JP2811963B2 - Gastric retentive preparation, puffed molded product and manufacturing method - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a gastroretentive preparation. More specifically, the present invention relates to an expanded molded article that can be produced using a multiaxial extruder, and a gastroretentive preparation containing the same.

A gastric retentive formulation is a formulation that has the effect of floating above the gastric juice or gastric contents in the stomach and gradually releasing the drug.

Here, the “expanded molded body” refers to an object that has expanded due to heat, pressure, chemical change, or the like, and has a void inside.

BACKGROUND ART Gastric retentive preparations are one of sustained-release preparations,
Sustained-release preparations have the advantages of generally reducing the number of doses, maintaining the effective concentration, and reducing side effects. In addition, the gastric retentive preparation is hardly affected by the gastric emptying rate, and can sufficiently release the drug at the absorption site. Therefore,
The gastric retentive preparation is a medically extremely useful preparation, and can be said to be a particularly useful preparation for a drug or the like which is expected to have a direct action in the stomach or upper intestine.

As gastric retentive preparations, those using a hydrocolloid so far (Japanese Patent Application Laid-Open No. 58-57315) and those formed by hollow molding and coating the outer layer with an active substance (Japanese Patent Application Laid-Open No. 55-1241)
No. 1), using foamable microcapsules (Japanese Unexamined Patent Publication No.
2-76418), a mixture of a water-soluble polymer and an oil or fat with a specific gravity of 1 or less (JP-A-61-43108, PCT WO91 / 06281), or a mixture of foamed ethylcellulose ( Japanese Patent Application Laid-Open No. Sho 62-145014) is known. Among these, there are excellent preparations in the stomach, but many of them have complicated structures and are destroyed by peristalsis in the stomach, so that sufficient buoyancy cannot be secured.

On the other hand, the multi-screw extruder is one of the screw-type kneading extruders that have completely different performances, uses, and the like from the single-screw extruder. Multi-axis extruder is 1
It is not a simple kneading extruder like a shaft type extruder, but has a mechanism similar to a screw type pump where multiple screws are entangled and interfere with each other to generate physically high energy. Raw materials can be subjected to processing that cannot be obtained with an extruder. Multiaxial extruders have developed mainly in the food and plastic fields, and are widely used in processing foods (cereals, proteins, livestock meat, fish meat, and the like) and in injection molding of plastics.

Techniques using an extruder in the field of medical products include PCT WO92 / 18106, PCT WO93 / 01472, and JP-A-5-1941.
No. 97 publication. These do not relate to a gastric retentive preparation, but to a preparation form having a different structure, effect and the like from a gastric retentive preparation.

In the food field, there is known a technique of treating a food material (for example, a starch material) with a multiaxial extruder to obtain an expanded molded product (Japanese Patent Laid-Open No. 5-28).
No. 4926, JP-A-5-192083, JP-A-5-2312
No. 5, JP-A-4-51849, JP-A-1-252267, JP-A-61-9253, etc.). However, these techniques are intended to solve problems specific to the food field (improving texture, improving appearance, etc.) of any of the techniques, and are different in the technical fields.

In addition, there is known a technique of using a screw type extruder to obtain a swollen molded body called a polymer network mainly composed of a lactic acid-based polymer (for example, polylactic acid) (Japanese Patent Laid-Open No. 5-205).
No. 177734). However, the expanded molded article is intended to be used as a material such as an absorbent such as oil or body fluid or a filter material. In addition, since these swollen molded articles are easily adapted to water, they cannot be applied to gastroretentive preparations.

DISCLOSURE OF THE INVENTION The main object of the present invention is to provide a gastric retentive preparation in a form completely different from conventional gastric retentive preparations.

The present inventors have studied various uses of a multiaxial extruder (hereinafter, simply referred to as “extruder”) in the field of pharmaceuticals, and have found a gastroretentive preparation that can achieve the above object, and completed the present invention. did.

The gastroretentive preparation according to the present invention (hereinafter, referred to as the “present invention preparation”) contains the swollen molded article according to the present invention (hereinafter, referred to as “the swollen present invention”). Preferred formulations of the invention have an apparent density of less than 1.

The expanded product of the present invention is an expanded molded product having an apparent density of less than 1, containing an acid-resistant polymer compound as a main component, and at least a cross-section containing at least a swelling aid and a drug. Since the cross-section is reticulated, the expanded body of the present invention has a large number of fine voids therein continuously or discontinuously.

The present inventors are the first to manufacture a gastric retentive preparation using an extruder.

 First, the expanded body of the present invention will be described in detail.

Since the expanded body of the present invention is mainly composed of an acid-resistant polymer compound, it is substantially insoluble in neutral water and acidic water, and has acid resistance in the stomach. Here, “main component” means a component having the highest content among all components.

Examples of the acid-resistant high-molecular compound include pH-dependent and pH-independent filming agents which are usually used in the formulation of pharmaceuticals. Specifically, hydroxypropyl methylcellulose acetate succinate (Aqoat-L, M, H, registered trademark), hydroxypropyl methylcellulose phthalate (HP-50, 55, 55S), methacrylic acid copolymer L, S
(Eudragit-L30d55, L100, L100-55, S100, registered trademark), carboxymethylethylcellulose (CMEC, registered trademark), cellulose acetate phthalate (CAP, registered trademark),
Ethyl cellulose, aminoalkyl methacrylate copolymer RS (Eudragit-RS, RN100L, RN100, RSPML, RSPM,
Registered trademark) and the like.

The acid-resistant polymer compound may be used alone or in combination of two or more. Even if two or more kinds are used, the object of the present invention can be sufficiently achieved.

The composition ratio of the acid-resistant high-molecular compound varies depending on the selected acid-resistant high-molecular compound, swelling aid, drug, intended swollen product of the present invention or preparation of the present invention, but is 25 to 94% (w /
w) is suitable, preferably 40-80% (w / w), 50-70%
% (W / w) is more preferred. Those having less than 25% (w / w) may not have sufficient acid resistance performance and strength.

The expansion aid is an additive for providing a large number of fine and uniform voids inside the expansion molded body. This leavening aid is
It is considered that an effect similar to zeolite action is given to the raw material when producing an expanded molded article by an extruder described later.
Without this expansion aid, it is difficult to obtain the expanded product of the present invention using an extruder. Therefore, the leavening aid is a very important component for the present invention.

As the expansion aid, dried aluminum hydroxide gel,
Synthetic aluminum silicate, calcium hydrogen phosphate, calcium carbonate, precipitated calcium carbonate, sodium hydrogen carbonate, calcium hydrogen carbonate, talc and the like can be mentioned.

The expansion aid may be used alone or in combination of two or more. Even if two or more kinds are used, the object of the present invention can be sufficiently achieved.

The composition ratio of the puffing aid varies depending on the selected acid-resistant polymer compound, puffing aid, drug, target puffed product of the present invention or preparation of the present invention, but is preferably 5 to 40% (w / w). Yes, preferably 10-30% (w / w), 15-20% (w / w)
Is more preferred. Less than 5% (w / w) may not have sufficiently fine uniform voids. 40 (w / w)%
More may have the form of the expanded body of the present invention, but may not have sufficient acid resistance and strength.

The drug according to the present invention is not particularly limited, but is preferably heat-stable. Specifically, the following drugs can be mentioned.

1. Antipyretic, analgesic and anti-inflammatory agent indomethacin, aspirin, diclofenac sodium, ketoprofen, ibuprofen, mefenamic acid, dexamethasone, dexamethasone sodium sulfate,
Hydrocortisone, prednisolone, azulene, phenacetin, isopropylantipyrine, acetaminophen, benzitamine hydrochloride, phenylbutazone, flufenamic acid, sodium salicylate, choline salicylate, sazapirin, clofezone, etodolac.

2.Sulpiride, cetraxate hydrochloride, gefarnate, anti-ulcer agent,
Irsogladine maleate, cimetidine, ranitidine hydrochloride, famotidine, nizatidine, roxatidine hydrochloride acetate.

3.coronary vasodilator nifedipine, diltiazem hydrochloride, trapidil, diviridamol, dilazep hydrochloride, methyl 2,6-dimethyl-
4- (2-nitrophenyl) -5- (2-oxo-1,3,
2-dioxaphospholinan-2-yl) -1,4-dihydropyridine-3-carboxylate, verapamil, nicardipine, nicardipine hydrochloride, verapamil hydrochloride.

4. Peripheral vasodilator Ifenprodil tartrate, cinepaside maleate, cyclandate, cinnarizine, pentoxifylline.

5. Antibiotics Ampicillin, amoxicillin, cephalexin, erythromycin ethylsuccinate, bacampicillin hydrochloride, minocycline hydrochloride, chloramphenicol, tetracycline, erythromycin.

6.Synthetic antibacterial agent nalidixic acid, pyromidic acid, pipemidic acid trihydrate, enoxacin, sinoxacin, ofloxacin, norfloxacin, ciprofloxacin hydrochloride, sulfamethoxazole trimethoprim, 6-fluoro-1-methyl-
7- [4- (5-Methyl-2-oxo-1,3-dioxolen-4-yl) methyl-1-piperazinyl] -4-oxo-4H [1,3] thiazeto [3,2-a] quinoline -3-carboxylic acid.

7. Antiseptics Propantheline bromide, atropine sulfate, oxapium bromide, timevidium bromide, butyl scopolamine bromide, trospium chloride, butropium bromide, N-methylscopolamine methyl sulfate, methyl octatropine bromide.

8. Antitussive, anti-asthmatic agents theophylline, aminophylline, methylephedrine hydrochloride, procaterol hydrochloride, trimethoquinol hydrochloride, codeine phosphate, sodium cromoglycate, trinilast, dextromethorphan hydrobromide, dimemorphan phosphate, clobutinol hydrochloride, Hominobene hydrochloride, benproperin phosphate, tipepidine hibenzate, eprazinone hydrochloride, clofedanol hydrochloride, ephedrine hydrochloride, noscapine, carbetapentene citrate, oxerazine tannate, isoaminyl citrate.

9.Bronchodilator 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.

10. Diuretics furosemide, acetazolamide, trichlormethiazide, methyclothiazide, hydrochlorothiazide, hydroflumethiazide, ethiazide, cyclopentiazide, spironolactone, triamterene, chlorothiazide, piretanide, mefluside, ethacrynic acid, azosemide, clofenamide.

11. Muscle relaxant chlorphenesin carbamate, tolperisone hydrochloride,
Eperisone hydrochloride, tizanidine hydrochloride, mefenesin, chlorzoxazone, fenprobamate, methocarbamol, chlormezanone, pridinol mesylate, afloqualone, baclofen, dantrolene sodium.

12. Brain metabolism improver meclofenoxate hydrochloride.

13.Minor Tranquilizer Oxazolam, Diazepam, Clotiazepam, Medazepam, Temazepam, Fludiazepam, Meprobamate,
Nitrazepam, chlordiazepoxide.

14. Major tranquilizer sulpiride, clocapramine hydrochloride, zotepine, chlorpromazine, haloperidol.

15.β-Blocker pindolol, propranolol hydrochloride, carteolol hydrochloride, metoprolol tartrate, labetalol hydrochloride, acebutolol hydrochloride, bufetrol hydrochloride, alprenolol hydrochloride, arotinolol hydrochloride, oxprenolol hydrochloride, nadolol, bucmolol hydrochloride, indenolol hydrochloride, malein Timolol acid, befnolol hydrochloride, bupranolol hydrochloride.

16.Antiarrhythmic agent Procainamide hydrochloride, Disopyramide, Azimarin,
Quinidine sulfate, Aprindine hydrochloride, Propafenone hydrochloride, Mexiletine hydrochloride.

17. Gout treatment allopurinol, probenecid, colchicine, sulfinpyrazone, benzbromarone, bucolome.

18. Anticoagulant Ticlopidine hydrochloride, dicoumarol, warfarin potassium.

19. Antiepileptics Phenytoin, sodium valproate, metalbital, carbamazepine.

20. Antihistamines Chlorpheniramine maleate, clemastine fumarate, mequitazine, alimemazine tartrate, cycloheptadine hydrochloride.

21. Emetics diphenidol hydrochloride, metoclpramide, domperidone, betahistine mesylate, trimebutine maleate.

22. Antihypertensive agent Reserpiric acid dimethylaminoethyl hydrochloride, resinamine, methyldopa, prazosin hydrochloride, pnazosin hydrochloride, clonidine hydrochloride, pudralazine, brapidil.

23. Sympathetic stimulants dihydroergotamine mesylate, isoproterenol hydrochloride, etilephrine hydrochloride.

24. Synthetic agent Bromhexine hydrochloride, carbocysteine, ethylcysteine hydrochloride, methylcysteine hydrochloride.

25. Oral diabetes treatment agent glibenglamide, tolbutamide, glymidine sodium.

26. Cardiovascular agent Ubidecarenone, ATP-2Na.

27. Iron agent Ferrous sulfate, dried iron sulfate.

28. Vitamins Vitamin B _1, vitamin B _2, vitamin B _6, vitamin
B ₁₂ , vitamin C, folic acid.

29. Treatment for pollakiuria Flavoxate hydrochloride, oxybutynin hydrochloride, terodiline hydrochloride, 4-diethylamino-1,1-dimethyl-2-butynyl (±) -α-cyclohexyl-α-phenylglycolate hydrochloride monohydrate.

30. Angiotensin converting enzyme inhibitors enalapril maleate, alacepril, delapril hydrochloride.

The composition ratio of the drug varies depending on the acid-resistant polymer compound selected, the swelling aid, the drug, the intended swollen product of the present invention or the preparation of the present invention, but is preferably 0.01 to 45% (w / w). It is preferably from 1 to 20% (w / w), more preferably from 5 to 15% (w / w). Less than 0.01% (w / w) may have the form of the swollen product of the present invention depending on the drug.
% (W / w) may not have sufficient acid resistance performance and strength.

In addition, if necessary, a drug release controlling agent, a plasticizer, a fluidizing agent, and the like can be appropriately compounded.

Examples of the drug release modifier include substances that dissolve or swell with an acid or water, and specifically, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyvinyl acetal diethylaminoacetate, polyvinyl pyrrolidone, polyvinyl alcohol, flour , Corn starch, mannitol, lactose, microcrystalline cellulose, low-substituted hydroxypropylcellulose, and the like.

The drug release modifier may be used alone or in combination of two or more. Even if two or more kinds are used, the object of the present invention can be sufficiently achieved.

The drug release modifier can be compounded up to about 45% (w / w) of the composition ratio. If it exceeds 45% (w / w), it may not have sufficient acid resistance performance and strength. Here, the drug release modifier refers to a substance that controls the rate of drug release from the preparation.

The plasticizer and the fluidizing agent are not particularly limited as long as they are usually used in pharmaceutical preparations, and specifically, polyethylene glycol, propylene glycol, glycerin,
Higher fatty acids (lauric acid, tridecanoic acid, myristic acid,
Pentadecanoic acid, palmitic acid, margaric acid, stearic acid, nonadecanoic acid, arachinic acid, behenic acid, lignoceric acid, serotinic acid, montanic acid, etc.), higher fatty acid ester derivatives (the higher fatty acid glycerin listed above,
Esters such as ethylene glycol, propylene glycol, sorbitol and polyethylene glycol. Glycerides of saturated fatty acids obtained from animals and plants, and mixtures thereof, and hardened fats and oils of glycerides derived from these animals and plants. Glycerides of unsaturated fatty acids such as oleic acid, linoleic acid, linolenic acid, ricinoleic acid and mixtures thereof, higher alcohols (pentadecanol, hexadecanol, cetyl alcohol, heptadecanol, stearyl alcohol, nonadecanol, eicosanol, wool) Alcohol, cholesterol, etc.) and higher alcohol ester derivatives (cholesteryl palmitate, plant sterol palmitate, etc.).

The plasticizers and fluidizers may be used alone or in combination of two or more. Even with two or more kinds, the object of the present invention can be sufficiently achieved.

The plasticizer and the fluidizing agent can be blended up to about 10% (w / w) of the composition ratio. If it exceeds 10% (w / w), poor expansion may occur.

By using a plasticizer and a fluidizing agent, frictional resistance generated in the barrel can be reduced, and processing by an extruder can be performed smoothly.

 Next, the method for producing the expanded body of the present invention will be described in detail.

The puffed body of the present invention is an acid-resistant polymer compound, a puffing aid,
It can be manufactured by collectively treating a drug and water as essential components with an extruder.

Here, "collective treatment" means that all the components and water are substantially simultaneously subjected to a treatment possessed by the extruder, such as shearing, mixing, kneading, compression, and extrusion.

In general, an extruder mainly includes a barrel called a barrel, a die corresponding to an outlet, and a screw. There are usually multiple barrels through which the screw passes. The screws include trapezoidal screws, trapezoidal cut screws, trapezoidal reverse cuts, ball screws, kneading paddles, and the like, and any combination thereof can be performed. The raw material sent to the extruder moves in the barrel by a screw, and is subjected to processing such as shearing and mixing in the barrel by the screw, and is extruded from the pores of the die. Normally, each barrel and die can be independently temperature controlled.

In the present invention, an extruder having a basic function such as a function of transporting a high moisture and high oil content raw material and a function of mixing, compressing, pulverizing, and heating, which is generally used in a food field, a plastic field, or the like, may be used as it is. Can be. As long as the extruder has two or more screws, any extruder can be used in the present invention. In addition, if the biaxial extruder having two screws is used, the expanded body of the present invention can be sufficiently obtained.

Batch processing in the extruder does not necessarily have to take place in all barrels and dies of the extruder. If the batch treatment is performed after the inside of a certain barrel, the expanded body of the present invention can be obtained.

As a method of batch treatment with an extruder, all components (acid-resistant polymer compound, expansion aid, drug, other components) and water are kneaded in advance, and this is supplied from the main supply hole of the extruder. Batch processing method, all components are mixed in advance, this is supplied from the main supply hole of the extruder, water is supplied from the auxiliary supply hole and batch processing is performed, `` some components '' in the components are Mixing in advance, supplying this from the main supply hole of the extruder, and supplying the "remaining components" and water from the auxiliary supply holes to collectively process, "one component" in the components
Can be supplied from the main supply hole of the extruder, and the “remaining components” can be supplied from the auxiliary supply hole to perform batch processing. Of these methods, is preferred.

Here, the "main supply hole" refers to the most basic supply hole capable of supplying the raw material into the barrel, and the "auxiliary supply hole" refers to the auxiliary supply of water, additives, and the like into the barrel. A supply hole other than the main supply hole that can be used.

In the above, if necessary, any constituent components and / or
Alternatively, water can be further supplied from the auxiliary supply hole.

In the above, an arbitrary component can be further supplied from the auxiliary supply hole as needed.

In the above description, for example, the acid-resistant polymer compound and the drug can be referred to as “some components”, and the leavening aid and other components can be referred to as “remaining components”. It is preferable to include the acid-resistant polymer compound in “some components”. The “remaining components” can be supplied as a mixture from one auxiliary supply hole, or individual components or a mixture of arbitrary components can be supplied from a plurality of auxiliary supply holes. In any case, the expanded body of the present invention can be obtained. In addition, one or more of the “several components” supplied from the main supply hole may be included in the “remaining components” and supplied from the auxiliary supply hole.

In the above, it is preferable that “one component” is an acid-resistant polymer compound. "Remaining components"
The mixture can be supplied from one auxiliary supply hole, or individual components or a mixture of arbitrary components can be supplied from a plurality of auxiliary supply holes. In any case, the expanded body of the present invention can be obtained. Note that “one component” supplied from the main supply hole may be included in “remaining components” and supplied from the auxiliary supply hole.

To mix or knead each component and water or each component in advance, use a machine such as a kneader mixer, a V-type mixer, a double cone mixer, a cubic mixer, a ribbon mixer, or manually. It can be carried out.

The supply of each component and water into the barrel can be performed manually or by a raw material feeder generally provided in an extruder to be used. It can be done without any restrictions. Examples of such an apparatus include a screw feeder, a table feeder, a belt-conveyor-type fixed feeder, and an electromagnetic feeder.

The amount of each component to be charged into the extruder can be appropriately set within the range of each component ratio described above.

The amount of water used varies depending on the constituent components, the type and type of the extruder, the processing conditions, the intended expanded product of the present invention, etc., but is added in the range of 5 to 20% (w / w) with respect to all the constituent components. be able to. If the amount is less than 5% (w / w), poor expansion may occur, and an excessive load may be applied due to an increase in frictional resistance in the barrel, which may not be discharged. If it exceeds 20% (w / w), poor expansion may occur.

The water mentioned here includes not only simple water but also isotonic water such as physiological saline, neutral or acidic or basic buffer, or aqueous ammonia.

 The processing conditions of the extruder will be described.

The temperature of the barrel and the die of the extruder can be appropriately set according to the constituent components, the model and type of the extruder, the intended expanded product of the present invention, and the like. Specifically, it can be set at 70 to 150 ° C, preferably 100 to 120 ° C. Although the swollen product of the present invention can be obtained at a temperature higher than 150 ° C., the drug or the like may be decomposed at an excessively high temperature. If the temperature is lower than 70 ° C., the expanded product of the present invention may not be obtained.

The number of rotations (processing speed) of the screw can be appropriately set according to the type and type of the extruder, the constituent components, the shape of the screw, and the like, and can be set within the allowable range of the extruder to be used. An extruder with a longer barrel length can increase the rotation speed. This is because the longer the barrel, the higher the processing capacity. Specifically, 50 rpm or more is appropriate, and 50 to 300 rpm is preferable.

Discharge pressure is suitably 10~150kg / cm ^2, 30~120kg
/ cm ² is preferred.

The shape and combination of screws that can be used can be selected without any particular limitation. In addition, it is preferable to use one or more paddles in the shape of kneading paddles (kneading blades) having strong kneading action and shearing action.

The discharge die can be appropriately changed depending on the intended expanded product of the present invention or the preparation of the present invention. Specifically, a discharge die having a pore diameter of 0.5 to 5 mmφ can be used.

It is considered that the expansion phenomenon caused by the extruder occurs because the raw material mixture that has been under appropriate heat and high pressure in the barrel is rapidly returned to normal pressure by being extruded from the die. At that time, since the water present in the raw material mixture is also vaporized at the same time, it is considered that the water vapor also plays a role in the expansion phenomenon by the extruder.

 Hereinafter, the preparation of the present invention will be described in detail.

All the constituent components batch-processed by the extruder become the expanded body of the present invention and are continuously extruded from the pores of the die. This can be cut to a desired length by a suitable cutting machine, for example, a roller type crusher, a cutter mill, a pin mill, or the like. The cut product can be used as it is in the form of granules or fine granules of the present invention. In addition, the expanded body of the present invention extruded from the pores of the die is, for example, a rotary cutter (e.g., rotary cutter, model: 2 blades, rotation speed 0 to 1750 rpm) provided at the tip of the die, and has a desired length. By cutting into pieces, the preparation of the present invention in the form of granules or fine granules can be directly obtained without a special sizing operation.

The capsule preparation of the present invention is obtained by packing only the cut granular or fine-grained expanded product of the present invention or a granular or fine-grained expanded product of the present invention and a drug, a drug-containing compounding agent or an excipient in a capsule or the like. The composition of the present invention can be made into a tablet form by compression molding.

Further, the expanded product of the present invention extruded from the pores of the die, or the product obtained by applying a coating treatment or the like to the cut expanded or compacted product of the present invention is packed as it is or in a capsule. It can also be an inventive formulation. Thereby, the strength of the puffed product of the present invention and the preparation of the present invention can be further improved, and the stability of the drug can be increased.

Effect of the Invention Since the preparation of the present invention has high strength and floating ability, it can be retained in the stomach for a longer time than conventional preparations in the stomach. Further, the preparation of the present invention can have both stable floating ability and drug releasing ability.

The puffed product of the present invention (the preparation of the present invention) can be produced in a large amount simply and basically continuously by an extruder. Therefore, the production method of the expanded product of the present invention (the preparation of the present invention) is industrially excellent.

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples, and Test Examples.

Example 1 Nicardipine hydrochloride 20 g, fudroxypropyl methylcellulose acetate succinate (trade name: Aqoat, AS-
MF, manufactured by Shin-Etsu Chemical Co., Ltd., the same applies hereinafter) 110 g, dried aluminum hydroxide gel 30 g, and flour 90 g were mixed, and this was mixed with a diameter of 3
2mmφ, effective L / D: 20, and screw pattern: 16P, 12P,
9.6P, 8P, 30deg, 8t x 3 screws, 30deg (reverse) screws (both 2 screws), 2-axis extruder equipped with a die of 1mmφ x 5 holes (KEXN-30S-20; Kurimoto Iron Works) , The same applies hereinafter) at a rate of 30 g per minute from the hopper into the main supply hole. The processing temperature was set at 100 ° C for each barrel and die, and the screw rotation speed was 80 rpm while adding purified water at a rate of 2 ml per minute from the auxiliary supply hole.
At the extrusion speed to obtain the expanded product of the present invention.

Example 2 Nicardipine hydrochloride (20 g), hydroxypropylmethylcellulose acetate succinate (200 g), dried aluminum hydroxide gel (20 g) and flour (10 g) were mixed.
The pulverized product of the present invention was obtained under the same conditions as described above.

Example 3 20 g of nicardipine chloride, 217.5 g of hydroxypropylmethyl cellulose acetate succinate and 12.5 g of dry aluminum hydroxide gel were mixed, and the mixture was treated under the same conditions as in Example 1 to obtain an expanded product of the present invention.

Example 4 20 g of nicardipine hydrochloride, 155 g of hydroxypropylmethylcellulose phthalate (trade name: HPMCP, HP-55F grade, manufactured by Shin-Etsu Chemical Co., Ltd .; the same applies hereinafter), 25 g of dried aluminum hydroxide gel, and 50 g of flour were mixed, and the mixture was mixed with each other. The treatment was carried out under the same conditions as in Example 1 to obtain an expanded product of the present invention.

Example 5 20 g of nicardipine hydrochloride, 60 g of hydroxypropyl methylcellulose acetate succinate, 60 g of ethylcellulose (trade name: Ethocel, STD-45 type, manufactured by Dow Chemical Company, the same applies hereinafter), 30 g of anhydrous calcium hydrogen phosphate,
80 g of polyvinyl acetal diethylaminoacetate (trade name; AEA, manufactured by Sankyo Pharmaceutical Co., Ltd .; the same applies hereinafter) was mixed and treated under the same conditions as in Example 1 except that each barrel and die were set at 140 ° C. An expanded body was obtained.

Example 6 20 g of oxybutynin hydrochloride, 150 g of hydroxypropylmethylcellulose acetate succinate, 30 g of dry aluminum hydroxide gel and 50 g of corn starch were mixed and treated under the same conditions as in Example 1 to obtain a puffed product of the present invention.

Example 7 20 g of oxybutynin hydrochloride, 100 g of ethylcellulose, 50 g of synthetic aluminum silicate, and 80 g of flour were mixed, and the mixture was placed in a twin-screw extruder equipped with the same screw and die as in Example 1 at a speed of 30 g per minute. It was thrown into the main supply hole. The processing temperature was set to 120 ° C for each barrel and die, and the screw rotation speed was 100 rpm while adding purified water at a rate of 4 ml per minute from the auxiliary supply hole.
At the extrusion speed to obtain the expanded product of the present invention.

Example 8 20 g of oxybutynin hydrochloride, 150 g of ethylcellulose, 50 g of calcium carbonate and 30 g of corn starch were mixed, and the mixture was supplied to a twin-screw extruder equipped with the same screw and die as in Example 1 at a speed of 30 g per minute from a hopper. It was charged into the supply hole. The processing temperature was set to 100 ° C for each barrel and die, and the propylene glycol 50% (w / w) aqueous solution was added at a rate of 2 ml per minute from the auxiliary supply hole while the screw was rotated at a pushing speed of 100 rpm. Was performed to obtain an expanded product of the present invention.

Example 9 4-diethylamino-1,1-dimethyl-2-butynyl (±) -α-cyclohexyl-α-phenylglycolate hydrochloride monohydrate) 20 g, hydroxypropylmethylcellulose acetate succinate 180 g, dried aluminum hydroxide gel 50 g were mixed, and the same screw as in Example 1 was used, and the diameter was 0.5 mmφ × 1.
A biaxial extruder equipped with a 5-hole die was charged into the main supply hole from the hopper at a rate of 20 g per minute.
The processing temperature was set at 90 ° C for each barrel and die, and the propylene glycol 50% (w / w) aqueous solution was added from the auxiliary supply hole at a rate of 2 ml per minute while the screw was rotated at a pushing speed of 100 rpm. Was performed to obtain an expanded product of the present invention.

Example 10 20 g of riboflavin, 150 g of aminoalkyl methacrylate copolymer RS (trade name; Eudragit, RSPM, publisher: Higuchi Shokai Co., Ltd.), 30 g of talc, and 50 g of polyvinylpyrrolidone (PVP) were mixed, and the mixture was the same as in Example 1. And a twin-screw extruder equipped with a screw having a diameter of 0.7 mmφ and an 8-hole die was charged into the main supply hole from the hopper at a speed of 20 g per minute. The processing temperature was set to 100 ° C for each barrel and die section, and processing was performed at a screw speed of 100 rpm while adding triethyl citrate 30% (w / w) at a rate of 2 ml per minute from the auxiliary supply hole. Was performed to obtain an expanded product of the present invention.

Example 11 50 g of sodium diclofenac, 100 g of hydroxypropylmethylcellulose acetate succinate, 60 g of sodium hydrogencarbonate and 90 g of low-substituted hydroxypropylcellulose were mixed, and the mixture was mixed with a screw having the same diameter as in Example 1 and a die having a diameter of 2 mmφ × 1 hole. The twin-screw extruder was loaded into the main feed hole at a rate of 30 g per minute from the hopper. The treatment temperature was set to 120 ° C. for each barrel and die, and the addition of purified water at a rate of 2 ml per minute from the auxiliary supply hole was carried out at a screw speed of 100 rpm for extrusion to obtain the expanded product of the present invention. Was.

Example 12 diphenidol hydrochloride 50 g, hydroxypropyl methylcellulose acetate succinate 70 g, sodium bicarbonate 20 g, low-substituted hydroxypropylcellulose 60 g
And mixed in a twin-screw extruder equipped with the same screw and die as in Example 1 for 30 minutes per minute.
It was fed into the main feed hole from the hopper at a speed of g. The treatment temperature was set to 120 ° C. for each barrel and die, and the addition of purified water at a rate of 2 ml per minute from the auxiliary supply hole was carried out at a screw speed of 100 rpm for extrusion to obtain the expanded product of the present invention. Was.

Comparative Example 1 Nicardipine hydrochloride (20 g) and hydroxypropyl methylcellulose acetate succinate (230 g) were mixed, and the mixture was supplied to a 12-screw extruder equipped with the same screw and die as in Example 1 at a rate of 30 g per minute from a hopper. It was thrown into the hole. The processing temperature was set to 120 ° C for each barrel and die, and the screw rotation speed was 80 r while adding purified water at a rate of 2 ml per minute from the auxiliary supply hole.
Processing was performed at an extrusion speed of pm to obtain a molded body.

Comparative Example 2 20 g of cycardipine hydrochloride, 220 g of hydroxypropylmethylcellulose acetate succinate and 10 g (4% (w / w)) of dried aluminum hydroxide gel were mixed, and the mixture was treated under the same conditions as in Comparative Example 1 to obtain a molded article. Obtained.

Test Example 1 The expanded product of the present invention obtained in Examples 1 and 2 and Comparative Example 1,
The pore distribution of the molded article obtained in 2 was measured by a mercury intrusion method (use model: Pore Sizer 9320, manufactured by Shimadzu).
The sample was cut to a length of about 8 to 12 mm, and pre-treated (decompressed
After drying at 50 ° C for 15 hours), the measurement was performed.

As a result, as shown in Table 1, the expanded molded articles obtained in Examples 1 and 2 showed large values in the porosity and the pore volume, which indicate the amount of internal voids, but did not contain the expansion aid. Alternatively, the compacts of Comparative Examples 1 and 2 in which the amount of addition was insufficient showed a small value, and it was confirmed that the internal voids of the compact were small. In Examples 1 and 2, the bulk density was also very small.

From these facts, the expanded body of the present invention had a large amount of voids occupying the inside thereof, and the average pore diameter was as fine as 10 to 20 μm.

Test Example 2 The expanded product of the present invention obtained in Examples 1 and 2 and Comparative Example 1,
The shaking strength of the molded body obtained in 2 and the buoyancy at each time point were measured.

100 ml of the Japanese Pharmacopoeia 1st liquid was placed in a 200 ml separating funnel, and each sample was placed therein. The KH shaker (Model VS amplitude 5c)
m, shaking frequency 300 times / min, manufactured by Iwaki Co., Ltd.) for 6 hours, and after a certain time, sampling was performed to measure buoyancy and observe the shape.

The measurement of buoyancy was measured using a micro load transducer (UL-10GR: Shinkoh
(Minebea), and attach the sample attachment to it, attach the sample,
The measurement was performed by electrically measuring the force required for submersion in the liquid.

Each sample was cut to a length of 2 cm, and valrelyse (registered trademark, size 2) containing diazepam as the main drug marketed in West Germany as a floating capsule (floating capsule) was similarly used as a control. Tested.

As a result, as shown in FIG. 1, the swollen body of the present invention obtained in Examples 1 and 2 floated immediately after the test liquid was injected, and the buoyancy was somewhat reduced by shaking. ,
In Example 2, floating was observed even after 6 hours.

On the other hand, in the molded articles of Comparative Examples 1 and 2, sedimentation was observed immediately after the injection of the test solution or a phenomenon of sedimentation shortly after shaking was observed. These floating properties confirmed the results of Test Example 1.

Further, the control product completely collapsed after 1 hour of shaking, whereas the test of Example 1 did not collapse after 4 hours of shaking and the test of Example 2 did not collapse after 6 hours of shaking. The expanded molded article had high strength.

Test Example 3 According to the Japanese Pharmacopoeia dissolution test method 2 (paddle method), 1st liquid 900m
l, a dissolution test of the expanded product of the present invention was performed under the conditions of a paddle rotation speed of 100 rpm.

The expanded product of the present invention as a sample was pulverized using a roll granulator (GRN-1041 type; manufactured by Nippon Granulator Co., Ltd.) to obtain granules in the range of No. 16 (1000 μ) to No. 30 (500 μ). Used for dissolution test.

1) From the granular sample of the swollen product of the present invention obtained in Examples 1, 2 and 3, an amount equivalent to 20 mg of nicardipine hydrochloride was weighed out, subjected to an elution test, sampled every hour, and subjected to nicardipine hydrochloride by high performance liquid chromatography. Was measured.

The swollen product of the present invention exhibited a gradual release property as shown in FIG. 2 while floating, and was also shown to provide an arbitrary release property by changing the amount of the drug release modifier added.

2) From the granular sample of the swollen product of the present invention obtained in Examples 7 and 8, an amount equivalent to 10 mg of oxybutynin hydrochloride was weighed, subjected to a dissolution test, sampled every hour, and subjected to high-performance liquid chromatography to measure the concentration of oxybutynin hydrochloride. Was measured.

The swollen body of the present invention exhibited a gradual release property as shown in FIG. 3 while floating, and it was shown that any release property was imparted by changing the amount of the drug release modifier added.

3) From the granular sample of the swollen product of the present invention obtained in Example 11, 25 g of diclofenac sodium was weighed out, subjected to a dissolution test, sampled every hour, and measured for the concentration of diclofenac sodium by high performance liquid chromatography. did.

The expanded body of the present invention exhibited a gradual release property as shown in FIG. 4 while floating.

4) From the granular sample of the swollen product of the present invention obtained in Example 12, 25 mg of diphenidol hydrochloride was weighed out, subjected to an elution test, sampled every hour, and measured for diphenidol hydrochloride concentration by high performance liquid chromatography. did.

The expanded body of the present invention exhibited a slow release property as shown in FIG. 5 while floating.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows the measurement results of buoyancy. The horizontal axis represents shaking time (hour), and the vertical axis represents buoyancy (mg), respectively. − ○
-Indicates the buoyancy of the expanded body of the present invention obtained in Example 1,-□-
Represents the buoyancy of the expanded product of the present invention obtained in Example 2,-△-represents the buoyancy of the molded product obtained in Comparative Example 1,-▽-represents the buoyancy of the molded product obtained in Comparative Example 2,-●. -Represents the buoyancy of the control product.

FIG. 2 shows the results of the dissolution test. The horizontal axis shows the elution time (minutes), the vertical axis shows the elution rate (%) of nicardipine hydrochloride,
Respectively. -○-represents the elution curve of the expanded product of the present invention obtained in Example 1,-□-represents the elution curve of the expanded product of the present invention obtained in Example 2, and-△-was obtained in Example 3. The elution curves of the swollen product of the present invention are respectively shown.

FIG. 3 shows the results of the dissolution test. The horizontal axis shows the elution time (minutes), and the vertical axis shows the elution rate (%) of oxybutynin hydrochloride.
Represents each. -○-represents the elution curve of the swollen product of the present invention obtained in Example 7, and-□-represents the elution curve of the swollen product of the present invention obtained in Example 8.

FIG. 4 shows the results of the dissolution test. The horizontal axis represents the elution time (minutes), and the vertical axis represents the elution rate (%) of diclofenac sodium. -O- represents an elution curve of the expanded product of the present invention obtained in Example 11.

FIG. 5 shows the results of the dissolution test. The horizontal axis shows the elution time (minutes), and the vertical axis shows the elution rate (%) of difenidol hydrochloride.
Represents each. -O- represents an elution curve of the expanded product of the present invention obtained in Example 12.

──────────────────────────────────────────────────続 き Continued on the front page (58) Fields surveyed (Int. Cl. ⁶ , DB name) A61K 9/00 A61K 9/20-9/22 A61J 3/00

Claims (7)

(57) [Claims] 1. A swollen molded article having an apparent density of less than 1, containing an acid-resistant polymer compound as a main component and at least a swollen auxiliary and a drug, and having a net-like cross section. 2. The expanded molded article according to claim 1, wherein the acid-resistant polymer compound is a pH-dependent coating agent or a pH-independent coating agent. 3. The acid-resistant polymer compound is selected from the group consisting of hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, methacrylic acid copolymer, carboxymethylethylcellulose, cellulose acetate phthalate, ethylcellulose and aminoalkyl methacrylate copolymer. The expanded molded article according to claim 1, which is formed. 4. The acid-resistant polymer compound is selected from the group consisting of hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, methacrylic acid copolymer, carboxymethylethylcellulose, cellulose acetate phthalate, ethylcellulose and aminoalkyl methacrylate copolymer. Wherein the leavening aid is selected from the group consisting of dry aluminum hydroxide gel, synthetic aluminum silicate, calcium hydrogen phosphate, calcium carbonate, precipitated calcium carbonate, calcium hydrogen carbonate and talc. 2. The expanded molded article according to 1. 5. The method according to claim 1, wherein all components and water are collectively processed by a multi-screw extruder.
A process for producing the expanded molded article according to the above. 6. The method for producing an expanded molded article according to claim 5, wherein the multi-axial extruder is a biaxial extruder. 7. A gastric retentive preparation comprising the expanded molded article according to claim 1 or 2.