KR20050093986A - Pharmaceutical pellet compositions for controlled release - Google Patents

Abstract

The present invention provides a pharmaceutical composition in the form of pellets capable of controlled release of the pharmacologically active substance. The present invention provides a composition comprising a) one or more pharmacologically active substances without melting the lipids; b) at least one lipid having a low melting point below 70 ° C. and solid at room temperature; c) at least one hydrophilic material; d) characterized by pharmaceutical compositions of controlled release pellets prepared with at least one water-insoluble binder as an essential component.

Description

Pharmaceutical pellet compositions for controlled release

It is an object of the present invention to provide a pharmaceutical composition of pellets capable of controlled release without the high temperature melting of lipids using solid lipids and water-insoluble binders for pharmacologically active substances.

In particular, since the present invention forms lipid pellets through low temperature heat processing of 60 ° C. or lower in the solid phase, it is possible to prepare pellets in which homogeneously mixed lipid components and hydrophilic active materials are homogeneously mixed, thereby controlling the release rate. It is also suitable for controlled release of heat labile drugs.

Korean Patent Laid-Open Publication No. 2003-0072557 describes a matrix in which an active ingredient is uniformly dispersed in a lipid selected from fatty alcohols, triglycerides, partial glycerides and fatty acid esters. The above patent is to prepare a matrix of the active ingredient by heating the lipid material to 90 ℃ or more to make a clear melt, suspending the drug therein, and then cold spraying. However, the present invention is characterized by forming solid pellets in which the active material is uniformly dispersed through assembly by a solvent without making melting of the solid lipid. In general, such a lipid material may not be formed by pellets simply by a solvent or by a general water-soluble binder commonly used in the art, and in this case, the burst property of the drug may not be obtained since the properties are easily broken after the assembly and the secondary processing is impossible. Will be triggered. Therefore, in the present invention, it was proved that the precursor of the pellet was formed using a water-insoluble binder for the low-melting solid lipid, and the release control pellet was formed through the thermal processing of lukewarm temperature below 60 ° C. This must be a very productive method that can be manufactured using existing equipment (fluid bed dryer, centrifugal granulator, heating air dryer) widely used in the manufacture of solid preparations in the art.

In Korean Patent 1993-0007245, a unit mixture is formed of an active substance with crystalline cellulose, chitin, and chitosan, which are again suspended in an aqueous suspension of an acrylic polymer, a water-insoluble cellulose derivative, an aqueous emulsion, an aqueous gel, an organic solvent solution, and sustained-release granules as water. It is written. Although similar in terms of using water-insoluble binders, there is no description of low melting point lipids and low temperature thermal processing used in the sustained release pellets of the present invention.

Korean Patent Laid-Open Publication No. 2002-0011992 discloses a method of forming an porous matrix by dissolving an active material in a volatile solvent and mixing it with a micropore forming agent to form an emulsion, a suspension, or a solution, and removing the volatile solvent and the micropore forming agent. It is described. However, hydrophilic polymers, sugars, pegylated excipients and isotonic agents are included as the micropore formers, and there are no mentions of lipid components and only the characteristics of rapid release, not slow release.

Korean Patent Publication No. 1997-0004906 describes the formation of sustained-release preparations using water-soluble or water-insoluble high molecular materials and fatty acids, alcohols, waxes and the like for buspyrone and salts thereof. However, the patent describes that sustained release is achieved by simply granulating and tableting in the form of a mixture without preparing pellets by thermal processing. In particular, the examples describe only the content of sustained-release tablets for forming hydrogels (water-soluble polymers) and water-insoluble polymers. Is mentioned only in the claims.

Korean Patent Laid-Open Publication No. 2003-0036877 discloses sustained release compositions containing hydrophobic polymers and materials for metformin salts. Here, as examples of hydrophobic polymers and substances, fatty components derived from fatty acids, shellac, rosin, polyethylene, etc. are used, but the hydrophobic substances are mixed and melted with the active substance by a typical high temperature melting method. It is different from the present invention in which pellets are formed by low temperature thermal processing.

As described above, the conventional prior art uses solid lipids for the purpose of emission control, but its manufacturing method is characterized by cooling by hot melting or by melt injection. This is a large difference from the formation of sustained-release pellets by the continuous low temperature thermal processing and the normal temperature solvent assembly method used in the present invention, and many drugs that are thermally unstable in that geological sustained-release pellets can be prepared without applying high-temperature melting energy. In addition, it can be said that there is a great advantage that the sustained release technology of the present invention can be applied. In addition, when pellets are prepared using lipids as the main agent, the assembling method using a solvent for the lipid base has not been applied in the prior art, and the water-soluble active substance which was practically impossible in the lipid processing by the conventional melting method. It has the advantage of homogeneous dispersion and miscibility with (active substance which has high polarity and cannot be mixed with liquid lipid) and insoluble or water-soluble excipient (excipient which has high polarity or is insoluble due to itself and incompatible with liquid lipid). Easy control of release rate

In addition, some prior arts control the release characteristics by simply mixing or wet granulating, tableting or compressing solid lipids. That is, the existing prior art has demonstrated that it is possible to control the release characteristics without melt processing only by making a tablet compression by physical compression, specifically, tableting commonly used in the art. Nevertheless, in this case, since the actual release control depends on the compressibility of the tablet formulation, if the formulation of the compressed lipids collapses in the gastrointestinal tract, the release of the drug may increase rapidly, which may cause a problem that the release control is impossible. In the present invention, however, low-melting solid lipid and water-insoluble binder are mixed together to perform granulation with solvent and low-temperature heat processing to prepare lipid pellets having excellent controlled release properties without the process of compression molding or melt molding of lipids. Proved possible.

The present invention

a) at least one pharmacologically active substance;

b) at least one lipid having a low melting point below 70 ° C. and solid at room temperature;

c) at least one hydrophilic material;

d) A pharmaceutical composition of controlled release pellets comprising at least one water-insoluble binder as an essential component and produced without melting the lipid, which is the main agent of the pellets.

Through this, release control is possible to reduce side effects due to rapid blood concentration increase and rapid drug duration according to physicochemical properties and pharmacokinetic factors of the pharmacologically active substance. In addition, by mixing the relative sustained-release pellets and immediate-release pellets according to the present invention for the same active material, it is possible to mix the release pattern so that the initial blood concentration can be quickly increased to above the effective drug concentration and the blood concentration can be maintained thereafter.

The pharmacologically active substance of the present invention is hypertension, hyperlipidemia, obesity, diabetes, prostate, sexual function, immunosuppressant, ulcer, narcotic, anti-inflammatory analgesic, rheumatism, steroid hormone, Neuro stabilizers, antidepressants, sleep depressants, antipsychotics, antiepileptics, anticonvulsants, antiemetic drugs, asthma treatment antitussives, rhinitis treatments, antibiotics, antifungal agents, antiviral agents, blood circulation agents, heart disease treatments, osteoporosis treatments, etc. It is not limited. Specific drugs for treating hypertension include amlodipine maleate, amlodipine besylate, felodipine, nifedipine, lercardidipine, nicardipine, diltiazem, lacidinpine, enalapril, ramipril, posinopril, silazapril , Imidapril, captopril, atenolol, carvedilol, doxazosin, terrazosin, prazosin, hyperlipidemia drugs include simvastatin, atorvastatin, lovastatin, fenofibrate, pravastatin, fluvastatin, gemfiprozil, bezafibrate, obesity Treatments include olistat, sibutramine, camelia sinensis, cholestyramine, cholestipol, phentermine, benzpetamine, diethylpropion, pendimethazine, bontril, and diabetes treatments such as glimepiride, rosiglitazone, pioglitazone, CKD -501, Metformin, Glyclazide, Acarbose, Boglybose, Glybenclamide, Repaglinide, Prostate Nasteride, tamsulosin, tolterodine, propiberine, tadalafil, sildenafil, vardenafil, yohimbine, yohimbe, apomorphine, pentolamine, testosterone, and immunosuppressants such as cyclosporin, tacrolimus, and mycophenolate (Mofetyl), azachioprine, ulcer medications such as ranitidine, levamipid, cimetidine, omeprazole, pamotidine, nizatidine, tefrenone, misoprostol, labeprazole, roxatidine, ecabet, panto Prasol, lansoprazole, esomeprazole, narcotic non-narcotic analgesics include paracetamol, caffeine, propifenazone, ibuprofen, tramadol, deanol, ketolockac, clonicin, mefenamic acid, acetylsalicylic acid, methionine, pranopropene , Fentanyl, codeine, oxycodone, morphine, pechidine, dihydrocodeine, anesthetics such as lidocaine, bupivacaine, oxybuprocaine, propofol, seboflurane, enflurane, mida Ram, isoflurane, and anti-inflammatory analgesics include aceclofenac, talniflumate, diclofenac, loxoprofen, naproxen, meloxycamp, celecoxib, nabumethone, etodolak, pyroxicam, rofecoxib, nimesulide , Dexiburofen, diacerane, zaltoprofen, rheumatoid hydroxychloroquine, busilamine, penicillamine, steroid hormones methylprednisolone, prednisolone, deplazacoat, dexamethasone, triamcinolone, hydrocortisone, betamethasone , Colistin, clobetasol, desomimethasone, desonide, neurostabilizers include alprazolam, buspyrone, topisopam, diazepam, clothiazepam, ethizolam, lorazepam, hydroxyzine, bromase Palm, Ethyl Loplazeate, antidepressants include paroxetine, fluoxetine, sertrarin, venlafaxine, mirtazapine, hypericum perforatum, quinupramine, trazodone, amitriptyline, Moclobemid, milnasifran, and sleep sedatives include triazolam, zolpidem, doxyramine, flunitrazepam, chloral hydrate, brotizolam, phenobarbital, zodiclones, estazolam, flurazepam, mida Zoram and antipsychotics include risperidone, olanzapine, clozapine, quetiapine, haloperidol, jotepin, nemonaprid, and anti-intervenants with valprophosphate, gabapentin, carbamazepine, topiramate, oxcarbazepine, and vivaba. Trine, lamotrigine, phenytoin, and anticonvulsants include tyropramid, cimethorium bromide, otylonium, pinaberium bromide, phloroglucinol, carobrine, scopolamine butyl hydroxide, dipemerine, mebeberine, Glycopyrronium Hydroxide, Aclatonium Napadisylate, Phenoberine, Antifreezes include ondansetron, granistron, scopolamine, trocetolone, dimenhydrinate, pyridoxine, lamoset , Meclozin, Chlorophenamine, Asthma treatment antitussives include methylephedrine, chlorphenamine, dextromethorphan, dehydrocodeine, guipenecin, noscapine, lysozyme, acebrophylline, levodropropine, Sulfogaiacol, phenylephrine, benproperine, pseudoephedrine, formoterol, salbutamol, bambuterol, phenoterol, terbutaline, clenbuterol, procaterol, fluticasone, salmeterol, formo Terrols, budesonides, rhinitis treatment agents such as phenylpropanolamine, chlorphenamine, aprofa belladonna, brompheniramine, phenylephrine, triproridine, glycyrrhizin acid, setrizine, evastin, terpenadine, and antibiotics such as netylmycin and ise Pharmamycin, ribostamycin, micronomycin, amikacin, astromycin, tobramycin, gentamicin, sisomycin, kanamycin, sefacller, ceftriaxone, cephmetazole, sefazedone, sepicsim, Cetithiam, flomoxef, ceftezol, cepradine, cefotaxime, cephadroxyl, ceftrozil, ceftyramide, cepharazone, ceftazidime, ceftinir, cefpodoxime proxetyl, sulbactam, ceft Minox, ceftizone, ceftyrylene sheath, cefuroxime axetyl, cephamandol, cefethetan, cephalexin, ceranidine, cefubuferazone, cefatrizine, cepuroxime, cefepime, cefteram sheath, ceflock Sardine, cefazoline, cefemenoxime, bencoamicin, teicoplanin, fuzidinic acid, spectinomycin, fosfomycin, meropenem, imipenem, cilastatin, aztreonam, loracarbef, amoxicillin, clavulanic acid , Ampicillin, Bacamcillin, Piperacillin, Cyclacillin, Tazobactam, Sultacillin, Ciprofloxacin, Levofloxacin, Ofloxacin, Norfloxacin, Tosufloxacin, Pefloxacin, Lomefloxacin, Sparfloxacin, Antifungal agents include itraconazole , Fluconazole, terbinafine, amphotericin B, ketoconazole, nystatin, antiviral agents include lamivudine, acyclovir, famciclovir, valassicrovir, mechisopriol, ribavirin, oseltamivir, and ganchic Rovier, Imiquimod, Indinavir, Nelfinavier, Stavudine, Zidovudine, blood circulation agents such as ginkgo biloba, nisergoline, nimodipine, pentoxifylline, proxiphylline, coumarin, cardinogenase, meli Lotus Officinalis, Azmalicin, Almitrin, Citicholine, Binburin, Ascorbic Acid, Acetylcarnitine, Oxyracetam, Choline, Piracetam, Digoxin, Methyldigoxin, Nicolandil , Trimetazidine, molecidomin, dilazeph, isosorbide nitrate, nitroglycerin, osteoporosis therapeutic agents include alendronic acid, pamidronic acid, menaterenone, salkatone, elcatonin, etc. Allowed as Salts are within the scope of the active material of the present invention.

And the lipid component which has a low melting point below 70 ℃ of the present invention and solid at room temperature is one selected from fatty acid, fatty alcohol, fatty acid fatty alcohol ester, fatty acid glycerol ester, fatty acid propylene glycol ester, sorbitan fatty acid ester, sucrose fatty acid ester It consists of the above substance. Since they all have a low melting point between 45 and 70 ° C., they have a uniform drug content through low temperature processing and are used in the production of pellets of the present invention which can control the release. In addition, since these lipids have an alkyl chain structure of 10 or more carbon atoms, they show fat solubility, thereby controlling drug release in aqueous solution or intestinal fluid. Lipid components of the present invention are fatty acids such as stearic acid, lauric acid and fatty acid glycerol such as cetyl palmitate, fatty acid fatty alcohol esters such as myristyl myristate, glyceryl monostearate, glyceryl palmitostearate, glyceryl behenate Esters, fatty acid propylene glycol esters such as propylene glycol monostearate, sorbitan monopalmitate, sorbitan fatty acid esters such as sorbitan monostearate, sucrose laurate (HLB = 1-5), sucrose stearate (HLB = 1 And at least one selected from sucrose fatty acid esters, such as ˜7). In addition, since the low melting point lipids are dissolved or partially dispersed and dissolved in alcohol or an organic solvent, it is possible to form pellet precursors by assembling a mixed solvent containing an organic solvent. Examples illustrating the characteristics of the lipids used in the present invention in more detail are shown in Table 1 below, but are not limited thereto.

  Melting point of low melting point lipids and solubility in various solvents Melting point (℃) Solubility by Solvent (practically) insoluble soluble Stearic acid > 54 water benzene, chloroform, ether, ethanol, hexane, PG Stearyl alcohol 55-62 water chloroform, ethanol, ether, hexane, PG, oils Glyceryl Monostearic Acid 55-60 water hot ethanol, ether, chloroform, hot acetone, mineral oil, fixed oils Glyceryl Palmitostearic Acid 52-55 ethanol (95%), mineral oil, water chloroform Glyceryl Behenate 65-77 ethanol (95%), hexane, mineral oil, water hot chloroform, hot MC Sorbitan Monopalmitate 43-48 water (dispersible) oils, solvents Sorbitan monostearic acid 53-57 water (dispersible) oils, solvents Sucrose stearic acid (HLB 3) 51-69 ethanol, water hot ethanol, hot PG ^* Sucrose lauric acid (HLB 1) 51-61 ethanol, water hot oils, hot ethanol, hot PG ^* Sucrose Lauric Acid (HLB 5) <70 oils water, ethanol ^*

  * Solvents or oils maintained at about 70 ° C

The hydrophilic material used in the present invention generally refers to a material having a relatively high solubility in water in a concept as opposed to lipophilic. Hydrophilic components are required to form the lipid pellets without high temperature melting and to be comminuteable in the process of formulation. That is, both the solid lipid and the water-insoluble binder of the present invention resemble the properties of lipids when partially or completely dissolved in the mixed solvent, and thus are not pulverized and then crushed (aggregated) even after drying, thereby obtaining no particles. Therefore, in order to be pulverized into the shape of uniform granules in granulation with a solvent, a water-soluble substance having a pulverization contrast with lipids is required. The hydrophilic material is selected from one or more of sugars, amino acids, inorganic electrolytes, water-soluble polymers and the like. Sugars include white sugar, lactose, fructose, mannitol, sorbitol, xylitol, inositol, isomalt, maltitol, alpha and beta, carboxymethyl cyclodextrin and derivatives thereof, carboxymethyl cyclodextrin, methyl cyclodextrin, which are present in the form of monosaccharides and oligosaccharides. , Maltosyl cyclodextrin, hydroxyethyl cyclodextrin, hydroxypropyl cyclodextrin, sulfobutyl (ester) cyclodextrin, amino acids include alanine, varine, leucine, isoleucine, proline, phenylalanine, methionine, glycine, serine, threonine At least one or a water-soluble polymer selected from cysteine, glutamine, tyrosine, asparagine, arginine, lysine, histidine, asparagine acid, glutamic acid or peptides of up to 10 oligomeric components thereof, polyethylene glycol and water-soluble derivatives thereof Polysacara Starch and its derivatives hydroxyethyl starch, cellulose derivatives hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, alginic acid alginic acid alkali metal salts, dextrins and derivatives thereof Phosphorus maltodextrin, polyvinylpyrrolidone as the pyrrolidone series, polyoxyethylene, poloxamer as the alkylene oxide series, carbomer as the acrylic acid series, polyvinyl alcohol of the vinyl alcohol series, etc. may be used. In view of the nature of the invention, the water-soluble substance is not limited thereto.

The water-insoluble binder of the present invention refers to a substance which is not dissolved in water at all, is soluble in a solvent in which an organic solvent is mixed, and exhibits a strong binding force to a lipidic base when dried. The present inventors have tried to form precursors of pellets without melting of lipids by applying a large number of pharmaceutically used water-soluble polymer binders and crosslinked polymer binders, inorganic binders, saccharide binders and the like. However, due to the nature of the solid lipid, no binder could provide the binding force to form a pellet precursor without melting by high temperature heat processing. However, since the water-insoluble binder of the present invention is dissolved by a mixed solvent including an organic solvent, in particular, it is possible to uniformly mix with solid lipids without heating, and to form a solid lipid pellet precursor after the organic solvent is removed. do. Such water-insoluble binders include shellac and prolamin-based zein and acrylic acid-based polymethacrylates and derivatives thereof, such as polymethylmethacrylate, polyethylmethacrylate, and polydimethylaminoethylmethylmethacrylate. Acrylate, polytrimethylaminoethylmethacrylate, hydroxypropylmethyl cellulose phthalate of cellulose series, hydroxypropylmethylcellulose acetate acetate, fatty acid hydrophobic derivative of hydroxypropylmethyl cellulose (Product name: Sangelose, Sangelose) One or more selected from among others.

The pharmaceutical composition is prepared by the following process, but is not limited thereto. First, the method of manufacturing the pellet precursor by the room temperature granulation method without heating is as follows.

The pharmacologically active substance, low melting point solid lipid and hydrophilic substance are mixed without melting and sieved with a standard mesh of 60 mesh or more, if necessary, to homogenize the mixture. In addition, the water-insoluble binder is dissolved in a mixed solvent containing an organic solvent to prepare a binder solution, or may be previously mixed in powder form with the mixture. As the organic solvent in the mixed solvent containing the organic solvent, at least one selected from chloroform, methylene chloride, dieth ether, tetrahydrofuran, acetone, isopropyl alcohol, ethanol, benzene, hexane, and the like may be used. Hydrofuran, acetone, isopropyl alcohol, ethanol and the like can be mixed with water, so that the water can be used by mixing up to 50% (volume ratio). The binder solution or the mixed solvent is physically associated with addition of the powdery final mixture to prepare the atherosclerosis or the needle-like association. This is passed through a standard mesh of 10 mesh to 30 mesh to form particles and dried by warm air or vacuum to remove the mixed solvent. The dried particles are passed through a standard mesh of 10 mesh to 45 mesh again to produce pellet precursor having a uniform particle size.

And described for the low temperature thermal processing carried out after for the prepared pellet precursor is as follows. The pellet precursors are suspended or suspended in high speed or in the air in devices such as fluid bed dryers and centrifugal granulators, tablet coaters, and cabinet dryers. In addition, by continuously injecting a warm air of a predetermined temperature of less than 60 ℃ into the inside of the device by low temperature heat processing for 10 minutes to 24 hours to prepare a controlled release pellet. At this time, the low temperature thermal processing is characterized in that the pellets are started in the solid state by heat below the melting point of the lipid and the lipid pellets are ripened while maintaining the solid phase continuously for the entire processing time to achieve controlled release. This enables the formation of controlled release pellets in which the lipid component is homogeneously mixed with the pharmacologically active substance or pharmaceutical excipient, regardless of the hydrophilicity or hydrophobicity thereof.

Hereinafter, the present invention will be described in detail through examples. However, these Examples are only illustrative of the present invention, and the scope of the present invention is not limited to these.

Examples 1-6

For Examples 1 to 6, tamsulosin hydrochloride as a pharmacologically active substance and glycerol palmitostearate as a lipid component, sodium alginate and lactose as hydrophilic substances, and croscarmellose sodium as a conventional disintegrant, as shown in Table 2 below. The mixture was mixed and passed through a 60 mesh standard mesh to prepare a homogeneous mixture. And as a water-insoluble binder, zein was homogeneously mixed in powder form to the mixture, and shellac was transparently dissolved in 90% ethanol and used as a binder solution.

  Pharmaceutical Compositions of Examples 1-6 (Unit: g) Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Tamsulosin HCl 0.05 0.05 0.05 0.05 0.05 0.05 Glyceryl palmitostearate 20 17 19 19 20 20 Sod. alginate 13 16 12 10 Lactose 10 6 Zein 2 2 3 2 Shellac 7 6.55 7 7 7 7 Sod. Croscarmellose 2 2 5 90% Ethanol 8.6 8.1 8.6 8.6 8.6 8.6

  * However, 90% ethanol is the volume unit (mL).

Then, the binder solution prepared in the homogeneous mixture of Examples 1 to 6 except for the binder solution was added as described above, coalesced until it became a needle shape or an atherosclerosis, and sieved to 14 mesh to carry out granulation. Thereafter, the mixed solvent was removed by drying from the granules and sieved by 16 mesh. The dried sieved material was put into a centrifugal granulator, and pellets containing tamsulosin hydrochloride were prepared by low temperature heat processing while rotating at high speed for 1 hour at an exhaust temperature of 54 ± 1 ° C. The prepared pellets were filled in capsules such that the amount of tamsulosin hydrochloride per capsule was 0.2 mg.

Examples 7-9

For Examples 7 to 9, carvedilol as a pharmacologically active substance, sucrose laurate as a lipid component (HLB = 1), and beta-cyclodextrin as a hydrophilic substance were mixed to form a standard mesh of 60 mesh as shown in Table 3 below. Passing produced a homogeneous mixture. And as a water-insoluble binder, zein was homogeneously mixed in powder form to the mixture, and shellac was transparently dissolved in 90% ethanol and used as a binder solution.

  Pharmaceutical Compositions of Examples 7-9 in g Example 7 Example 8 Example 9 Carvedilol 25 25 25 Sucrose laurate (HLB = 1) 60 70 80 beta-cyclodextrin 40 30 20 Zein 8 8 8 Shellac 5 10 15 90% Ethanol 22 25 25

  * However, 90% ethanol is the volume unit (mL).

Then, the binder solution prepared in the homogeneous mixture of Examples 7 to 9 except for the binder solution was added as described above, coalesced until it became a knee phase or an atherosclerosis, and sieved to 14 mesh to carry out granulation. Thereafter, the mixed solvent was removed by drying from the granules and sieved by 16 mesh. The dried sieved material was put into a centrifugal granulator, and pellets containing carvedilol were prepared by low temperature heat processing while rotating at high speed for 1 hour at an exhaust temperature of 56 ± 1 ° C. The prepared pellet was 25 mg of carvedilol per tablet, and 15% of lactose, 5% of microcrystalline cellulose, and 1% of magnesium stearate were added, mixed, and then compressed into tablets to prepare a tablet.

Examples 10-13

For Examples 10 to 13, a homogeneous mixture was prepared by mixing ranitidine hydrochloride as a pharmacologically active substance, stearic acid as a lipid component and polyvinyl alcohol as a hydrophilic substance and passing through a 60 mesh standard network as shown in Table 4 below. And as a water insoluble binder, Jane was homogeneously mixed in powder form to the mixture, and shellac was dissolved in ethanol transparently and used as a binder solution.

  Pharmaceutical Compositions of Examples 10-13 (Unit: g) Example 10 Example 11 Example 12 Example 13 Ranitidine HCl 300 300 300 300 Stearic acid 300 400 300 400 Polyvinylalcohol 50 50 100 100 Zein 25 25 50 50 Shellac 50 50 50 50 Ethanol 480 480 520 520

  * Ethanol is the volume unit (mL).

As described above, the homogeneous mixture of Examples 10 to 13 except for the binding liquid was buried in a fluid bed dryer and granulated to pass through 14 mesh while spraying the binding liquid. After all of the binding solution was sprayed, the solvent was completely removed from the granules. Then, pellets containing ranitidine hydrochloride were prepared by low-temperature heat processing in a continuous operation for 1 hour under a condition of an exhaust temperature of 56 ± 1 ° C. The prepared pellets were filled in capsules such that the amount of ranitidine hydrochloride per capsule was 150 mg.

Examples 14-16

For Examples 14 to 16, a homogeneous mixture was prepared by mixing tramadol hydrochloride as a pharmacologically active substance, glyceryl monostearate as a lipid component, lactose as a hydrophilic substance, and passing through a standard mesh of 60 mesh as shown in Table 5 below. It was. And polymethacrylate (eudragit RS PO) as a water-insoluble binder was mixed homogeneously in powder form to the mixture, and zein was transparently dissolved in 80% ethanol and used as a binder solution.

  Pharmaceutical Compositions of Examples 14-16 in g Example 14 Example 15 Example 16 Tramadol HCl 200 200 200 Glyceryl monostearate 150 200 250 Lactose 50 50 50 Eudragit RS PO 25 50 75 Zein 25 25 25 80% Ethanol 150 150 150

  * 80% ethanol is the volume unit (mL).

Then, the binder solution prepared in the homogeneous mixture of Examples 14 to 16 except for the binder solution was added as described above, coalesced until it became a knee phase or an atherosclerosis, and sieved through 14 mesh. Thereafter, the mixed solvent was removed by drying from the granules and sieved by 16 mesh. The dried sieved material was put into a centrifugal granulator, and pellets containing tramadol hydrochloride were prepared by low temperature heat processing while rotating at high speed for 1 hour at an exhaust temperature of 56 ± 1 ° C. The prepared pellets were filled in capsules such that the amount of tramadol hydrochloride per capsule was 150 mg.

Experimental Examples 1-6

The dissolution test was performed for each capsule prepared through Examples 1 to 6 to confirm the controlled release dissolution curve. To this end, six capsules in each example were eluted at 100 rotations per minute at 37 ± 0.5 ° C. 5 ml of the eluate was purified 2 hours after the start of the dissolution test in 500 mL of an elution medium containing pH 1.2 containing Tween 80. Immediately, the pellets were transferred to 500 mL of the elution medium at pH 7.2, and 5 mL of the eluate was removed 3 and 5 hours after the start of the dissolution test. After 2 hours, 3 hours, and 5 hours after the start of the dissolution test, the eluate was filtered through a 0.45 μm membrane filter with a pore size, and the filtrate was analyzed by the following HPLC method to calculate the dissolution rate and to prepare the dissolution curve.

HPLC Analysis of Tamsulosin Hydrochloride

Column: Chromasil C18 (4.6 ㅧ 15 cm, 5 μm)

Column Temperature: 40 ℃

Detector: Ultraviolet 225 nm

Flow rate: 1.0 mL / min

Injection volume: 100 μl

Mobile phase: mixture of perchloric acid buffer / acetonitrile (65/35) at pH 2.0

Experimental Example 7-9

The dissolution test was carried out for each tablet prepared through Examples 7 to 9 to confirm the controlled release dissolution curve. To this end, six tablets in each example were eluted at 90 revolutions per minute and 37 ± 0.5 ° C. After 2 hours, 6 hours, and 12 hours after the start of the dissolution test in 1,000 mL of the elution medium at pH 4.5, 5 mL of the eluate was purified. The purified eluate was filtered with a 0.45 탆 pore membrane filter, and the filtrate was analyzed by the following HPLC method to calculate the dissolution rate and to prepare the dissolution curve.

HPLC Analysis of Carvedilol

Column: Chromasil C18 (4.6 ㅧ 25 cm, 5 μm)

Detector: ultraviolet 285 nm

Flow rate: 1.5 mL / min

Injection volume: 40 μl

Mobile phase: mixture of phosphate buffer / methanol (50/50) at pH 2.0

Since the present invention forms lipid pellets through low temperature heat processing of 60 ° C. or lower, it is possible to prepare pellets in which homogeneous mixing of lipid components and hydrophilic active materials is difficult to mix, and thus, it is easy to control the release rate and is particularly unstable to heat. Suitable for controlled release of drugs.

1 is a tamsulosin hydrochloride elution curve by the pharmaceutical formulation of Examples 1-6.

2 is a carvedilol dissolution curve according to the pharmaceutical formulation of Examples 7-9.

Claims (5)

a) at least one pharmacologically active substance; b) at least one lipid having a low melting point below 70 ° C. and solid at room temperature; c) at least one hydrophilic material; d) Pellets containing at least one water-insoluble binder as an essential component are produced by mixing with a solvent containing an organic solvent and heat-processing in a solid state without melting the lipid, which is a periodic agent. Pharmaceutical compositions. The acrylic acid-based polymethacrylate, polymethylmethacrylate, polymethylmethacrylate, polydimethylmethamine according to claim 1, wherein the water-insoluble binder is a shellac and prolamin-based zener derived from natural products. 1 type selected from ethylmethacrylate, polytrimethylaminoethylmethacrylate, hydroxypropylmethyl cellulose phthalate of cellulose series, hydroxypropylmethyl cellulose acetate, hydroxypropyl methyl cellulose, and fatty acid hydrophobic derivatives of hydroxypropylmethyl cellulose Pharmaceutical composition of controlled release pellets characterized in that the above. According to claim 2, wherein the water-insoluble binder is at least one selected from the group consisting of shellac and prolamine derived from natural products, acrylic acid-based polymethacrylate and derivatives thereof. Pharmaceutical composition. 4. The pharmaceutical composition of controlled release pellets according to claim 3, wherein the water-insoluble binder is at least one selected from shellac and prolamin-based zein derived from natural products. The pharmaceutical composition of controlled release pellets according to claim 1 or 2, wherein the pharmacologically active substance is in the form of tamsulosin or a pharmaceutically acceptable salt thereof.