliably, for example, the excipient powder whose surface is covered with a uniform layer of the drug powder by the compounding is used. Obtainable.

In the method for producing drug-containing composite particles of the present invention, the above-mentioned excipient powder has an average particle size of 1 μm or more and 50 or more.
It is preferably 00 μm or less.

In the method for producing drug-containing composite particles of the present invention, the average particle size of the drug powder is preferably 0.01 μm or more and 500 μm or less.

In the method for producing drug-containing composite particles of the present invention, the content of the drug powder in the drug-containing composite particles is preferably 0.01% by weight or more and 90% by weight or less.

In the method for producing drug-containing composite particles of the present invention, the drug powder may be an antipyretic analgesic or antiphlogistic.

[0022]

BEST MODE FOR CARRYING OUT THE INVENTION An embodiment of the present invention will be described below with reference to FIGS. 1 and 2.

The method for producing drug-containing composite particles of the present embodiment comprises applying a compressive force and a shearing force to a mixture of two or more kinds of powder raw materials containing a drug powder to compound different kinds of powders. A method for producing drug-containing composite particles.

The above-mentioned drug powder is used as a powder and means a drug which can be made into fine particles by applying mechanical energy. Further, the drug powder preferably has an average particle diameter of 0.01 μm or more and 10 μm or less, and more preferably 0.01 μm or more and 1 μm or less. By using a drug powder having an average particle size within the above range, it is possible to more reliably bond and integrate with another powder raw material by compounding.

The compounding amount of the drug powder is preferably 0.01% by weight or more and 50% by weight or less, more preferably 0.01% by weight or more and 10% by weight or less, of the drug-containing composite particles obtained by the compounding.
It is more preferable that the content is not more than weight%.

Examples of the drug powder include antipyretic and analgesic anti-inflammatory agents, steroidal anti-inflammatory agents, antitumor agents, coronary vasodilators, peripheral vasodilators, antibiotics, synthetic antibacterial agents, antiviral agents, anticonvulsants, Antitussives, expectorants, bronchodilators, cardiotonics, diuretics, muscle relaxants, cerebral metabolism improvers, minor tranquilizers, major tranquilizers, β-blockers, antiarrhythmics, gout remedies, anticoagulants, thrombolytics , Liver disease agents, antiepileptic agents, antihistamines, antiemetics, antihypertensive agents, hyperlipidemia agents, sympathomimetic agents,
Oral antidiabetic agent, oral anticancer agent, alkaloid narcotics,
Vitamin preparations, treatment agents for frequent urination, angiotensin converting enzyme inhibitors, etc. are used.

Examples of the antipyretic analgesic and anti-inflammatory agent include indomethacin, aspirin, diclofenac sodium, ketoprofen, ibuprofen, mefenamic acid,
Azulene, phenacetin, isopropylantipyrine,
Examples include acetaminophen, benzadac, phenylbutazone, flufenamic acid, sodium salicylate, salicylamide, sazapyrine, etodolac and the like.
Examples of the steroidal anti-inflammatory agent include dexamethasone, hydrocortisone, prednisolone, triamcinolone and the like. Examples of the above-mentioned antitumor agent include ecabet sodium, enprostil, sulpiride, cetraxate hydrochloride, gefarnate, irsogladine maleate, cimetidine, ranitidine hydrochloride, famotidine, nizatidine, roxatidine acetate hydrochloride and the like.

Examples of the coronary vasodilators include nifedipine, isosorbide dinitrate, diltiazem hydrochloride, trapidil, diviridamol, dilazep hydrochloride, verapamil, nicardipine hydrochloride, veraparimil hydrochloride.
Examples of the peripheral vasodilator include ifenprodil tartrate, cinepaside maleate, cyclanderate, cinnarizine, pentoxifylline and the like. Examples of the antibiotics include ifenprodil tartrate,
Examples thereof include cinepaside maleate, cyclanderate, cinnarizine, and pentoxifylline.

Examples of the above synthetic antibacterial agents include nalidixic acid, pyromidic acid, pipemidic acid trihydrate, enoxacin, sinoxacin, ofloxacin, norfloxacin, ciprofloxacin hydrochloride, sulfamethoxazole / trimethoprim and the like. Examples of the antiviral agent include acyclovir and ganciclovir. Examples of the antispasmodic agent include propantheline bromide, atropine sulfate, oxapium bromide, timepidium bromide, butylscopolamine bromide, trospium chloride, butropium bromide, N-methylscopolamine methylsulfate, and methyloctaropine bromide. Can be mentioned.

Examples of the antitussive agents include tipepidine hibenzate, methylephedrine hydrochloride, codeine phosphate,
Tranilast, dextromethorphan hydrobromide, dimemorphan phosphate, clobutynol hydrochloride, hominoben hydrochloride, benproperine phosphate, epradinone hydrochloride, clofedanol hydrochloride, ephedrine hydrochloride, noscapine, pentoxyberine citrate, oxerazine citrate, citric acid Examples include isoaminyl and the like. Examples of the above-mentioned stripping agent include bromhexine hydrochloride, carbocysteine,
Examples thereof include ethyl cysteine hydrochloride and methyl cysteine hydrochloride. Examples of the bronchodilators include theophylline, aminophylline, sodium cromoglycate, procaterol hydrochloride, trimethoquinol hydrochloride, diprophylline, salbutamol sulfate, chlorprenaline hydrochloride, formoterol fumarate, orciprenaline sulfate, pyrbuterol hydrochloride, hexoprenaline sulfate, and vitorterol mesylate. , Clenbuterol hydrochloride, terbutaline sulfate,
Examples include mabuterol hydrochloride, fenoterol hydrobromide, and methoxyphenamine hydrochloride.

Examples of the cardiotonic agent include dopamine hydrochloride, dobutamine hydrochloride, docarpamine, denopamine, caffeine, digoxin, digitoxin, and ubidecarenone. Examples of the diuretics include furosemide, acetazolamide, trichlormethiazide, metyclothiazide, hydrochlorothiazide, hydroflumethiazide, ethiazide, cyclopenthiazide, spironolactone, triamterene, fluorothiazide, pyrethanide, mefluside, ethacrynic acid, azosemide, etc. To be Examples of the muscle relaxant include chlorphenesin carbamic acid, tolperisone hydrochloride, eperisone hydrochloride, tizanidine hydrochloride, mephenesin, chlorzoxazone, fenprobamate, methocarbamol, chlormezanone, pridinol mesylate, afroqualone,
Baclofen, dantrolene sodium, etc. are mentioned.

Examples of the cerebral metabolism-improving agent include nicergoline, meclofenoxate hydrochloride, taltirelin and the like. Examples of the above-mentioned minor tranquilizers include oxazolam, diazepam, clothiazepam, medazepam, temazepam, fludiazepam, meprobamate, nitrazepam, chlordiazepoxide and the like. As the above major tranquilizer,
Examples thereof include sulpiride, clocapramine hydrochloride, zotepine, chlorpromazine, haloperidol and the like.

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, oxpreh hydrochloride. Nolol, nadolol, bumolol hydrochloride, indenolol hydrochloride, timolol maleate, befnolol hydrochloride, bupranolol hydrochloride and the like can be mentioned.
Examples of the antiarrhythmic agents include procainamide hydrochloride, disopyramide phosphate, cibenzoline succinate, azimarin, quinidine sulfate, aplindine hydrochloride, propaphenone hydrochloride, mexiletine hydrochloride, and azimilide hydrochloride. Examples of the therapeutic agent for gout include allopurinol, probenecid, colchicine, sulfinpyrazone, benzbromarone, bucolome and the like.

Examples of the blood coagulation inhibitors include ticlopidine hydrochloride, dicoumarol, warfarin potassium,
(2R, 3R) -3-acetoxy-5- [2- (dimethylamino) ethyl] -2,3-dihydro-8-methyl-
2- (4-methylphenyl) -1,5-benzothiazepin-4 (5H) -one maleate and the like can be mentioned. Examples of the thrombolytic agent include methyl (2E, 3
Z) -3-benzylidene-4- (3,5-dimethoxy-
Examples include α-methylbenzylidene) -N- (4-methylpiperazin-1-yl) succinamate / hydrochloride. Examples of the liver disease agent include (±) r-5
Examples thereof include hydroxymethyl-t-7- (3,4-dimethoxyphenyl) -4-oxo-4,5,6,7-tetrahydrobenzo [b] furan-c-6-carboxylic acid lactone.

Examples of the above antiepileptic agents include phenytoin, sodium valproate, metalpital, carbamazepine and the like. Examples of the antihistamines include chlorpheniramine maleate, clemastine fumarate, mequitazine, alimemazine tartrate, cyclohebutazine hydrochloride, bepotastine besylate, and the like. Examples of the antiemetic agent include diphenidol hydrochloride, metoclopramide, domperidone, betahistine mesylate, trimebutine maleate and the like.

Examples of the antihypertensive agent include dimethylaminoethyl reserpine hydrochloride, resinamine, methyldopa,
Pralozosin hydrochloride, bunazosin hydrochloride, Klondine 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 and the like. Examples of the hyperlipidemic agent include pravastatin sodium and fluvastatin sodium. Examples of the sympathomimetic agents include dihydroergotamine mesylate, isoproterenol hydrochloride, etilefrine hydrochloride and the like.

Examples of the therapeutic agent for oral diabetes include glibengramid, tolbutamide, glymidine sodium and the like. Examples of the oral anticancer agent include marimasat. Examples of the alkaloid narcotics include morphine, codeine, cocaine and the like.

Examples of the above vitamin agents include vitamin B1, vitamin B2, vitamin B6, vitamin B12,
Examples include vitamin C and folic acid. Examples of the therapeutic agent for frequent urination include flavoxate hydrochloride, oxybutynin hydrochloride, telolizine hydrochloride and the like. Examples of the angiotensin converting enzyme inhibitor include imidapril hydrochloride, enalapril maleate, alacepril, and delapril hydrochloride.

The powder raw material used in the method for producing drug-containing composite particles of the present embodiment is used as a powder, and means a material which can be made into fine particles by applying mechanical energy.

Powder raw materials other than the above-mentioned drug powders include, for example, excipients, lubricants, coating agents, ultraviolet scattering agents and the like. By using a powder raw material according to the properties required for the drug-containing composite particles, the drug-containing composite particles can be provided with the necessary properties.

For example, when a excipient is used as the powder raw material, the tableting characteristics and the like when the drug-containing composite particles are formulated can be improved and a very good product can be obtained. Further, by using a lubricant or a coating agent, for example, the bitterness of the drug in the drug-containing composite particles can be masked or the solubility of the drug can be suppressed. Further, by using an ultraviolet scattering agent, it is possible to impart an ultraviolet protection function to the drug-containing composite particles. It should be noted that powder raw materials other than the drug powder may be selected according to the properties required for the drug-containing composite particles, and may be used alone or in several kinds.

Examples of the above-mentioned excipients include microcrystalline cellulose, methyl cellulose, carmellose sodium,
Carmellose calcium, low-substituted hydroxypropyl cellulose and other celluloses, wheat starch, rice starch, corn starch, potato starch,
Examples thereof include starches such as hydroxypropyl starch, sodium carboxymethyl starch, α-cyclodextrin and β-cyclodextrin, and polymers such as polymethylmethacrylate (PMMA). Among those exemplified as the above-mentioned excipient, microcrystalline cellulose,
Corn starch, potato starch and polymethylmethacrylate are preferred.

Examples of the lubricant include lactose, sucrose,
Examples include mannitol and sorbitol.

Examples of the above-mentioned coating agent include hydroxypropyl cellulose, polyethylene glycol, lactose, sucrose, hydroxypropylmethyl, calcium carbonate, talc, titanium oxide, gum arabic, crystalline cellulose, iron oxide, carboxymethylethylcellulose, gelatin and the like. Is mentioned.

Examples of the ultraviolet scattering agent include fine particle titanium oxide, fine particle zinc oxide and the like.

Method of manufacturing drug-containing composite particles of the present embodiment
The powder processing equipment used to carry out the method contains drug powder
Can apply strong compressive force and shearing force to powder raw materials
Anything can be used, but 3 × 10³Pa over 3 × 10⁷P
Compressive force less than a and 1 x 10 ³Pa over 1 × 10⁷Pa
Those capable of imparting the following shearing force are preferable. Powder processing
As the device, for example, a mixer having a strong stirring force,
A kneader, a ball mill or the like can be used.

An example of a powder processing apparatus that can be used for producing the drug-containing composite particles of the present invention will be described below with reference to FIGS. 1 and 2.

As shown in FIG. 1, the powder processing apparatus 1 has a casing 2 that forms a closed space having a substantially cylindrical shape, and a substantially cylindrical shape with a bottom provided inside the casing 2. The cylindrical rotating body 3 and the press head 4 disposed inside the cylindrical rotating body 3 in order to process an object to be processed by generating a pressing force and a shearing force on the inner peripheral surface of the cylindrical rotating body 3. Consists of. By rotating the cylindrical rotating body 3, the receiving surface 5 formed on the inner peripheral surface of the cylindrical rotating body 3 and the press head 4 are relatively rotated, and as shown in FIG. 5 and the press head 4, a pressing force and a shearing force are applied to the object to be processed 7 existing in the pressing portion 6 formed as a gap, thereby performing the compounding process.

As shown in FIG. 1, inside the casing 2, there is provided a cylindrical rotating body 3 which is substantially cylindrical and rotatable about a vertical rotation axis X. The tubular rotating body 3 includes a rotating shaft portion 12, a bottom portion 14 connected to the rotating shaft portion 12, and a cylindrical wall portion 15 connected to the bottom portion 14.

Powder processing apparatus 1 used for carrying out the present invention
In the above, as the object exclusion means for positively circulating the object 7 to the pressing portion 6, the cylindrical rotary member 3 is provided at a plurality of locations near the lower portion 14 of the cylindrical rotary member 3.
The slit 8 that penetrates the cylindrical wall portion 15 is formed. The slit 8 removes a part of the workpiece 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, and will be described later. Thus, all the objects 7 to be processed are sequentially circulated and supplied to the pressing portion 6.

Casing 2 constituting 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 sealed processing space 9 for processing the object 7 is formed. The casing 2 has a processing object input port 10. A part of the bottom edge of the casing 2 main body is provided with a processing object take-out port 11 for taking out the processed object 7 to be processed. With the configuration of the powder processing apparatus 1 described above, the object 7 to be processed can be continuously processed.

The rotary shaft portion 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 the cylindrical rotating body is 3 is rotationally driven. By rotating the cylindrical rotating body 3, a centrifugal force acts on the object 7 to be processed, and the object 7 is pressed against the receiving surface 5 of the cylindrical rotating body 3.

The bottom portion 14 of the cylindrical rotating body 3 serves as a function of connecting the rotating shaft portion 12 and the cylindrical wall portion 15 of the cylindrical rotating body 3 and as a holding means for holding the workpiece 7. Have a function. That is, the bottom portion 14 has a relationship in which the surfaces thereof are bent in relation to the cylindrical wall portion 15 described later, and when the cylindrical rotating body 3 rotates, the workpiece 7 is pressed without being sufficiently treated. Prevents escape from the portion 6 downward.

The inner peripheral surface of the cylindrical wall portion 15 serves as a receiving surface 5 for the object to be processed 7 that is going to move outward due to the centrifugal force. That is, the workpiece 7 is retained on the pressing portion 6,
By the cooperation of the receiving surface 5 and the press head 4, a pressing force and a shearing force are applied to the object to be processed 7 to perform the powder processing.

A plurality of slits 8 are formed near the bottom of the cylindrical wall 15 as shown in FIG. The slits 8 penetrate the receiving surface 5, that is, the cylindrical wall portion 15, and are provided at, for example, a total of 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 object 7 held by the pressing section 6 to the outside of the pressing section 6, and
Function as a means of discharging. The slit 8 is formed such that the ratio of the opening area on the lower side is larger than that on the upper side so that the processed object 7 held on the lower side of the receiving surface 5 is discharged more.

In the present embodiment, for example, the slit 8 is formed in the shape of a semi-circular ridge. Object 7
Is pressed against the receiving surface 5 by centrifugal force,
At the same time, it is affected by gravity. Therefore, in the case of the cylindrical wall portion 15 shown in FIG. 1, the object 7 tends to move vertically downward and accumulate near the boundary between the receiving surface 5 and the bottom portion 14. The object 7 to be deposited on this portion increases the rotational load of the cylindrical rotating body 3 and inhibits the circulation of the object 7 to the pressing portion 6. Therefore, the above-mentioned inconvenience is eliminated and the efficiency of the powder processing is improved by positively discharging the object 7 to be processed deposited on the portion through the slit 8.

According to the above construction, most of the object 7 to be processed existing in the pressing portion 6 is discharged to the outside of the pressing portion 6 through the slit 8. Therefore, the object to be processed 7 is held on the pressing portion 6 for a certain period of time, a pressing force and a shearing force are applied thereto, and the powder processing is reliably performed.

Inside the cylindrical rotary member 3, there is provided a press head 4 arranged on the receiving surface 5 with a predetermined space. The press head 4 cooperates with the receiving surface 5 to apply a pressing force and a shearing force to the object to be processed 7. Therefore, the horizontal cross-sectional shape of the press head 4 is, for example, a semicircular shape as shown in FIG. With this configuration, the object to be processed 7 that is about to enter between the press head 4 and the receiving surface 5 is compacted, and an advantageous effect can be obtained for the complexing and spheroidizing of the powder particles.

When the horizontal cross-sectional shape of the press head 4 is semi-circular, the curvature is made larger than the curvature of the surface 5. As a result, the object 7 fixed to the receiving surface 5 of the tubular rotating body 3 receives a strong compressive force / shearing force when passing through the pressing portion 6 due to the rotation of the tubular rotating body 3. Here, when a mixture of a plurality of types is used as the object to be treated 7, it is subjected to a strong compressive force and a shearing force, whereby the particles are composited, the particle surface is modified, the particle shape is controlled,
Fine and precise dispersion mixing (powder fusion) at the particle level will occur, and the particle characteristics can be controlled.

The press head 4 has a casing 2
The structure may be fixed similarly to the above, or may be rotationally driven by using some kind of driving means and positively rotated relative to the receiving surface 5. That is, by appropriately setting the rotation direction or 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 condition according to the object 7 can be set. It should be noted that the temperature of the press head 4 may be controlled. For example, although not shown, if a heat medium passage is secured inside the press head 4, it is optimal according to the thermal characteristics of the workpiece 7. It becomes easy to set various processing conditions.

A circulating blade 16 is provided on the lower portion of the outer periphery of the casing 2. Circulation blade 1
A plurality of 6 are provided along the circumferential direction of the tubular rotating body 3,
The number of sheets is arbitrary. The circulation blade 16 is for circulating the object to be processed 7 discharged from the slit 8 to the outside of the cylindrical rotary body 3 to the pressing portion 6 again.
The circulation blade 16 raises the object 7 to be processed along the outer peripheral surface of the cylindrical wall portion 15 and returns to the processing space 9 of the cylindrical rotating body 3 beyond the upper end of the cylindrical wall portion 15 to cause the pressing portion. In order to convey smoothly and surely so as to return to 6, it is formed so as to conform to the inner surface shape of the casing 2.

By treating the object to be treated 7 using the powder processing apparatus 1 described above, the object to be treated 7 is pressed against the receiving surface 5 of the cylindrical rotary member 3 by the centrifugal force, and receives the collective action. In the receiving surface 5, a layer 7 of the object to be treated in a consolidated state is generated. On the other hand, a part of the compacted target object 7 is discharged to the outside of the cylindrical rotary body 3 through the slit 8, and the target object 7 present inside the cylindrical rotary body 3 is ,
The press head 4 receives a certain amount of stirring action. That is, according to the apparatus of the present embodiment, the compounding process of the object to be processed 7 can be rapidly advanced.

As described above, according to the powder processing apparatus 1, the object 7 to be processed is the object input port 10 of the casing 2.
Further, it is put into the processing space 9 and subjected to a strong compressive force / shearing force by the cylindrical rotating body 3 and the press head 4 to perform a composite treatment. Further, since the slit 8 is formed on the wall surface of the tubular rotary body 3, the mixture is passed through the slit 8 of the tubular rotary body 3 and the processing space 9 of the tubular rotary body 3 is processed.
Sent to the outside of. Then, as shown in FIG. 1, the workpiece 7 sent to the outside is conveyed to the upper part of the cylindrical rotating body 3 by the circulation blade 16 and returned to the inside of the cylindrical rotating body 3 again. It will be subjected to compressive and shearing forces again.
In this way, the object 7 to be processed is effectively subjected to a compounding process by repeatedly receiving a strong compressive force / shearing force by the cylindrical rotating body 3 and the press head 4.

The powder processing apparatus 1 may be capable of appropriately changing the inside of the casing 2, that is, the atmosphere of the processing space 9, depending on the type of the object 7 to be processed. For example, various gases such as an inert gas and a heating gas may be introduced into the casing 2 through the object inlet 10 or a pressure / vacuum pump may be used to increase or decrease the pressure inside the casing 2. Good. In this case, for example, by providing a seal member (not shown) between the casing 2 and the rotary shaft portion 12 of the cylindrical rotary body 3, the atmosphere inside the processing space 9 can be adjusted reliably.

Around the casing 2, a jacket 13 is mainly provided for adjusting the temperature of the processing space 9. A heating medium or a cooling medium from a tank (not shown) provided separately is circulated and supplied to the jacket 13 as necessary. Thereby, the internal temperature of the casing 2 can be adjusted. For example, in the case of treating a drug that may be deteriorated due to a temperature change as the object to be treated 7, the heating medium or the cooling medium is circulated and supplied to the jacket 13 to obtain the desired temperature of the object to be treated 7. It can prevent the deterioration of the drug as the temperature of.

Although the case of using the powder processing apparatus 1 has been described, the powder processing apparatus for carrying out the method for producing drug-containing composite particles of the present embodiment is not limited to this. For example, the drug-containing composite particles of the present embodiment can be obtained by using a mixer, a stirrer, a ball mill, or the like having a strong stirring force capable of imparting a strong compressive force and a shearing force to the powder raw material. The manufacturing method of can be implemented.

Next, other conditions for carrying out the method for producing drug-containing composite particles of the present embodiment will be described below. In the present embodiment, a mixture of two or more kinds of powder raw materials containing a drug powder is treated as a substance to be treated by a powder treatment apparatus to obtain complexed drug-containing composite particles.

The method of introducing two or more kinds of powder raw materials containing the above-mentioned drug powder into the powder processing apparatus is not particularly limited, and for example, two or more kinds of powder raw materials may be charged in a premixed state. Alternatively, the powder raw materials may be separately charged and mixed in the powder processing apparatus. The order of charging the both separately is not particularly limited, and two or more kinds of powder raw materials may be charged simultaneously.

When the powder raw materials are charged separately,
It is also possible to add the same or different powder raw materials a plurality of times to form a composite. By adding the powder raw material in plural times, the layers of the powder raw material are formed according to the number of inputs. In other words, the drug-containing composite particles obtained by compounding two or more powder raw materials are further compounded by adding the powder raw material to form a powder raw material layer on the surface of the drug-containing composite particles. The Rukoto. As described above, by charging the powder raw material in plural times, it is possible to obtain drug-containing composite particles having a multilayered powder raw material layer formed on the surface thereof.

The powder raw materials which are charged in a plurality of times may be of the same kind or of different kinds. Since the plurality of layers of the same kind of powder material are formed by charging the same kind of powder material in plural times, it is possible to surely cover the surface of the powder material to be coated with the powder material. Also, by inputting different kinds of powder raw materials in plural times for each kind, it is possible to obtain drug-containing composite particles in which a plurality of layers of different kinds of powder raw materials are formed on the surface of the powder raw material to be coated. You can Therefore, drug-containing composite particles in which layers of a plurality of types of drug powder are formed can be obtained. For example, a drug-containing composite particle obtained by complexing a powder raw material to be coated and a drug powder that dissolves in the intestine to exert its function, and further compound a drug powder that dissolves in the stomach to exert its function. By doing so, a layer of multiple types of drug powder is formed, and after ingestion into the human body,
Thus, drug-containing composite particles that sequentially express different functions over time can be obtained. In this way, it becomes possible to impart a plurality of properties to the drug-containing composite particles.

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 is not altered. Further, when a powder raw material having a property of being changed by heat is used, in order to prevent the powder raw material from being changed in quality due to a temperature rise during compounding, while cooling the powder raw material or the powder processing apparatus. It will be composited. As a result, it is possible to prevent the powder raw material from deteriorating during compounding.

The time for applying the compressive force and the shearing force for the compounding may be appropriately determined depending on the size of the powder processing apparatus, the kind and the amount of the powder raw material to be compounded, and is not particularly limited. Although not performed, for example, the processing time can be set to 5 to 20 minutes. Further, the end point of the above treatment is judged 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.

Further, since the method for producing the drug-containing composite particles of the present embodiment does not use a binder, there is no need to adjust the temperature to bring the inside of the powder processing apparatus to a temperature suitable for this. Further, it is not necessary to dry the binder. Therefore, drug-containing composite particles can be obtained in a shorter time than the conventional composite method using a binder.

In order to apply a compressive force and a shearing force to a mixture of two or more powder raw materials containing drug powder, the rotation speed of the powder processing apparatus depends on the size of the powder processing apparatus, the kind of powder raw material, and the amount. 50r
pm (revolutions per minute) or more and 5000 rpm or less, preferably 100 rpm or more and 3000 r
It is more preferably pm or less.

The drug-containing composite particles obtained by the manufacturing method of the present embodiment are a composite of two or more powder raw materials containing drug powder. As the drug-containing composite particles,
For example, a powdered raw material (hereinafter referred to as mother particle) that serves as a core,
An example is a composite of a powder raw material (hereinafter, referred to as a child particle) that forms a layer covering the surface of the powder raw material serving as the nucleus. In this drug-containing composite particle, since the surface of the mother particle is covered with the child particles, the surface of the mother particle can be modified.

In order to cover the surface of the mother particles with the child particles, it is preferable that the mother particles have a spherical shape, and that the difference between the diameter of the mother particles and the diameter of the child particles is large. Used. Further, the particle size of the mother particles is preferably 10 times or more the particle size of the child particles, and is preferably 100 times or less.

For example, a drug-containing composite particle obtained by compositing an excipient as a mother particle and a drug powder as a child particle, and a complex of this excipient and a drug as a mother particle is further prepared. By compounding with other child particles, the solubility of the drug powder can be improved, the fluidity of the drug-containing composite particles can be controlled, and the drug-containing composite particles can have DDS (Drug Deli
It is possible to add characteristics suitable for very system).

As the drug-containing composite particles having the characteristics suitable for the DDS, specifically, starch particles having a particle diameter of about 75 μm are used as mother particles and anti-inflammatory drug powder is compounded as child particles. Can be mentioned. When inhaled, the drug-containing composite particles adhere to the mucous membrane of the throat and the anti-inflammatory agent is absorbed from the mucous membrane. Here, since the fine particles are more compatible with the mucous membrane than the liquid, the drug powder of the anti-inflammatory agent can be retained for a long time in the mucous membrane by inhaling the drug-containing composite particles and adhering them to the mucous membrane. Therefore, it becomes possible to efficiently deliver the anti-inflammatory agent to the mucous membrane and exert the drug effect for a long time. Since starch is used as the mother particles, it is safe for the drug-containing composite particles to enter the body as they are without sticking to the mucous membrane.

The particle size of the drug-containing composite particles is 1 μm
When it is 5 μm, the drug-containing composite particles can be delivered to the lung.

As the drug-containing composite particles in which a plurality of drug powders are used as the child particles, specifically, the drug powder layer that acts by dissolving in the intestine and the drug powder in the stomach are sequentially dissolved from the mother particle side. Examples thereof include those in which a layer of drug powder that acts by being formed is formed. The drug-containing composite particles can effectively work an appropriate drug in the stomach and the intestine.

The surface of the drug-containing composite particles may be further covered with at least one of a lubricant and a coating agent (protective agent). Thereby, the bitterness of the drug powder can be masked and the solubility can be suppressed.

As described above, by compounding two or more kinds of powder raw materials containing drug powder as described above, masking of bitterness of drug, handling property of drug,
It is possible to obtain drug-containing composite particles having adjusted tableting properties, solubility, DDS properties and the like.

[0083]

[Embodiment 1] FIG. 3 shows an embodiment of the present invention.
It will be described below based on. In this example, 40 g of microcrystalline cellulose having an average particle size of 290 μm and 16 g of ibuprofen (drug powder) having an average particle size of 27 μm were used as powder raw materials to perform a compounding process with a powder processing apparatus to prepare drug-containing composite particles. did. Ibuprofen is an antipyretic analgesic.

In the preparation of the drug-containing composite particles, the treatment temperature was 26 ° C., the rotational speed of the cylindrical rotor 3 was 1300 rpm, and the total treatment time was 20 minutes. In this embodiment,
An operation of adding 4 g of ibuprofen and performing the complexing treatment for 5 minutes was repeated 4 times to perform the complexing treatment for a total of 20 minutes. That is, 40 g of microcrystalline cellulose,
4 g of ibuprofen was divided into 4 parts, and each time ibuprofen was added, the compounding treatment was performed for 5 minutes, and the compounding-containing complex particles were prepared by the compounding treatment for a total of 20 minutes. In this example, a mechanofusion (registered trademark, manufactured by Hosokawa Micron Co., Ltd.) system having the structure described with reference to FIG. 1 was used as the powder processing apparatus.

FIG. 3 (a) shows an electron micrograph (150 times) of microcrystalline cellulose before conjugation, and FIG. 3 (b) shows an electron micrograph of ibuprofen before conjugation (2500).
(X), the figure (c) shows an electron micrograph (150 times) of the drug-containing composite particles obtained by complexing microcrystalline cellulose and ibuprofen, and the figure (d) shows the drug-containing composite particles. The electron micrograph (150 times) of the cross section of FIG. The magnification of the electron micrograph described above indicates the magnification at the time of photographing. Also in the following examples, when the magnification of an electron micrograph is described, the magnification at the time of photographing is used as in the case of this example.

As shown in (c) and (d) of the figure, drug-containing composite particles in which the entire surface of the microcrystalline cellulose is covered with ibuprofen by compositing the microcrystalline cellulose with the ibuprofen It turns out that

[Embodiment 2] Another embodiment of the present invention will be described below with reference to FIG. 40 g of potato starch having an average particle diameter of 35 μm and 16 g of etenzamid (drug powder) having an average particle diameter of 3 μm were used as powder raw materials, the treatment temperature was set to 29 ° C., and the rotation speed of the tubular rotating body 3 was set to 2950 rpm. Drug-containing composite particles were prepared in the same manner as in Example 1 except for the above. Also in this example, as in Example 1, the amount of etenzamid added was divided into 4 parts by 4 g each. Etenzamid is an anti-inflammatory agent.

FIG. 4 (a) shows an electron micrograph (× 1000) of potato starch before conjugation, and FIG. 4 (b).
Is an electron micrograph (2500) of etenzamid before complexation.
And (c) shows an electron micrograph (1500 times) of drug-containing composite particles obtained by compositing potato starch and ethenzamid.

As shown in (c) of the figure, it can be seen that the compound-containing composite particles in which the entire surface of the potato starch is covered with ethenzamid can be obtained by subjecting the potato starch and ethenzamid to the composite treatment.

[Embodiment 3] Another embodiment of the present invention will be described below with reference to FIGS. As powder raw material,
35 g of corn starch having an average particle size of 20 μm, and etenzamid having an average particle size of 3 μm and an average particle size of 0.015
Example 1 except that 14 g of a mixture obtained by mixing 1 μm by weight of titanium oxide having a particle diameter of μm was used, the treatment temperature was 29 ° C., and the rotational speed of the cylindrical rotor 3 was 3500 rpm. Drug-containing composite particles were prepared in the same manner as in. In addition, also in this Example, as in Example 1, the above-mentioned mixture was charged in 3.5 g portions in four times. Further, the mixture of the above-mentioned ethenzamid and fine particle titanium oxide was used for the purpose of investigating the structure of the film when the drug powder was charged in plural times.

FIG. 5 (a) shows an electron micrograph (2500 times) of maize starch before conjugation, and FIG. 5 (b) shows an electron micrograph of ethenzamid before conjugation (2).
500 times), and FIG. 7 (c) shows an electron micrograph (2500 times) of the drug-containing composite particles obtained by compositing corn starch with a mixture of ethenamide and fine titanium oxide particles.

As shown in (c) of the figure, it can be seen that the complexing forms drug-containing complex particles in which the entire surface of corn starch is covered with the above mixture.

Further, by comparing the figure (a) and the figure (c), the corn starch was
It can be seen that the protruding part is removed and has a shape close to a sphere. That is, it is understood that the cornstarch is spheroidized by forming a layer of the mixture on the surface thereof by the complexing.

FIG. 6 shows an electron micrograph (× 2000) of a cross section of drug-containing composite particles obtained by compositing corn starch and the above mixture. In addition, FIG.
2 shows an electron micrograph (30000 times) of a cross section near the surface of the drug-containing composite particles shown in FIG. 6 and 7,
It is shown that four layers are formed on the surface of the corn starch corresponding to the number of times the mixture is added. That is, when the powder raw material is divided into a plurality of times at the time of compounding, a number of layers corresponding to the number of times of addition are formed. Therefore, it is understood that layers of a plurality of different types of powder raw materials can be formed by sequentially adding different types of powder raw materials.

[Embodiment 4] Another embodiment of the present invention will be described below with reference to FIGS. 8 and 9. As a powder raw material, polymethylmethacrylate (PM having an average particle size of 10 μm)
MA) 30 g and 6 g of etenzamid (drug powder) having an average particle size of 3 μm and 6 g of fine particle titanium oxide having an average particle size of 0.015 μm, and at a treatment temperature of 33 ° C., the rotational speed of the cylindrical rotary body 3 was 4800 rpm Then, the above mixture was added at once, and the treatment time was set to 20 minutes to form a composite. The same processing device as in Example 1 was used as the processing device used for compounding.

FIG. 8 (a) shows an electron micrograph (3,000 times) of polymethylmethacrylate before conjugation, and FIG. 8 (b) shows an electron micrograph of ethenamide before conjugation (2).
500 times), and FIG. 6 (c) shows an electron micrograph (3000 times) of the drug-containing composite particles obtained by compositing poly (methyl methacrylate) with a mixture of etenzamid and fine particle titanium oxide.

As shown in FIG. 7C, the complexing treatment described above forms drug-containing complex particles in which the entire surface of polymethylmethacrylate is covered with the layer of the mixture.

FIG. 9 shows an electron micrograph (5000 times) of a cross section obtained by cutting the drug-containing composite particles of this example. As shown in the figure, on the surface of polymethylmethacrylate,
It can be seen that a layer having a uniform thickness of the mixture of ethenzamid and fine particle titanium oxide is formed.

[Embodiment 5] Another embodiment of the present invention will be described below with reference to FIGS. In order for the drug-containing composite particles obtained by compounding two or more powder raw materials containing drug powder to function as a drug, no chemical change occurs in the drug due to compounding, that is, compounding treatment. Therefore, it is necessary that the drug does not deteriorate. Therefore, the ultraviolet absorption spectrum (UV spectrum), X-ray diffraction and melting point of the drug were measured before and after the conjugation to examine the effect of the conjugation on the drug.

As the powder raw material, the average particle diameter is 290 μm.
Using 40 g of microcrystalline cellulose and 16 g of ibuprofen (drug powder) having an average particle size of 27 μm, the compounding treatment was carried out for 20 minutes with the rotational speed of the cylindrical rotator 3 being 1300 rpm to prepare drug-containing composite particles. . In this example, the processing temperature at the time of compounding was 26 ° C., 66 ° C.
C. and 84.degree. C. were prepared, and three types of drug-containing composite particles having different treatment temperatures were prepared. The same powder processing device as in Example 1 was used.

The ultraviolet absorption spectrum of ibuprofen extracted with methanol from the drug-containing composite particles prepared as described above was measured and compared with the ultraviolet absorption spectrum of ibuprofen before conjugation. The results are shown in FIG.
FIG. 10 shows the result of measurement after filtering the methanol extract in order to exclude the influence of the suspension of the methanol extract. The UV absorption spectrum of ibuprofen after conjugation is the same as the UV absorption spectrum of ibuprofen before conjugation, regardless of the treatment temperature.
0 is shown. That is, it can be seen that even after the complexing treatment, ibuprofen has the same structure as that before the treatment, that is, ibuprofen is not chemically changed by the complexing treatment.

Further, the results of examining the influence of the complexation on the crystallinity of microcrystalline cellulose and ibuprofen are shown in FIGS. 11 and 12. FIG. 11 shows the measurement results of X-ray diffraction of microcrystalline cellulose and ibuprofen before complexation, and FIG. 12 shows the measurement results of X-ray diffraction of a simple mixture of both, and drug-containing complex particles obtained by complexation. The measurement result of X-ray diffraction of is shown.

As shown in FIG. 12, the measurement results of the X-ray diffraction of the drug-containing composite particles are the same as the measurement results of the X-ray diffraction of a simple mixture of microcrystalline cellulose and ibuprofen. The angle at which the peak due to the crystallinity of the microcrystalline cellulose indicated by C and the peak due to the crystallinity of ibuprofen indicated by I appear are the same. This shows that the crystallization does not change the crystallinity of microcrystalline cellulose and ibuprofen. The simple mixing means a process of manually mixing microcrystalline cellulose and ibuprofen at room temperature.

From the results of the differential thermal analysis shown in FIG. 13, the melting point of ibuprofen was that of a simple mixture, the treatment temperature was 2
It is shown that the melting point of both the composites at 6 ° C. and the composite at the treatment temperature of 66 ° C. did not change. From this also, it can be seen that ibuprofen does not change due to conjugation.

FIG. 14 shows the results of measuring the influence of the complexation on the elution rate of ibuprofen. To measure the dissolution rate,
Drug-containing composite particles that have been composited at a treatment temperature of 26 ° C.,
It carried out about what was simply mixed and what was not compounded. Here, the dissolution rate indicates the ratio of ibuprofen dissolved in water among the ibuprofen in water.

As shown in the figure, the drug-containing composite particles obtained by the conjugation treatment had a high elution rate of ibuprofen immediately after the start of the test, and after the elution time of 1000 seconds, it was almost 1%.
It reaches to 00%, which is very large compared with the elution rates of the simple mixture and the ibuprofen alone. This is considered to be because ibuprofen, which constitutes the drug-containing composite particles, has a large contact area with water due to the fact that the particle size becomes extremely small when subjected to strong compressive force and shearing force during compounding. To be The dissolution rate of ibuprofen is also improved by improving the dispersibility by simply mixing microcrystalline cellulose and ibuprofen, but as shown in the figure, the extent is limited.

[Embodiment 6] Another embodiment of the present invention will be described below with reference to FIGS. Fourier transform infrared absorption spectra (F
(T-IR spectrum) was measured to examine the effect of the complexing treatment on the drug powder. In the present example, the same powder raw material and the same processing device as in Example 1 were used under the same conditions.

FT-IR spectra of the drug-containing composite particles, microcrystalline cellulose and ibuprofen obtained by the above composite treatment were measured and the results are shown in FIGS.
It shows in FIG. From these, it can be seen that the peaks of the FT-IR spectrum of the drug-containing composite particles shown in FIG. 15 are all present in the FT-IR spectrum of FIG. 16 or FIG.

That is, FT-IR of drug-containing composite particles
The spectra are the FT-IR spectrum of the microcrystalline cellulose and the F of ibuprofen that compose the drug-containing composite particles.
It is the sum of the T-IR spectrum. Therefore, it can be seen that the microcrystalline cellulose and ibuprofen have not been chemically changed by the complexing treatment, and no new substances other than these have been formed. In this way, the complexing treatment does not alter the drug,
It was also confirmed from the measurement result of the FT-IR spectrum.

Example 7 As a powder raw material, the average particle size was 2
90 μm of microcrystalline cellulose 40 g and average particle size 50 μ
Drug-containing composite particles were prepared in the same manner as in Example 1 except that 16 g of m-acetaminophenone (drug powder) was used. As in Example 1, acetaminophenone was added in 4 g portions in 4 batches. In addition, acetaminophenone is an antipyretic analgesic.

As a result of taking an electron micrograph of the drug-containing composite particles at the stage where the first 4 g of acetaminophenone was added, drug-containing composite particles in which the entire surface of the microcrystalline cellulose was covered with acetaminophenone were formed. It was recognized that it was done. In addition, it was confirmed by visual observation of the appearance that the microcrystalline cellulose and acetaminophenone were composited at the stage of adding 16 g of acetaminophenone.

Example 8 As a powder raw material, an average particle size of 3
12 µm of etenzamid (medicine powder) and average particle size of 0.
Using 0.15 μm of titanium oxide (5.14 g),
The processing temperature is 13.8 ° C., and the rotation speed of the cylindrical rotating body 3 is 500.
Complexing was carried out at 0 rpm for 10 minutes to prepare drug-containing complex particles. The same processing device as in Example 1 was used as the processing device used for compounding. In this way, it was possible to form a composite of ethenzamide and particulate titanium oxide.

Example 9 As a powder raw material, the average particle size was 5
Preparation of drug-containing composite particles using 20 g of lactose of μm and 8 g of ibuprofen (drug powder) having an average particle size of 3 μm at a treatment temperature of 20 ° C., a rotational speed of the cylindrical rotor 3 of 4700 rpm, and a treatment time of 20 minutes. did. As in Example 1, ibuprofen was added in 2 g portions in 4 batches.
The same processing device as in Example 1 was used as the processing device used for compounding. In this way, lactose and ibuprofen could be complexed.

Example 10 12 g of ibuprofen (drug powder) having an average particle size of 3 μm and 5.1 g of fine titanium oxide particles having an average particle size of 0.015 μm were used as powder raw materials, the treatment temperature was 20 ° C., and a tubular shape was used. Rotating speed of the rotating body 3 is 560
Complexing was carried out at 0 rpm for 10 minutes to prepare drug-containing complex particles. The same processing device as in Example 1 was used as the processing device used for compounding. In this way, ibuprofen and particulate titanium oxide could be composited.

[0115]

INDUSTRIAL APPLICABILITY As described above, the method for producing drug-containing composite particles of the present invention is to apply a compressive force and a shearing force to a composite of a mixture of two or more powder raw materials containing a drug powder to form a composite. .

Therefore, the drug powder can be combined with other powder raw materials without using a binder. As a result, it is possible to produce the drug-containing composite particles in a short time without deteriorating the stability of the drug powder.

Further, the above mixture may contain a excipient powder. Thus, by combining the drug powder and the excipient powder, it is possible to produce, for example, drug-containing composite particles having good handleability during formulation.

The method for producing drug-containing composite particles of the present invention is as follows:
The above-mentioned excipient powder is preferably selected from the group consisting of celluloses and starches.

The method for producing drug-containing composite particles of the present invention is as follows:
The average particle size of the excipient powder is preferably 1 time or more and 10000 times or less the average particle size of the drug powder.

The average particle size of the above-mentioned excipient powder is 1 μm.
m or more and 5000 μm or less, the average particle size of the drug powder is preferably 0.01 μm or more and 500 μm or less, and the content ratio of the drug powder in the drug-containing composite particles is 0.01% by weight. % Or more and 90% by weight or less is preferable.

As a result, the composite of the excipient powder and the drug powder can be more reliably formed.

Further, in the method for producing drug-containing composite particles of the present invention, the drug powder may be an antipyretic analgesic or an anti-inflammatory agent.

[Brief description of drawings]

FIG. 1 is a cross-sectional view showing a configuration example of a powder processing apparatus used for carrying out the present invention.

FIG. 2 is a cross-sectional view illustrating an operation when a compressive force and a shearing force are applied to an object to be processed by the powder processing apparatus shown in FIG.

FIG. 3 (a) is a drawing-substitute electron micrograph (150 times) of microcrystalline cellulose before conjugation, and (b) is a drawing-substitute electron micrograph of ibuprofen before conjugation (250).
(0 times), (c) is a drawing-substitute electron micrograph (150 times) of the drug-containing composite particles of Example 1 obtained by complexing microcrystalline cellulose and ibuprofen,
(D) is a drawing-substitute electron micrograph (150 times) of a cross section of the drug-containing composite particle of (c).

FIG. 4 (a) is a drawing-substitute electron micrograph (1,000 ×) of potato starch before conjugation, and (b) is a drawing-substitute electron micrograph of ethenzamid before conjugation (25).
And (c) is a drawing-substitute electron micrograph (1,500 times) of the drug-containing composite particles of Example 2 obtained by complexing potato starch and ethenzamid.

FIG. 5 (a) is a drawing-substitute electron micrograph (2500 times) of corn starch before conjugation, and (b).
Is a drawing-substitute electron micrograph (2500 times) of ethenzamid before conjugation, and (c) is a drug-containing composite particle of Example 3 obtained by conjugating corn starch with a mixture of ethenzamid and particulate titanium oxide. 2 is a drawing-substitute electron micrograph (2500 times).

FIG. 6 is a drawing-substitute electron micrograph (× 2000) of a cross section of the drug-containing composite particles of FIG. 5 (c).

FIG. 7 is a drawing-substitute electron micrograph (30000 times) of a cross section of a surface portion of the drug-containing composite particles of FIG. 5 (c).

FIG. 8 (a) is a drawing-substitute electron micrograph (3,000 times) of polymethylmethacrylate before complexing, and FIG. 8 (b).
Is a drawing-substitute electron micrograph (2500 times) of ethenzamid before conjugation, and (c) is a drug-containing sample of Example 4 obtained by conjugating poly (methyl methacrylate) with a mixture of ethenzamid and particulate titanium oxide. It is a drawing-substitute electron micrograph (3000 times) of the composite particles.

9 is a drawing-substitute electron micrograph (5000 times) of a cross section of the drug-containing composite particles of FIG. 8 (c).

FIG. 10 is an explanatory diagram showing an ultraviolet absorption spectrum of ibuprofen after filtering the methanol extract of Example 5.

FIG. 11 is an explanatory diagram showing the measurement results of X-ray diffraction of microcrystalline cellulose and ibuprofen before complexing.

FIG. 12 is an explanatory diagram showing the measurement results of X-ray diffraction of a simple mixture of microcrystalline cellulose and ibuprofen, and the drug-containing composite particles of Example 5 obtained by complexing.

FIG. 13 is an explanatory diagram showing the results of evaluating the melting point of ibuprofen by differential thermal analysis.

FIG. 14 is an explanatory diagram showing the results of measuring the dissolution rate of ibuprofen in water.

FIG. 15 is a diagram showing an FT-IR spectrum of drug-containing composite particles of Example 6 in which microcrystalline cellulose and ethenzamid were composited.

FIG. 16 is an explanatory diagram showing an FT-IR spectrum of microcrystalline cellulose.

FIG. 17 is an explanatory diagram showing an FT-IR spectrum of etenzamid.

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Toyokazu Yokoyama             Hosokata, Hirakata, Osaka             Clon Co., Ltd. (72) Inventor Mitsuru Kondo             Hosokata, Hirakata, Osaka             Clon Co., Ltd. (72) Inventor Tsunehiro Yoshitomi             Hosokata, Hirakata, Osaka             Clon Co., Ltd. (72) Inventor Hiroyuki Tsujimoto             Hosokata, Hirakata, Osaka             Clon Co., Ltd. (72) Inventor Yoshiyuki Inoue             Hosokata, Hirakata, Osaka             Clon Co., Ltd. F-term (reference) 4C076 AA31 CC04 EE31 EE38 FF05                       GG12                 4C206 AA01 AA02 DA24 MA02 MA05                       MA61 NA03 ZB11

Claims (8)

[Claims] 1. A method for producing drug-containing composite particles, which comprises applying a compressive force and a shearing force to a mixture of two or more powder raw materials containing a drug powder to form a composite. 2. The method for producing drug-containing composite particles according to claim 1, wherein the mixture contains a excipient powder. 3. The excipient powder is selected from the group consisting of celluloses and starches.
A method for producing the drug-containing composite particles according to 1. 4. The drug-containing composite particles according to claim 2, wherein the excipient powder has an average particle size of 1 to 10,000 times the average particle size of the drug powder. Production method. 5. The average particle diameter of the excipient powder is from 1 μm to 5000 μm, inclusive.
Alternatively, the method for producing the drug-containing composite particles according to item 4. 6. The drug powder has an average particle diameter of 0.01 μm.
6. The method for producing drug-containing composite particles according to claim 1, wherein the particle diameter is 500 μm or less. 7. The content of the drug powder in the drug-containing composite particles is 0.01% by weight or more and 90% by weight or less, according to any one of claims 1 to 6. A method for producing drug-containing composite particles. 8. The method for producing drug-containing composite particles according to claim 1, wherein the drug powder is an antipyretic analgesic or antiphlogistic.