KR101757147B1 - Process for preparing a melt-extruded release controlled pharmaceutical composition - Google Patents

Abstract

A polymer coating layer comprising a water-insoluble ammonium methacrylate copolymer and a polymer coating layer comprising a polyvinyl acetate and a melt-extruded pellet comprising an active ingredient, and a water-insoluble ammonium methacrylate copolymer formed on the pellet surface; And an oral preparation containing the same.

Description

PROCESS FOR PREPARING A MELT-EXTRUDED RELEASE CONTROLLED PHARMACEUTICAL COMPOSITION [0002]

A polymer coating layer comprising a water-insoluble ammonium methacrylate copolymer, a polymer-coated layer formed by melt-extruded pellets comprising polyvinyl acetate and an active ingredient, and a water-insoluble ammonium methacrylate copolymer formed on the pellets, and ≪ / RTI > is provided.

Controlled release formulations are intended to modulate the release of the active ingredient as intended to effectively control the drug ' s blood levels, and often to maintain the drug ' s blood concentration in the treatment area for prolonged periods of time, . Such a controlled-release preparation has been spotlighted as a preparation which improves convenience of patient's medication by maintaining the drug concentration, maintains an appropriate blood concentration, improves treatment efficiency, and increases safety because of reduced side effects. Especially, the need for more frequent use of medication (for example, 2 to 4 times a day) is more urgent for patients who are uncomfortable or for patients whose medication compliance is low.

Schizophrenia is often mixed with a multitude of emotional, behavioral, and mental disabilities that require long-term treatment because of persistent or recurrent psychotic states. In addition, patients have low self-medication intentions and often refuse to take medication. Therefore, they are developed as a controlled-release medicine, and they are often developed as a sustained-release injectable drug once a day for oral administration or for more than one week or one month.

Paliperidone is a treatment for atypical schizophrenia called 9-hydroxy risperidone. It was designed by Janssen as an OROS (Osmotic Release Oral Delivery System) formulation and was released as a once-a-day sustained-release formulation in which the drug is released in zero order for 24 hours. (Invega ^TM Seojungjeong) is also available as an injectable once-monthly injection of paliperidone palmitate. (Invega ^TM Sustenna) paliperidone is one of the active metabolites of risperidone, which has a structure with additional hydroxyl groups in addition to risperidone. Is being used in the treatment of acute and chronic schizophrenia. Because it does not go through liver metabolism, it is not influenced by factors such as liver dysfunction, liver damage, metabolic enzyme, individual difference. Paliperidone does not dissolve well in water, it dissolves well in methylene chloride, and dissolves in methanol and 0.1 N hydrochloric acid.

Hot melt extrusion, which has been used for a long time in the plastics industry, has recently been combined with the pharmaceutical business, and many studies have been conducted to improve the bioavailability and control the release of the drug.

US 6488963 discloses the preparation of controlled release formulations by high temperature melt extrusion of high molecular weight polyethylene (poly (ethylene oxide)] and active ingredients having molecular weights of approximately one million to ten million. However, with this composition, sustained-release preparations can be formed within a period of 12 hours, but there may be a disadvantage that release control is difficult for more time.

KR10-1189038 discloses a controlled release pharmaceutical formulation comprising hot molten extruded multiparticulates comprising a rubbery matrix containing an active ingredient and a neutral poly (ethyl acrylate, methyl methacrylate) copolymer. (Ethyl acrylate, methyl methacrylate) copolymer is provided in a form dispersed in an aqueous solution. Therefore, it is necessary to add an additional process such as a wet granulation method before use .

WO 9614058 discloses a melt extrusion formulation made from a drug and at least one material selected from the group consisting of alkyl celluloses, acrylic and methacrylic polymers and copolymers, shellac, jane, hydrated castor oil, hydrated vegetable oils and mixtures thereof .

However, these prior studies may lack control of release to a variety of drugs, especially if they last for more than 12 hours, or that drug release is not significantly affected by pH, or that drug release is close to zero I can not.

Thus, it is possible to control the side effects of rapid drug release and to control the release pattern of the drug so that the effect of the drug can be sustained, the release of the drug for a longer period of time, There is still a need for a composition for controlling emission which can be stably controlled so as to be close to zero difference without being influenced.

The present invention relates to a pharmaceutical composition for controlled release comprising a polymer coating layer comprising a water-insoluble ammonium methacrylate copolymer, a melt-extruded pellet comprising polyvinyl acetate and an active ingredient, and a water-insoluble ammonium methacrylate copolymer formed on the pellet Thereby providing a technique for effectively controlling the release of the active ingredient as desired.

One embodiment is a controlled release pharmaceutical composition comprising a polymeric coating layer comprising a water insoluble ammonium methacrylate copolymer, a melt extruded pellet comprising polyvinyl acetate and an active ingredient, and a water insoluble ammonium methacrylate copolymer formed on the pellet Lt; / RTI >

Another embodiment provides an oral preparation comprising the pharmaceutical composition for controlled release.

Another embodiment provides a method for preparing the pharmaceutical composition for controlled release.

The present invention relates to a pharmaceutical composition for controlled release which is capable of effectively controlling the release of an active ingredient as desired and an oral preparation containing the same.

Hereinafter, the pharmaceutical composition for controlled release according to the present invention and the oral preparation containing the same will be described in more detail.

Definition of Terms

Unless expressly stated otherwise, some terms used throughout this specification may be defined as follows.

The word "comprising" or "containing ", unless the context clearly dictates otherwise throughout the specification, refers to any element (or component), including without limitation, the addition of another component .

In addition, the "active ingredient" may be a drug (a base drug without a separate salt), a pharmaceutically acceptable salt of the drug, an isomer of the drug, or a mixture thereof.

Also, "release control" means that the release of the active ingredient contained is controlled according to a desired pattern and includes controlled release, slow release, delayed release, pulsed release, or mixed release.

Pharmaceutical composition for controlled release

The pharmaceutical composition for controlled release comprising melt-extruded pellets comprising a polymer material in combination with the active ingredient provided in the present invention and a polymer coating material for release control formed to enclose the pellets,

1) effectively control the release of the active ingredient as desired,

2) the release of the active ingredient can be sustained for up to 24 hours,

3) the release of active ingredient can be kept constant regardless of pH change,

4) the release of the active ingredient is kept close to zero.

Accordingly, the pharmaceutical composition for controlled release can effectively maintain the effective blood concentration of the active ingredient for a certain period of time or longer, thereby enhancing the convenience of taking the patient, improving the compliance with the medication, and improving the bitter taste It is possible to increase the therapeutic effect on the patient when administered orally.

According to one embodiment,

Water insoluble ammonium methacrylate copolymer, polyvinyl acetate, and melt extruded pellets comprising the active ingredient, and

A polymer coating layer comprising a water-insoluble ammonium methacrylate copolymer formed on the pellet surface

And a pharmaceutically acceptable carrier.

In another embodiment, there is provided an oral preparation comprising the pharmaceutical composition for controlled release.

Pellets

The pellet comprises a water insoluble ammonium methacrylate copolymer, polyvinyl acetate and an active ingredient.

The water-insoluble ammonium methacrylate copolymer may be poly (ethyl acrylate / methyl methacrylate / trimethyl ammonium methacrylate chloride). The water-insoluble ammonium methacrylate copolymer may have a molecular weight range of 20,000 to 500,000 Da, such as 50,000 to 300,000 Da, or 100,000 to 200,000 Da.

In one embodiment, the water-insoluble ammonium methacrylate copolymer may have an ability to penetrate water or the like depending on the content ratio of the trimethylammonium chloride methacrylate unit. For example, the water-insoluble ammonium methacrylate copolymer may have a composition in which the content of trimethylammonium methacrylate chloride unit is 8.0 to 15.0% by weight based on the weight of the total copolymer (e.g., Eudragit RL, Evonik) 2.0 to 7.99 wt% (for example, trade name: Eudragit RS, Evonik), or a mixture thereof.

The higher the content of the trimethylammonium methacrylate unit in the water-insoluble ammonium methacrylate copolymer, the faster the penetration of water or the release of the drug. The lower the content of the trimethylammonium methacrylate unit, Release is slow. For example, when the content of the trimethylammonium chloride chloride methacrylate unit is 8.0 to 15.0% by weight (for example, trade name: Eudragit® RL, Evonik), the permeation of water or the release of the drug is relatively fast, and trimethylammonium chloride When the content of the acrylate unit is from 2.0 to 7.99% by weight (for example, trade name: Eudragit RS, Evonik), the penetration of water or the release of the drug is relatively slow.

All of the polymers contained in the water-insoluble ammonium methacrylate copolymer are insoluble polymers and do not dissolve in water or a dissolution test solution, and the release rate of the drug is hardly changed according to the pH.

The polyvinyl acetate may be used alone or as a mixture physically mixed with polypyrrolidone. The polyvinyl acetate may have an average molecular weight of 50,000 to 1,000,000 Da, for example, 100,000 to 800,000 Da or 300,000 to 600,000 Da. The polypyrrolidone may have a molecular weight of 10,000 to 500,000 Da, for example, 10,000 to 200,000 Da. When the polyvinyl acetate is a mixture with polypyrrolidone, the mixing ratio is 9.9: 0.1 to 5: 5, specifically 9.5: 0.5 to 6: 4, more specifically 9: 1 to 7: 3, To 9: 1 to 8: 2 (polyvinyl acetate weight: polypyrrolidone weight). In the present invention, the inclusion of polyvinyl acetate in the pellet enables the controlled release of the drug to be carried out to be more variously and smoothly performed.

The polyvinyl acetate may be Kollicot® SR30D or Cololidon® SR. The above-mentioned Kollicot® SR30D is a solution in which polyvinyl acetate is dispersed in 30% by weight, and in order to stabilize dispersion, polypyrrolidone is mixed with polyvinyl acetate in a ratio of 9: 1. ColliDon® SR is a physical blend of polyvinyl acetate and polypyrrolidone at 8: 2 by weight. At this time, the polyvinyl acetate may have an average molecular weight of 50,000 to 1,000,000 Da, for example, 100,000 to 800,000 Da or 300,000 to 600,000 Da. The polypyrrolidone may have a molecular weight of 10,000 to 500,000 Da, for example, 10,000 to 200,000 Da. In one example, the polyvinyl acetate may be Colidon SR.

In the pellet, the mixing ratio of the water-insoluble ammonium methacrylate copolymer to the polyvinyl acetate is 1: 0.05 to 20, more preferably 1: 0.1 to 10 (by weight, water-insoluble ammonium methacrylate copolymer weight: Acetate weight). If the mixing ratio of the water-insoluble ammonium methacrylate copolymer and polyvinyl acetate is out of the above range, the degree of alignment of the polymer chains may be changed, and the effect of delaying the late dissolution may be excessively exhibited.

The weight ratio of the polymer mixture in which the water insoluble ammonium methacrylate copolymer and polyvinyl acetate are mixed with respect to the active ingredient in the pellet is 1: 1 to 100, specifically 1: 5 to 80, more specifically 1:10 to 60 (Above, active ingredient weight: polymer mixture weight). If the weight ratio of the polymer blend to the active ingredient is less than the above range (i.e., the content of the active ingredient is excessive), the pellets may not be properly formed and may be crumbled or debris may be generated excessively. That is, when the content of the active ingredient is too small), there is a problem that the size of the preparation becomes excessively large.

The active ingredient may comprise at least one member selected from the group consisting of a drug, a pharmaceutically acceptable salt of the drug, and an isomer of the drug.

The active ingredient applicable may be any active ingredient which requires release control and is not particularly limited. For example, the active ingredient that can be formulated into the pharmaceutical composition for controlled release of the present invention may be at least one selected from the group consisting of, but not limited to,

Aripiprazole, clozapine, olanzapine, quetiapine, risperidone, ziprasidone, fluphenazine, haloperidol, perphenazine, trifluoperazine, phimozide, aripiprazole, prochlor Antipsychotic drugs such as ferrazine, thiothysene, paliperidone, and the like;

Amlodipine, mirtazapine, bupropion, amoxapine, phenelzine, tranylcypromine, citalofram, fluoxetine, fluobosamine, paroxetine, sertraline, venlafaxine, mafrotilin, trazodone, Antidepressants such as tiline, clomipramine, desipramine, dessefine, imipramine, nortriptyline, prothropylline, trimipramine and the like;

Degenerative neurodegenerative drugs such as amantadine, benztropine mesylate, carbidopa and levodopa, donepezil, bromocriptine, pergolide, pramiphexol, lopinilol and the like;

Anti-ADHD (Attention Deficit Hyperactivity Disorder) drugs such as methylphenidate, achomocetin and the like;

Pravastatin, phenytozine, thiabergine, topiramate, topiramate, topiramate, topiramate, pregabalin, racosaimide, carbamazepine, clonazepam, ethoxysilide, felbamate, gabapentin, lamotrigine, levetiracetam, oxacarbazepine, Anticonvulsants such as mate, valproic acid, divalproex sodium, and jonisamid;

The present invention relates to a medicament for the treatment and / or prevention of a disease, such as alprazolam, lorazepam, oxazepam, chlordiazepoxide, clorazepate, diazepam, halazepam, midazolam, triazolam, zaleprone, zolpidem, , Anaphylactic, sedative or hypnotic agents such as meflobamate, phenobarbital, chloral hydrate, etchlorvinol, glutetimide, pentobarbital, secobarbital and the like;

Erectile dysfunction drugs such as sildenafil, vardenafil, alprostadil, tadalafil, mirodenefil, and udenafil;

Immunosuppressive agents such as azathioprine, cyclosporin, mycophenolate mopetil, sylolimus, tacrolimus and the like;

But are not limited to, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, Examples such as minoxidil, moexipril, trandolapril, candesartan, irbesartan, losartan, telmisartan, valsartan, guanabenzoate acetate, guanadrel sulfate, guanfacine hydrochloride, Hypertensive drugs;

Beta-adrenergic receptor antagonists such as cortisol, cortisol, cortisol, cortisol, cortisol, cortisol, cortisol, Adrenaline blocking drugs;

Calcium channel blockers such as amlodipine, bepridil, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisol dipine, verapamil and the like;

Lipid lowering drugs such as fenofibrate, gemfibrozil, niacin, atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin and the like;

But are not limited to, simpuride, itopride, domperidone, trimesbutin, metoclopramide, bisacodyl, diphenoxylate hydrochloride and atropine sulfate, doxate salts, looperamide, magnesium salts, methocloframide, The same gastrointestinal motility drug;

Clotting agents and anticoagulants such as clopidogrel bisulfate, phytonadione, ticlopidine, and sodium paraparin;

Vasodilators such as lima frost, vera frost, and sapogrelate;

Anti-migraine drugs such as almotriptan, ergotamine tartrate, probastriptan, methysergide maleate, sumatriptan succinate, zolmitriptan and the like;

Anti-rheumatic drugs such as auranopin, azathioprine, cyclosporine, hydroxychloroquine sulfate, reupunomide, methotrexate, penicillamine, sulfasalazine and the like;

But are not limited to, acetaminophen, aspirin, dichlorophenac, etodolac, fenoprofen, ibuprofen, ketoprofen, naproxen, indol methacin, ketoalloc, sulindac, tolmetin, meclofenamate, mefenamic acid, Non-steroidal anti-inflammatory drugs such as meloxicam, piroxicam, celecoxib, rofecoxib and the like;

Opioids such as buprenorphine, codeine, fentanyl, hydrocodone, hydro morphone, laborpanol, meperidine, morphine, oxicodone, pentazocine, propoxyphene and the like;

Non-analgesic analgesics such as tramadol, tampertol;

Anticancer agents such as imatinib, elotinib, sunitinib, sorafenib, lapatinib, zetitnib, dasatinib and lenalidomide;

Anti-mycobacterium drugs such as aminosalicylate, clofazimine, cycloserine, ethionamide, rifabutin and the like;

Anti-parasitic drugs such as albendazole, ivermethine, mebendazole, plagiocantel, and the like;

Antiviral drugs such as valacyclovir, didanosine, palmyclovir, published cyclovir, indinavir, lamivudine, nelfinavir mesylate, nevirapine, ritonavir, stavudine, oseltamivir phosphate and the like;

Beta-lactam such as amoxicillin, amoxicillin and potassium clavulanate, ampicillin, cefuroxin sodium, cefuroxime acetyl, penicillin G and Y salts, cefditoren, sepicc, clock factin sodium, dicloxycin sodium and the like;

Markrolide antibiotics such as erythromycin esters, erythromycin ethyl succinate, erythromycin stearate, and the like;

Fluoroquinolones such as ciprofloxacin, enoxacin, and the like;

Tetracycline such as demeclocycline hydrochloride, doxycycline calcium, tetracycline, tetracycline hydrochloride and the like;

Alkylating agents such as althretamine, vanillin, chlorambucil, melphalan, cyclophosphamide, proccarbazine hydrochloride, temozolomide and the like;

Antimetabolites such as methotrexate, mercaptopurine, thioguanine and the like;

Hormonal drugs and antagonists such as bicalutamide, flutamide, nilutamide, aminoglutethimide, anastrozole, exemestane, letrozole, tamoxifen citrate, toremifensitrate and the like;

Mitotic inhibitors such as etoposide phosphate and the like;

Aminodalon hydrochloride, digoxin, dysopyramide phosphate, dofetilide, plicainide acetate, mesylate hydrochloride, morishine hydrochloride, procainamide hydrochloride, propphenone hydrochloride, quinidine sulfate, quinidine glucoside Drugs for treating arrhythmias such as Nate, Sartorol Hydrochloride, Tocanide and the like;

Nitrates such as isosorbide dinitrate, nitroglycerin, sodium nitroprusside and the like;

Glaucoma medications such as acetazolamide, dichlorphenamide, metazolamide and the like;

Drugs for the treatment of acid-pepsin such as aluminum carbonate, aluminum hydroxide, magnesium hydroxide, sodium bicarbonate, calcium carbonate, mangaldate and the like;

Bismuth salts, cimetidine, famotidine, nizatidine, ranitidine, misoprostol, lansoprazole, omeprazole, pantoprazole, rabeprazole, sucralfate and the like;

But are not limited to, but are not limited to, but are not limited to, butyricin, cyclin, cyclin, dimenhydrinate, diphenhydramine, , Pomegranate agents such as dolasitone, granisetron, ondansetron, dexamethasone, laajepam, ganisitron, ramosetron, aprepitant and the like;

Hematopoietic drugs such as iron salts;

Adrenal hormones such as cortisone, hydrocortisone, methylprednisolone, prednisone, triamcinolone, betamethasone, dexamethasone, furoproctcisone and the like;

Such as anti-diabetic drugs such as acarbose, metformin, nateglinide, repaglinide, acetohexamide, chlorpropamide, tolazamide, tolbutamide, glymefrid, glipizide, gliburide, pioglitazone, rosiglitazone, drug;

Contraceptives such as Norrettinone, Norgestrel, Levonorgestrel and the like;

Feminine hormones such as estradiol and its esters, estrogen, estropypate, medroxyprogesterone, mifepristone, norretindron acetate, progesterone, laloxifene and the like;

Thyroid and antithyroid drugs such as iodide, sodium levothioxin, sodium thiothiocyanate, riotrix, methimazole, propylthiouracil and the like;

But are not limited to, amylolide hydrochloride, bumetanide, ethacrynic acid, furosemide, torsemide, hydrochlorothiazide, chlothiazide, chlortalidone, indapamide, metolazone, polythiazide, Diuretics such as tricomethiazide, spironolactone, triamterene and the like;

Electrolytic materials such as chelated magnesium, magnesium chloride, magnesium hydroxide, magnesium oxide, potassium salts and the like;

Gout treatment drugs such as allopurinol, colchicine, probenecid, sulfinpyrazone and the like;

Asthma treatment agents such as albuterol sulfate, montelukast sodium, theophylline, zileuton and the like;

But are not limited to, acarbastine, azatadine, bromopenyramine maleate, carbinoxamine maleate, cetirizine hydrochloride, chlorpenilamine maleate, diphenhydramine hydrochloride, clemastine fumarate, ciprohepadine hydrochloride, Antihistamines such as hydroxyzine, loratadine, desloratadine and the like;

Cough suppressing drugs or cold treatment drugs such as dextromethorphan hydrobromide, guaifenesin, pseudoephedrine hydrochloride and the like; And

Health functional foods.

According to one embodiment, the pellets may have an average particle size of 5 to 4500 占 퐉, specifically 10 to 4500 占 퐉, more specifically 20 to 2000 占 퐉, more specifically 50 to 1500 占 퐉 or 100 to 1200 占 퐉. If the size of the pellet is smaller than the above range, there may be disadvantages due to static electricity and manufacturing disadvantage. In the next process, polymer coating may take an excessive amount of time and coating solution. If the pellet size is larger than the above range, It may be difficult to take, and it may be difficult to make a uniform preparation. Therefore, the pellet size should be within the above range.

The shape of the pellet is not particularly limited and may be, for example, a cylinder, a sphere, a rugby ball, an oval, a disk, a cube, a rectangular parallelepiped, or other polyhedron.

The pellets may have a predetermined shape and size in order to uniformly form the polymer coating layer on the surface.

The pellet may be prepared by various methods, and the production method thereof is not particularly limited, but the pellet may be prepared by a high-temperature melt extrusion method in order to improve the bioavailability and / or the sustained release of the active ingredient. High-temperature melt extrusion is applied to the pharmaceutical industry, which has been mainly used in the plastics industry, and can be applied within a range in which the stability of the drug can be confirmed.

The method of producing the pellet includes: mixing an active ingredient, a water-insoluble ammonium methacrylate copolymer, and polyvinyl acetate; Hot-melt extruding the mixture; And optionally stretching and / or cutting the extruded extrudate.

The hot melt extrusion step may be performed using a conventional extruder, such as a hot melt extruder, which may be a single screw or a double screw extruder. Basically, the mixture for making the pellets can be injected to pass through a cylinder containing a screw having a different temperature for each zone. For example, the extruder can be a double screw extruder, which is advantageous for conveying, compounding, and compressing the mixture, as well as for providing better mechanical energy. The extruder may further be equipped with heating means and cooling means as necessary. Tubes containing screws with different temperatures in each zone may be divided into two zones or three or more zones. For example, the high-temperature melt extrusion may be performed at a temperature of 50 to 250 ° C, specifically 60 to 200 ° C, more specifically 70 to 180 ° C, have. For example, the temperature of the introduction part into which the mixture is introduced may be set to a relatively low level of about 50 to 130 ° C, and the temperature of the middle part may be set to the highest level of about 120 to 250 ° C so as to melt the polymer and smoothly mix with the active ingredient, The temperature of the last part may be set to be lower than the middle part, but it is not limited thereto.

The mixing and kneading steps (high temperature melting step in the extruder) may vary depending on the number, shape, length and arrangement of the screws. For smooth melt extrusion, it is preferred that the residence time of the mixture is short and the shear force is usually below that, which is especially important when the active ingredient is sensitive to heat.

The rotational speed of the screw can play an important role in the quality of the pellet produced. For example, if the screw rotation is too slow, the residence time of the mixture becomes unnecessarily long, and if the screw rotation is too fast, the pellets having unnecessary voids can be produced if the mixing rate of the mixture does not follow, So that an unreasonable force can be applied. Therefore, the rotation speed of the screw is preferably in the range of 30 to 300 rpm.

A vacuum may be connected to the extruder barrel to remove residual water and solvent remaining in the entrapped air and components in the extruder barrel and to facilitate the manufacture of dense pellets without unnecessary voids .

The contents in the extruder can be extruded through the head of the extruder. The head of the extruder can be manufactured in various shapes. Typically, it can be produced in a circular shape having a fixed diameter, for example, a diameter of 0.1 to 10 mm, and can also be formed into a triangular, rectangular, or polygonal structure. For example, the head of the extruder may be circular.

In one embodiment of the present invention, the strands melt extruded and discharged from the head can be wound into a winder while stretching, and the thickness of the strand can be adjusted according to the winding speed. At this time, a laser measuring instrument can be used to continuously measure the diameter of the strand.

In one embodiment, the strands that are melt extruded and released from the head can be cut and connected to a cutter. The cutter may be located immediately before the head of the extruder or after the extruded extrudate has undergone a cooling process while passing through air or a tube filled with a medium (air, solvent, or solution). Alternatively, after the melt extrusion is completed, it may be cut off using separate separate operations and equipment. For example, a rotary blade cutter can be used as a cutter. The shape and size of the pellets can be varied by adjusting the shape of the blades of the strands, the direction and speed of rotation of the blades, and the feed rate.

The overall shape, quantity, quality and reproducibility of the pellet are important factors affecting the shape, quantity, and quality of the pellet, so that the shape, quantity, quality and reproducibility of the pellet are influenced by the arrangement of the mixer, the melt extruder, the conveyor, And it is easily understood by a person having ordinary skill in the art to which the present invention belongs.

When pellets are produced using high temperature melt extrusion, it is possible to eliminate the use of unnecessary solvents, to simplify the process, to maintain the crystalline form of the drug or to convert it into an amorphous form, and to manufacture the pellet in a relatively short time . In addition, the size and shape of the pellets can be variously manufactured by various methods such as dicing, drawing, and cutting method at the time of extrusion.

When the stability of the drug is deteriorated at high temperatures, it may be solved by lowering the operating temperature by a method such as the addition of a plasticizer.

As described above, in the process of manufacturing the pellet through the high-temperature melt extrusion method, the additional purpose of high-temperature melt extrusion efficiency, stability of the active ingredient, appearance, color, protection, maintenance, bonding, performance improvement, In addition, a variety of biologically inert ingredients may be used.

The specific kind of the biologically inert ingredient, how to use it, and how to add the substance to the pellet can be easily performed in view of the technical skill of a person skilled in the art, and can be modified in various categories Do.

According to one embodiment, the biologically inert ingredient which may additionally be included in the pellet is selected from the group consisting of plasticizers, lubricants, colorants, flavors, surfactants, stabilizers, antioxidants, foaming agents, defoamers, paraffins, waxes and the like It may be more than one kind. The specific kind and content of each of the illustrated biologically inert ingredients can be easily selected in view of the technical skill of a person skilled in the art and can be modified in various categories.

For example, the plasticizer may be used in an amount of 30 wt% or less (e.g., 0 to 30 wt% or 0.1 to 30 wt%), specifically 20 wt% or less (e.g., 0 to 20 wt% % Or 0.1 to 20% by weight), more specifically 10% by weight or less (e.g., 0 to 10% by weight or 0.1 to 10% by weight).

For example, the plasticizer is selected from the group consisting of triethyl citrate, dibutyl phthalate, diethyl phthalate, dibutyl sebacate, diethyl sebacate, tributyl citrate, acetyl triethyl citrate, acetyl triethyl citrate, propylene glycol, triacetin , Polyethylene glycol, cetyl alcohol, stearyl alcohol, and cetostearyl alcohol. However, the present invention is not limited thereto. In an embodiment, the plasticizer may be at least one selected from the group consisting of triethyl citrate, dibutyl phthalate, diethyl phthalate, dibutyl sebacate, and diethyl sebacate.

The lubricant may be contained in an amount of 0.01 to 30% by weight based on the dry weight of the whole polymer used in each pellet. The content of the lubricant is preferably 0.01 wt% or more with respect to the dry weight of the whole polymer in order to improve the flowability of the mixture to be introduced into the high-temperature melt extruder and to reduce the friction inside the screw to produce a smooth extrusion effect. Considering the efficiency, it can be made up to 30% by weight or less.

Specifically, the lubricant may be at least one selected from the group consisting of stearic acid, glyceryl behenate, glyceryl monostearate, magnesium stearate, calcium stearate, silicon dioxide, talc, and magnesium silicate.

Polymer coating layer

In the pharmaceutical composition for controlled release, the polymer coating layer formed on the surface of the pellet is coated to wrap the pellet, thereby forming a coating film on the pellet surface to effectively control the release of the active ingredient contained in the pellet.

Particularly, the pharmaceutical composition for controlled release according to the present invention has an advantage that it can more effectively control the release pattern of the active ingredient by having a polymer coating layer on the pellet surface as well as a sustained-release matrix of the active ingredient contained in the pellet have. In addition, by controlling the weight ratio of the coating layer, it is possible to more easily design a pharmaceutical composition having an ideal release pattern.

The coating layer may comprise a water-insoluble ammonium methacrylate copolymer. The water-insoluble ammonium methacrylate copolymer may be poly (ethyl acrylate / methyl methacrylate / trimethyl ammonium methacrylate chloride). The water-insoluble ammonium methacrylate copolymer may have a molecular weight range of 20,000 to 500,000 Da, such as 50,000 to 300,000 Da, or 100,000 to 200,000 Da.

In one embodiment, the water-insoluble ammonium methacrylate copolymer may have an ability to penetrate water or the like depending on the content ratio of the trimethylammonium chloride methacrylate unit. For example, the water-insoluble ammonium methacrylate copolymer may contain 8.85 to 11.96 wt% (for example, trade name: Eudragit® RL, Evonik) or 2.0 to 8 wt% of a trimethylammonium methacrylate unit based on the weight of the total copolymer 7.99% by weight (e.g., trade name: Eudragit RS, Evonik), or a mixture thereof.

The higher the content of the trimethylammonium methacrylate unit in the water-insoluble ammonium methacrylate copolymer, the faster the penetration of water or the release of the drug. The lower the content of the trimethylammonium methacrylate unit, Release is slow. For example, when the content of the trimethylammonium chloride chloride methacrylate unit is 8.0 to 15.0% by weight (for example, trade name: Eudragit® RL, Evonik), the permeation of water or the release of the drug is relatively fast, and trimethylammonium chloride When the content of the acrylate unit is from 2.0 to 7.99% by weight (for example, trade name: Eudragit RS, Evonik), the penetration of water or the release of the drug is relatively slow.

The water-insoluble ammonium methacrylate copolymer contained in the pellet and the water-insoluble ammonium methacrylate copolymer contained in the polymer coating layer are the same in terms of the content ratio of each unit, the molecular weight of each unit and / or the total molecular weight Or may be different, and may be appropriately selected depending on the kind of the active ingredient.

The weight of the polymer coating layer formed on the surface of the pellet is 1 to 500% (0.01 to 5 times), for example, 2 to 300% (0.02 to 3 times), 3 to 100% (0.03 to 1 time) Or 4 to 50% (0.04 to 0.5 times).

On the other hand, the polymer coating layer may have an average thickness of 2 to 500 μm, specifically 3 to 400 μm, more specifically 4 to 250 μm. The average thickness of the active ingredient may preferably be 2 占 퐉 or more so that the active ingredient release control effect can be exhibited and the average thickness thereof is preferably 500 占 퐉 or less so that the active ingredient can be effectively released from the intestine.

The polymer coating layer may be formed from a coating solution in which the water-insoluble ammonium methacrylate copolymer is mixed with a suitable solvent. The solvent may be at least one selected from the group consisting of water and a straight chain or branched alcohol having 1 to 4 carbon atoms such as methanol, ethanol, isopropyl alcohol, propanol, and the like. The water insoluble ammonium methacrylate aerial The coalescent concentration may be from 1 to 40% by weight.

According to one embodiment, the polymer coating layer may be formed by coating the polymer coating liquid on the surface of the pellet using a conventional apparatus such as a general coater, a fluidized bed coater, a fluidized bed coater, or a fluidized bed granulator. Specifically, the fluidized bed system with bottom spray, Centrifugal granulator, and Granurex (manufactured by Freund) can be used for the above process.

On the other hand, for the additional purpose of forming the polymer coating layer, such as coating efficiency, stability of the active ingredient, appearance, color, protection, maintenance, bonding, performance improvement, manufacturing process improvement or auxiliary emission control, The polymeric coating solution may further comprise various biologically inert components in addition to the water-insoluble ammonium methacrylate copolymer.

The biologically inert ingredient may be at least one selected from the group consisting of a plasticizer, a lubricant, a surfactant, a lubricant, a defoamer, a colorant, a flavoring agent, a sweetener, a stabilizer, an antioxidant, a paraffin, a wax, The details of this are as described in the description of the pellet described above.

The pharmaceutical composition for controlled release according to the present invention is prepared by a method described in Korean Pharmacopoeia (KP VIII) dissolution test method (Method 2 paddle method: 100 revolutions per minute, pH 1.2, pH 4.0, pH 6.8, water, 0.1N HCl , Elution pattern in which 80% by weight of the total amount of the active ingredient is eluted for 8 to 24 hours.

Oral preparation

Another embodiment provides an oral preparation comprising the pharmaceutical composition for controlled release. The oral preparation may have an elution pattern in which 80% by weight of the total amount of the active ingredient elutes for 8 to 24 hours. Thus, the oral preparation can slowly release the active ingredient for a relatively long period of time, so that the efficacy can be sustained.

The oral preparation may contain 0.005 to 2000 mg of the active ingredient per unit dosage form, and it shows the elution pattern of the optimized active ingredient, so that even if it is taken once or twice per day, the desired drug efficacy is continuously obtained have.

The oral preparation can be formulated in a conventional manner in the art to which the present invention belongs without any particular limitation.

According to one embodiment of the present invention, the oral preparation may be a capsule, a tablet (general tablet, double tablet, chewable tablet, disintegrating tablet), a dry syrupy preparation, a syrup, a jelly or a granule, May be a capsule or tablet, and more preferably it may be a fast-disintegrating tablet.

The oral preparation may be selected from the group consisting of an excipient, a disintegrant, a binder, a lubricant, a colorant, an aroma, a sweetener, a surfactant, a stabilizer, a foaming agent, an antioxidant and the like in addition to the pharmaceutical composition for controlled release, And may further comprise at least one additive.

According to one embodiment of the present invention, the capsules may be prepared by mixing the pharmaceutical composition for controlled release according to the present invention with one or more additives selected from the group consisting of a lubricant, an excipient, and the like, and then filling the composition into a hard capsule. The above general tablet or chewable tablet may be prepared by subjecting the composition for controlling release according to the present invention together with additives to at least one selected from the group consisting of excipients, disintegrants, binders, lubricants, colorants, fragrances and sweeteners. The syrup may be prepared by uniformly dispersing the controlled release composition according to the present invention in a syrup and preventing the active ingredient from being released into the syrup during storage.

In addition, when formulated in the form of a rapid-release marine tablet that improves the patient's convenience of taking, it can be disintegrated in the oral cavity and taken without water, so that in the case of elderly patients, patients with dysphagia, It is easy to take medication even in the back. In addition, in the case of the fast-disintegrating tablet, the release pattern of the active ingredient can be controlled by the pellets contained in the pharmaceutical composition according to the present invention to exhibit optimal drug efficacy.

Particularly, since the fast-disintegrating tablets remain in the oral cavity for a while when they are taken, it is preferable to shield the bitter taste of the drug. However, the addition of sweeteners, fragrance and the like may not provide sufficient shielding of bitter taste. However, when the pharmaceutical composition for controlled release according to the present invention is used, the release of the drug is inhibited in the oral cavity for 1 minute or more (for example, 3 minutes or more). The fast-breaking tablet may contain known disintegration ingredients such as WOWTAB®, Zydis®, OraSolv®, DuraSolv®, QuickSolv®, FlashTab®, AdvaTab®, Lyoc®, FlashDose®, Frosta®, And the mixing ratio and mixing method thereof can be easily selected in view of the technical skill of a person skilled in the art to which the present invention belongs.

In order to prevent damage to the polymer coating layer for controlling the release of the pellets contained in the pharmaceutical composition, it is preferable to apply a proper pressure or a buffering substance in the formulation process. In addition, the pharmaceutical composition for controlled release according to the present invention may be directly mixed with an excipient without granulating, so that a direct tablet method can be used. A granulation method may be used in which the pharmaceutical composition is first granulated and mixed with another excipient to be tableted; It is also possible to mix the pharmaceutical composition with an excipient, granulate it and then tablet it.

The pharmaceutical composition for controlled release according to the present invention can easily control the release pattern of the active ingredient as intended, thereby preventing the active ingredient from being rapidly transferred into the blood, minimizing adverse effects, Time, it is possible to shield the bitter taste for a certain period of time even when it is exposed in the oral cavity, so that the therapeutic effect on the patient can be increased upon oral administration.

Best Mode for Carrying Out the Invention Hereinafter, preferred embodiments are described to facilitate understanding of the present invention. However, the following examples are intended to illustrate the present invention without limiting it thereto.

First, the characterization performed in each of the following Examples was carried out with reference to the following Reference Example 1 and Reference Example 2.

Reference example  1. Dissolution test

The dissolution test of active ingredients of pellets, release-controlled coatings, pellets, tablets, capsules, chewing tablets and decongestible tablets was carried out according to Method 2 of the 36th dissolution test method of KP VIII (KP VIII) Lt; / RTI > At this time, 500-1000 ml was selected as an eluent from among pH 1.2 buffer, pH 4.0 buffer, pH 6.8 buffer, water and 0.1N HCl, and the test was carried out at 50-100 revolutions per minute.

Analysis after elution was carried out using high performance liquid chromatography (HPLC).

The HPLC conditions were as follows:

Mobile phase: 21.76 g of potassium dihydrogenphosphate was dissolved in 4 L of water, and a solution of pH 2.0 adjusted with phosphoric acid and 1 L of acetonitrile

Column: XBridge phenyl. 150 x 4.6 mm, 3.5 m

Flow rate: 1.0 ml / min

Column Temperature: 27 ℃

Wavelength: 238 nm

Injection volume: 10 μl

Standard Solution: Take 180.0 mg of paliperidone standard accurately, dissolve in a 100 mL volumetric flask, dissolve with eluent, and align the mark. Take 1.0 ml of this solution accurately, place it in a 100-ml volumetric flask, and use the same eluent as the standard solution.

Reference example  2. Content test

The content of the active ingredient contained in the pellet, the release-controlled coating, the pellet, the tablet, the capsule, the masticatory tablet and the fast-disintegrating tablet is tested by adding the active ingredient-containing preparation and the shake- The supernatant was obtained, and the solution was filtered and diluted to prepare a sample solution, which was analyzed by HPLC.

The HPLC conditions were as follows:

Mobile phase: 21.76 g of potassium dihydrogenphosphate was dissolved in 4 L of water, and a solution of pH 2.0 adjusted with phosphoric acid and 1 L of acetonitrile

Column: XBridge phenyl. 150 x 4.6 mm, 3.5 m

Flow rate: 1.0 ml / min

Column Temperature: 27 ℃

Wavelength: 238 nm

Injection volume: 5 μl

Standard solution: 180.0 mg of paliperidone standard is precisely taken, placed in a 100 ml volumetric flask, dissolved with mobile phase, and fitted with a mark. 10.0 ml of this solution is precisely taken, placed in a 100 ml volumetric flask, and the same reference solution is used as the standard solution.

[ Example ]

Example  One: Pellet  Produce

15.8 g of paliperidone, 47.4 g of Eudragit RL PO (Evonik; content of trimethylammonium methacrylate unit of about 10% by weight) and 236.8 g of Colidon SR were mixed well and mixed with PET-015 (Vanho, Korea ) Double screw extruder. The temperature control was divided into three zones, and the temperature was set at 70 to 140 캜 (zone: 70 캜, mixing zone: 140 캜, release zone: 125 캜, rotation speed: 100 rpm). The extruded strands from the die head were made to have a uniform thickness of about 800 micrometer using a winder and cut to a cylinder of about 800 um in height using a separate cutter after extrusion.

Example  2-A: In pellet  Formation of polymer coating layer

3.08 g of Eudragit RS 100 (Evonik; trimethylammonium methacrylate unit content about 5% by weight) was dissolved in a mixed solvent of 44 g of ethanol and 2.35 g of water. Then, 0.308 g of dibutyl sebacate and 0.308 g of talc ) Were added to prepare a polymer coating solution.

20 g of the pellets obtained in Example 1 were mixed with 0.05 g of Aerosil and then introduced into a mini-glatt (Glatt, Germany) equipped with a microkit as a seed. The prepared coating solution was sprayed by a bottom spray method The coating was carried out while spraying. After the spraying of the coating solution was finished, 22 g of a release-controlling composition containing the drug was obtained by drying.

The core (pellet) of the obtained composition contained about 5.3% by weight of the drug (paliperidone) when measured by the above-described content test method (HPLC; see Reference Example 2) , It was confirmed that the drug slowly released from 2 hours to 24 hours, and the emission pattern was close to zero. The results are shown in Table 1 below:

time Dissolution rate (%) time Dissolution rate (%) One 0 12 58.4 2 0 15 71.7 4 10.0 18 85.0 6 22.9 21 96.1 8 33.9 24 98.0

Example  2-B: formation of a coating layer for emission control on the core

2.77 g of Eudragit RS 100 (Evonik; about 5% by weight of a trimethylammonium chloride methacrylate unit) and 10% by weight of Eudragit RL 100 (Evonik, trimethylammonium chloride methacrylate unit content about 10% ) Was dissolved in a mixed solvent of 44 g of ethanol and 2.35 g of water, 0.308 g of dibutyl sebacate and 1.5 g of talc were added to prepare a polymer coating solution.

20 g of the pellets obtained in Example 1 were mixed with 0.05 g of Aerosil and then introduced into a mini-glatt (Glatt, Germany) equipped with a microkit as a seed. The prepared coating solution was sprayed by a bottom spray method The coating was carried out while spraying. After the spraying of the coating solution was finished, 21.8 g of a release-controlling composition containing the drug was obtained by drying.

The core (pellet) of the obtained composition contained about 5.3% by weight of the drug (paliperidone) when measured by the above-described content test method (HPLC; see Reference Example 2) , It was confirmed that the drug slowly released from 1 hour to 20 hours. The results are shown in Table 2 below:

time Dissolution rate time Dissolution rate One 0 12 81.4 2 3.6 15 87.9 4 12.1 18 96 6 32.1 21 98 8 55.2 24 100.4

Comparative Example  One:

15.8 g of paliperidone and 284.2 g of Eudragit RS PO (Evonik) were well mixed and charged into a PET-015 (Vanho, Korea) double screw extruder. The temperature control was divided into three zones, and the temperature was set at 70 to 140 캜 (zone: 70 캜, mixing zone: 140 캜, release zone: 125 캜, rotation speed: 100 rpm). The extruded strands from the die-head were cut to a constant thickness of about 800 um using a winder and cut to a cylinder of about 800 um in height using a separate cutter after extrusion.

3.08 g of Eudragit RS 100 (Evonik) was dissolved in a mixed solvent of 44 g of ethanol and 2.35 g of water, and then 0.308 g of dibutyl sebacate and 1.5 g of talc were added to prepare a polymer coating solution.

20 g of the obtained pellets were mixed with 0.05 g of Aerosil, and the mixture was added to a mini-glatt (Glatt, Germany) equipped with a microkit as a seed, and coating was performed while spraying the prepared coating solution in an upward spraying manner Respectively. After the spraying of the coating solution was finished, 22 g of a release-controlling composition containing the drug was obtained by drying.

The core (pellet) of the obtained composition contained about 5.3% by weight of the drug (paliperidone) when measured by the above-described content test method (HPLC; see Reference Example 2) , The drug was released to less than 60% within 24 hours. The results are shown in Table 3 below:

time Dissolution rate time Dissolution rate One 0 12 27.3 2 0 15 34.4 4 4.3 18 40.0 6 9.5 21 44.9 8 16.9 24 49.8

Example  3:

15.8 g of paliperidone, 47.4 g of Colloidal® SR and 236.8 g of Eudragit® RL PO (Evonik) were well mixed and charged into a PET-015 (Vanho, Korea) double screw extruder. The temperature control was divided into three zones, and the temperature was set at 70 to 140 캜 (zone: 70 캜, mixing zone: 140 캜, release zone: 125 캜, rotation speed: 100 rpm). The extruded strands from the die-head were cut to a constant thickness of about 800 um using a winder and cut to a cylinder of about 800 um in height using a separate cutter after extrusion.

3.08 g of Eudragit RS 100 (Evonik) was dissolved in a mixed solvent of 44 g of ethanol and 2.35 g of water, and then 0.308 g of dibutyl sebacate and 1.5 g of talc were added to prepare a polymer coating solution.

20 g of the obtained pellets were mixed with 0.05 g of Aerosil, and the mixture was added to a mini-glatt (Glatt, Germany) equipped with a microkit as a seed, and coating was performed while spraying the prepared coating solution in an upward spraying manner Respectively. After the spraying of the coating solution was finished, 12 g of a release-controlling composition containing the drug was obtained by drying.

The core (pellet) of the obtained composition contained about 5.3% by weight of the drug when measured by the above-described content test method (HPLC; see Reference Example 2), and when the drug was tested by the dissolution test method described in Reference Example 1 It was confirmed that the drug slowly released over 24 hours. The results are shown in Table 4 below:

time Dissolution rate time Dissolution rate One 0 12 71.7 2 0.8 15 86.6 4 7.1 18 95.0 6 13.4 21 98.1 8 37.7 24 101.2

Example  4: Capsules Filling

Aerosil (0.5 g) was added to 10 g of the release-controlling composition obtained in Example 2-A and filled in a No. 3 capsule (gelatin material capsule, available from Seoheung Capsule) in an amount of 170 mg.

The results of the dissolution test of the filled capsules with reference to the method of Reference Example 1 are shown in Table 5 below. It was confirmed that the drug (paliperidone) was gradually released from 2 hours to 24 hours, and the release pattern was close to zero difference, which was the same as the release pattern obtained before the capsule filling as in Example 2-A.

time Dissolution rate (%) time Dissolution rate (%) One 0 12 57.1 2 0 15 72.3 4 11.0 18 84.0 6 22.0 21 94.6 8 33.6 24 97.0

Claims (8)

Water insoluble ammonium methacrylate copolymer, polyvinyl acetate, and an antipsychotic drug as an active ingredient;
Melt extruding the mixture;
Preparing a pellet by stretching, cutting, or stretching and cutting the extrudate; And
Coating the surface of the pellet with a polymer coating liquid containing a water-insoluble ammonium methacrylate copolymer to form a polymer coating layer;
/ RTI >
The water insoluble ammonium methacrylate copolymer contained in the pellet and the water-insoluble ammonium methacrylate copolymer contained in the polymer coating layer are poly (ethyl acrylate / methyl methacrylate / trimethyl ammonium methacrylate) copolymer ,
The poly (ethyl acrylate / methyl methacrylate / trimethylammonium chloride methacrylate) copolymer has a content of trimethylammonium methacrylate chloride units of 8.0 to 15.0 wt% based on the total weight of the copolymer, or 2.0 to 7.99 wt% %, Or a mixture thereof.
A method for preparing a pharmaceutical composition for controlled release. The method according to claim 1, wherein the polyvinyl acetate is in a form of being physically mixed with the polyvinyl acetate alone or with polypyrrolidone. The pharmaceutical composition for controlled release according to claim 2, wherein the polyvinyl acetate has a mixing ratio of polyvinyl acetate and polypyrrolidone in a weight ratio of 9.9: 0.1 to 5: 5 (polyvinyl acetate weight: polypyrrolidone weight) ≪ / RTI > The emulsion polymerization method according to claim 1, wherein the mixing ratio of the water-insoluble ammonium methacrylate copolymer to polyvinyl acetate is 1: 0.05 to 20 (weight of water-insoluble ammonium methacrylate copolymer: polyvinyl acetate) ≪ / RTI > The method of claim 1, wherein in the pellet, the weight ratio of the active ingredient to the polymer mixed with the water-insoluble ammonium methacrylate copolymer and polyvinyl acetate is 1: 1 to 100 (weight of active ingredient: polymer mixture) A method for preparing a pharmaceutical composition for control. The method according to claim 1, wherein the weight of the polymer coating layer is 0.01 to 5 times the weight of the pellet. The method of claim 1, wherein at least one of the pellet and the polymer coating layer is selected from the group consisting of a plasticizer, a lubricant, a colorant, a flavor, a sweetener, a surfactant, a stabilizer, an antioxidant, a foaming agent, a paraffin, a wax, ≪ / RTI > wherein the composition further comprises one or more components. 8. The method according to any one of claims 1 to 7, wherein the antipsychotic drug is paliperidone or a pharmaceutically acceptable salt thereof.