WO2005123138A1 - Compositions de pastilles pharmaceutiques a liberation controlee - Google Patents

Compositions de pastilles pharmaceutiques a liberation controlee Download PDF

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Publication number
WO2005123138A1
WO2005123138A1 PCT/KR2005/000666 KR2005000666W WO2005123138A1 WO 2005123138 A1 WO2005123138 A1 WO 2005123138A1 KR 2005000666 W KR2005000666 W KR 2005000666W WO 2005123138 A1 WO2005123138 A1 WO 2005123138A1
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WIPO (PCT)
Prior art keywords
water
pellets
lipids
composition according
controlled release
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Application number
PCT/KR2005/000666
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English (en)
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WO2005123138A9 (fr
Inventor
Sang-Joon Lee
Hee-Jong Shin
Min-Hyo Ki
Bok-Young Yoon
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Chong Kun Dang Pharmaceutical Corp.
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Publication of WO2005123138A1 publication Critical patent/WO2005123138A1/fr
Publication of WO2005123138A9 publication Critical patent/WO2005123138A9/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin

Definitions

  • the present invention relates to a pharmaceutical composition for controlled release pellets prepared by use of a solid lipid and a water-insoluble binding agent in conjunction with a pharmacologically active substance, without melting the lipid at high temperature.
  • the present invention enables preparation of pellets in which poorly- mixable lipid components and hydrophilic active substances are homogeneously mis- cibilized by formation of lipid pellets through low-temperature solid phase heat processing below 60°C, thereby facilitating easy control of release rate and being suited for controlled release of heat-labile drugs.
  • Korean Patent Laid-open Publication No. 2003-0072557 discloses a matrix in which an active ingredient is uniformly dispersed in lipid materials selected from fatty alcohols, triglyceride, partial glyceride and fatty acid esters. This patent prepares the matrix by warming lipid materials to 90°C or higher to obtain a clear molten liquid, suspending a drug of interest therein, and then cold-spraying the resulting suspension to prepare a matrix of the active ingredient.
  • the present invention is characterized by formation of solid pellets in which the active ingredient is uniformly dispersed through solvent granulation, even without melting of solid lipids.
  • the present inventors have demonstrated that controlled release pellets can be prepared by forming pellet precursors using the water-insoluble binding agent relative to low-melting solid lipids, and heat-processing the pellet precursors at a tepid temperature of less than 60°C. Therefore, the present invention is a method having very high productivity whereby preparation of solid formulations can be implemented using existing equipment and apparatuses widely used in the art, such as fluid bed dryers, centrifugal granulators and hot air dryers.
  • Korean Patent Publication No. 1993-0007245 B 1 discloses a method for preparing a sustained release pharmaceutical composition, comprising mixing an active substance with crystalline cellulose, chitin and chitosan to form a unit mixture, adding, to the resulting mixture, an aqueous suspension, aqueous emulsion, aqueous gel or organic solvent solution of an acrylate polymer or water-insoluble cellulose derivative and water and granulating the resulting mixture to obtain a sustained release composition.
  • Korean Patent Laid-open Publication No. 2002-0011992 discloses a method for preparing a porous matrix, comprising dissolving an active substance in a volatile solvent to form a drug solution, combining the solution with a pore-forming agent to form an emulsion or suspension, and then removing the volatile solvent and pore- forming agent from the emulsion or suspension so as to yield a porous drug matrix .
  • the method of this patent involves use of hydrophilic polymers, sugars, pegylated excipients and tonicity agents as the pore-forming agent, does not mention lipid components and describes immediate-release characteristics only, not sustained release characteristics.
  • Korean Patent Publication No. 1997-0004906 B 1 discloses a method for preparing a sustained release preparation using water-soluble or water-insoluble polymeric materials and fatty acids, alcohols and waxes, in conjunction with buspirone and salts thereof as an active substance.
  • sustained release is accomplished by simple granulating and tableting of the mixed components, without preparation of pellets through heat processing.
  • examples in this patent describe only hydrogel (a water-soluble polymer)-forming sustained release tablets and mention of water-insoluble polymers is made only in claims.
  • Korean Patent Laid-open Publication No. 2003-0036877 discloses a sustained release composition comprising a metformin salt as the active substance and a hydrophobic polymer and other hydrophobic materials.
  • This patent employs fatty components derived from fatty acids and shellac, rosin, polyethylene and the like, as the hydrophobic polymer and hydrophobic materials, but is characterized in that the hydrophobic materials and active substance are mixed and melted by typical hot-melt methods. As such, this patent is different from the method of the present invention involving granulation without a warming process, followed by low-temperature heat processing to form pellets. Disclosure of Invention Technical Problem
  • water-soluble active substances i.e., active substances that are immiscible with liquid lipids, due to their high polarity
  • insoluble or water-soluble excipients i.e., excipients that are immiscible with liquid lipids, due to their high polarity or intrinsic insolubility
  • Pharmacologically active substances that are applicable to the present invention include, but are not limited to, antihypertensives, anti-hyperlipidemics, anti-obesity drugs, anti-diabetics, prostatic hypertrophy treatment, drugs for improving sexual function, immunosuppressive drugs, anti-ulcer drugs, narcotic and non-narcotic analgesics, anesthetics, anti-inflammatory analgesics, antirheumatics, steroidal hormones, tranquilizers, antidepressants, sedative hypnotics, antipsychotics, anti- convulsants, antispasmodics, anti-emetics, antitussives, rhinitis drugs, antibiotics, antifungal agents, anti-viral agents, blood flow agents, cardiovascular drugs, osteoporosis therapeutics and the like.
  • the antihypertensives may include amlodipine maleate, amlodipine besylate, felodipine, nifedipine, lercanidipine, nicardipine, diltiazem, lacidipine, enalapril, ramipril, fosinopril, cilazapril, imidapril, captopril, atenolol, carvedilol, doxazosin, terazosin and prazosin.
  • the anti-hyperlipidemics may include simvastatin, atorvastatin, lovastatin, fenofibrate, pravastatin, fluvastatin, gemfibrozil and bezafibrate.
  • the anti-obesity drugs may include orlistat, sibutramine, Camellia sinensis, cholestyramine, colestipol, phentermine, benzphetamine, diethylpropion, phendimetrazine and bontril.
  • the anti-diabetics may include glimepiride, rosiglitazone, pioglitazone, CKD-501, metformin, gliclazide, acarbose, voglibose, glibenclamide and repaglinide.
  • the prostatic hypertrophy treatments may include finasteride, tamsulosin, tolterodine and propiverine.
  • the drugs for improving sexual functions may include tadalafil, sildenafil, vardenafil, yohimbin, yohimbe, apomorphine, phentolamine and testosterone.
  • the immunosuppressive drugs may include cyclosporine, tacrolimus, my- cophenolate (mofetil) and azathioprine.
  • the anti-ulcer drugs may include ranitidine, rebamipide, cimetidine, omeprazole, famotidine, nizatidine, teprenone, misoprostol, rabeprazole, roxatidine, ecabet, pan- toprazole, lansoprazole and esomeprazole.
  • the narcotic and non-narcotic analgesics may include paracetamol, caffeine, propifenazone, ibuprofen, tramadol, deanol, ketorolac, clonixine, mefenamic acid, acetyl salicylic acid, methionine, pranoprofen, fentanyl, codeine, oxycodone, morphine, pethidine and dihydrocodeine;
  • the anesthetics may include lidocaine, bupivacaine, oxybuprocaine, propofol, sevoflurane, enflurane, midazolam and isoflurane.
  • the anti-inflammatory analgesics may include aceclofenac, talniflumate, diclofenac, loxoprofen, naproxen, meloxicam, celecoxib, nabumetone, etodolac, piroxicam, rofecoxib, nimesulide, dexibuprofen, diacerhein and zaltoprofen.
  • the antirheumatics may include hydroxychloroquine, bucillamine and peni- cillamine.
  • the steroidal hormones may include methylprednisolone, prednisolone, deflazacort, dexamethasone, triamcinolone, hydrocortisone, betamethasone, colistin, clobetasol, desoxymethasone and desonide.
  • the tranquilizers may include alprazolam, buspirone, tofisopam, diazepam, clotiazepam, etizolam, lorazepam, hydroxyzine, bromazepam and ethyl loflazepate.
  • the antidepressants may include paroxetine, fluoxetine, sertraline, venlafaxine, mirtazapine, Hypericum perforatum, quinupramine, trazodone, amitriptyline, mo- clobemide and milnacipran.
  • the sedative hypnotics may include triazolam, zolpidem, doxylamine, flu- nitrazepam, chloral hydrate, brotizolam, phenobarbital, zopiclone, estazolam, flurazepam and midazolam.
  • the antipsychotics may include risperidone, olanzapine, clozapine, quetiapine, haloperidol, zotepine and nemonapride.
  • the anti-convulsants may include valproic acid, gabapentin, carbamazepine, topiramate, oxcarbazepine, vigabatrin, lamotrigine and phenytoin.
  • the antispasmodics may include tiropramide, cimetropium bromide, otilonium, pinaverium bromide, phloroglucinol, caroverine, scopolamine butylhydroxide, difemerine, mebeverine, glycopyrronium hydroxide, aclatonium napadisilate and fenoverine.
  • the anti-emetics may include ondansetron, granisetron, scopolamine, tropisetron, dimenhydrinate, pyridoxine, ramosetron, meclozine and chlorphenamine.
  • the antitussives may include methylephedrine, chlorphenamine, dextromethorphan, dihydrocodeine, guaifenesin, noscapine, lysozyme, acebrophylline, levodropropizine, sulfogaiacol, phenylephrine, benproperine, pseudoephedrine, formoterol, salbutamol, bambuterol, fenoterol, terbutaline, clenbuterol, procaterol, fluticasone, salmeterol, formoterol and budesonide.
  • the rhinitis drugs may include phenylpropanolamine, chlorphenamine, Atropa belladonna, brompheniramine, phenylephrine, triprolidine, glycyrrhizic acid, cetirizine, ebastine and terfenadine.
  • the antibiotics may include netilmicin, isepamicin, ribostamycin, micronomicin, amikacin, astromicin, tobramycin, gentamycin, sisomicin, kanamycin, cefaclor, ceftriaxone, cefmetazole, cefazedone, cefixime, cefotiam, flomoxef, ceftezol, cephradine, cefotaxime, cefadroxil, cefprozil, cefpiramide, cefoperazone, ceftazidime, cefdinir, cefpodoxime proxetil, sulbactam, cefminox, ceftizoxime, cefditoren pivoxil, cefuroxime axetil, cefamandole, cefotetan, cephalexin, ceforanide, cefbuperazone, ce- fatrizine, cefuroxime, cef, ce
  • the antifungal agents may include itraconazole, fluconazole, terbinafine, am- photericin B, ketoconazole and ny statin.
  • the anti- viral agents may include lamivudine, acyclovir, famcyclovir, valacyclovir, methisoprinol, ribavirin, oseltamivir, gancyclovir, imiquimod, indinavir, nelfinavir, stavudine and zidovudine.
  • the blood flow agents may include Ginkgo biloba, nicergoline, nimodipine, pen- toxifylline, proxyphylline, coumarin, kallidinogenase, Melilotus officinalis, ajmalicine, almitrine, citicoline, vinburnine, ascorbic acid, acetyl carnitine, oxiracetam, choline and piracetam.
  • the cardiovascular drugs may include digoxin, methyldigoxin, nicorandil, trimetazidine, molsidomine, dilazep, isosorbide nitrate and nitroglycerin.
  • the osteoporosis therapeutics may include alendronic acid, pamidronic acid, menatetrenone, salcatonin and elcatonin.
  • the lipid component having a low melting point of less than 70°C and existing as a solid at room temperature in accordance with the present invention may include one or more materials selected from fatty acids, fatty alcohols, fatty acid-fatty alcohol esters, fatty acid glycerol esters, fatty acid propylene glycol esters, sorbitan fatty acid esters and sucrose fatty acid esters. Since these materials all have low melting points within the range of 45 to 70°C, they are employed in preparation of pellets having uniform drug content and controlled release in accordance with the present invention through low temperature processing.
  • these low-melting point lipids are soluble or are partially dispersible/soluble in alcohols or organic solvents and thus it is possible to form pellet precursors through granulation via the use of a mixed solvent containing the organic solvent. More specifically, without being limited to the following, physico-chemical properties of lipids utilized in the present invention are listed in Table 1 below. [49] Table 1
  • the hydrophilic material used in the present invention is a concept opposite to lipophilicity and refers to material having relatively superior solubility in water.
  • hydrophilic components are necessary. That is, since both solid lipids and water-insoluble binding agents of the present invention have the characteristics and shapes of lipids when they are partially or completely dissolved in the mixed solvent and then granulated, they are not pulverized but mashed even after being dried, and thereby, particles cannot be obtained. Therefore water-soluble materials that do not behave like lipids during grinding are required in order to achieve effective solvent granulation and to produce uniform granules.
  • the hydrophilic material may be at least one selected from saccharides, amino acids, inorganic electrolytes and water-soluble polymers.
  • Saccharides include, but are not limited to, white sugar, lactose, fructose, mannitol, sorbitol, xylitol, inositol, isomalt, maltitol, alpha, beta and gamma cyclodextrin and their derivatives, for example carboxymethyl cyclodextrin, methyl cyclodextrin, maltosyl cyclodextrin, hydroxyethyl cyclodextrin, hydroxypropyl cyclodextrin and sulfobutyl (ester) cyclodextrin.
  • All saccharides may be in monosaccharide or oligosaccharide form.
  • Amino acids include, but are not limited to, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, glycine, serine, threonine, cysteine, glutamine, tyrosine, asparagine, alginine, lysine, histidine, asparaginic acid and glutamic acid, tryptophan or oligopeptides containing less than 10 component amino acids.
  • Inorganic electrolytes include, but are not limited to, sodium chloride, sodium carbonate, sodium bicarbonate, dicalcium phosphate, calcium carbonate, ferric oxide.
  • the water-soluble polymers include, but are not limited to, polysaccharides such as starches and their derivatives including hydroxyethyl starch, cellulose derivatives such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose and carboxymethyl cellulose, alginic acid such as alkali metal salts of alginic acid dextrin and its derivative such as maltodextrin, pyrollidone derivatives such as polyvinylpyrollidone, alkylene oxides such as poly- oxyethylene and poloxamer, acrylic acid derivatives such as carbomer, and vinyl alcohols such as polyvinyl alcohol.
  • polysaccharides such as starches and their derivatives including hydroxyethyl starch
  • cellulose derivatives such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose and carboxymethyl cellulose
  • alginic acid such as alkali metal salts of alginic acid dex
  • the water-insoluble binding agent in accordance with the present invention refers to a material that is completely insoluble in water and is soluble in a solvent in which an organic solvent has been mixed, and exhibits strong bindability to lipid base materials upon drying.
  • the present inventors have made attempts to form pellet precursors by application of various water-soluble polymeric binding agents and cross-linked polymeric binding agents, inorganic binding agents and saccharide binding agents, which are widely utilized in the pharmaceutical field, without lipid melting.
  • any binding agent cannot provide binding capacity sufficient to form pellet precursors without melting the lipid at high temperature.
  • the water-insoluble binding agents in accordance with the present invention are solubilized by the mixed solvent containing the organic solvent, in particular in the granulation process, it is possible to effect homogeneous miscibilization between the binding agents and solid lipids without the warming process. Furthermore, after removal of the organic solvent, firm lipid pellet precursors are formed.
  • water-insoluble binding agents that can be utilized in the present invention, mention may be made of shellac and maize prolamin, Zein, derived from natural products, acrylic acid derivatives, for example, polymethacrylate and its derivatives, such as polymethylmethacrylate, polyethylmethacrylate, polydimethy- laminoethylmethacrylate and polytrimethylaminoethylmethacrylate, cellulose deivatives such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methyl- cellulose acetate succinate and a hydrophobic fatty acid derivative of hydroxypropyl methylcellulose (product name: Sangelose), and any combination thereof.
  • acrylic acid derivatives for example, polymethacrylate and its derivatives, such as polymethylmethacrylate, polyethylmethacrylate, polydimethy- laminoethylmethacrylate and polytrimethylaminoethylmethacrylate
  • cellulose deivatives
  • the pharmacologically active substance, low-melting point solid lipid and hydrophilic substance are mixed without melting, and if necessary, the resulting mixture is screened through a standard mesh screen having a mesh size of 60 or higher to render the mixture homogeneous. Then, the water-insoluble binding agent is dissolved in the mixed solvent containing the organic solvent to prepare a binding solution which is subsequently used, or the water-insoluble binding agent is previously mixed in the above mixture and then the mixture is used for a subsequent process.
  • organic solvent contained in the mixed solvent mention may be made of chloroform, methylenechloride, diethyl ether, tetrahydrofuran, acetone, isopropyl alcohol, ethanol, benzene, hexane and any combination thereof. Tetrahydrofuran, acetone and isopropyl alcohol and ethanol, among them, are water-miscible and thus can be used by mixing with less than 50% (by volume) of water.
  • the binding solution or mixed solvent is physically mixed and kneaded with the final powdered mixture so as to prepare a slurry or sludge material.
  • the resulting materials are passed through a standard mesh screen having a mesh size from 10 to 30 to form particles which are then dried under warm air or vacuum to remove the mixed solvent. Dried particles are additionally passed through a standard mesh screen having a mesh size from 10 to 45 to prepare pellet precursors having a uniform particle size.
  • Pellet precursors are rotated at a high speed, or floated, or allowed to stand in an apparatus such as a fluid bed dryer, a centrifugal granulator, a tablet coater, a cabinet dryer or the like. This is followed by low-temperature heat processing for 10 minutes to 24 hours by continuous injection of warm air at a predetermined temperature of less than 60°C to the apparatus, thereby preparing controlled release pellets.
  • an apparatus such as a fluid bed dryer, a centrifugal granulator, a tablet coater, a cabinet dryer or the like.
  • low-temperature heat processing is characterized in that this process is carried out at below the melting point of the lipids and is initiated with the pellet precursors in solid phase, and lipid pellets are matured to achieve controlled release while continuously maintaining the solid phase during the entire processing time.
  • this process is carried out at below the melting point of the lipids and is initiated with the pellet precursors in solid phase, and lipid pellets are matured to achieve controlled release while continuously maintaining the solid phase during the entire processing time.
  • controlled release pellets in which lipid components are homogeneously miscibilized with pharmacologically active substances or pharmacological excipients, regardless of their hydrophilicity or hydrophobicity.
  • Examples 1 through 6 [62] For examples 1 through 6, as shown in Table 2 below, tamsulosin hydrochloride as a pharmacologically active substance, glycerol palmitostearate as a lipid component, sodium alginate and lactose as hydrophilic substances, and croscarmellose sodium as a conventional disintegrating agent were mixed and the resulting mixture was passed through a 60 mesh standard screen to prepare a homogeneous mixture. As a water- insoluble binding agent, powedered zein was homogeneously admixed to the mixture, and shellac was dissolved in 90% ethanol to obtain a transparent solution, which was used as a binding solution.
  • HLB sucrose laurate
  • beta- cyclodextrin as a hydrophilic substance
  • Tablets were formulated by filling with the prepared pellets in an amount of 25 mg carvedilol per tablet, and additionally adding 15% of lactose, 5% of microcrystalline cellulose and 1% of magnesium stearate, based on the total weight, followed by mixing and compressing the mixture into a tablet.
  • Examples 10 through 13 As shown in Table 4 below, ranitidine hydrochloride as a pharmacologically active substance, stearic acid as a lipid component, and polyvinyl alcohol as a hydrophilic substance were mixed and the resulting mixture was passed through a 60 mesh standard screen to prepare a homogeneous mixture.
  • powdered Zein was homogeneously admixed to the mixture, and shellac was dissolved in ethanol to obtain a transparent solution, which was used as a binding solution.
  • Examples 14 through 16 [77]
  • tramadol hydrochloride as a pharmacologically active substance
  • glyceryl monostearate as a lipid component
  • lactose as a hydrophilic substance
  • Table 5 As a water- insoluble binding agent, powdered polymethacrylate (Eudragit RS PO) was homogeneously mixed with the mixture, and Zein was dissolved in 80% ethanol to obtain a transparent binding solution.
  • the present invention enables preparation of pellets in which lipid components and hydrophilic active substances are homogeneously miscible by formation of lipid pellets through low-temperature heat processing below 60°C, and thereby it is easy to control a release rate thereof and particularly suited for controlled release of heat-labile drugs.

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Abstract

La présente invention concerne une composition pharmaceutique sous forme de pastille, dont la libération contrôlée des substances actives au niveau pharmacologique peut être réalisée. Cette invention a, notamment, trait à une composition pharmaceutique pour pastilles à libération contrôlée qui contient, essentiellement, a) au moins une substance active au niveau pharmacologique, b) au moins un lipide possédant un point de fusion bas inférieur à 70 °C et existant sous forme solide à température ambiante, c) au moins une substance hydrophile, et d) au moins un agent liant insoluble dans l'eau, ladite composition étant préparée sans fusion des lipides.
PCT/KR2005/000666 2004-03-17 2005-03-10 Compositions de pastilles pharmaceutiques a liberation controlee WO2005123138A1 (fr)

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KR10-2004-0017872 2004-03-17
KR1020040017872A KR100681660B1 (ko) 2004-03-17 2004-03-17 방출제어 펠릿의 약제학적 조성물

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WO2005123138A9 WO2005123138A9 (fr) 2006-04-06

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008070072A2 (fr) * 2006-12-01 2008-06-12 Mutual Pharmaceutical Company, Inc. Formes, compositions de carvédilol, et leurs procédés de préparation
WO2012090218A1 (fr) 2010-12-30 2012-07-05 Zota Health Care Ltd Effets synergiques de la combinaison de composés spécifiques avec le paracétamol et leurs effets sur diverses maladies
CN115702883A (zh) * 2021-08-05 2023-02-17 上海博志研新药物技术有限公司 布洛芬药物组合物、其制备方法及应用

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100679111B1 (ko) * 2004-11-20 2007-02-07 대우약품공업주식회사 독사조신을 포함하는 서방성 정제
KR20140001357A (ko) * 2012-06-26 2014-01-07 현대약품 주식회사 아세브로필린을 포함하는 속효성과 지속성을 동시에 갖는 약제학적 조성물

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4772475A (en) * 1985-03-08 1988-09-20 Yamanouchi Pharmaceutical Co., Ltd. Controlled-release multiple units pharmaceutical formulation
WO2000072827A2 (fr) * 1999-05-27 2000-12-07 Acusphere, Inc. Matrices medicamenteuses poreuses et procedes de fabrication associes
WO2002045693A1 (fr) * 2000-12-07 2002-06-13 Altana Pharma Ag Preparation pharmaceutique comprenant un principe actif disperse sur une matrice

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4772475A (en) * 1985-03-08 1988-09-20 Yamanouchi Pharmaceutical Co., Ltd. Controlled-release multiple units pharmaceutical formulation
WO2000072827A2 (fr) * 1999-05-27 2000-12-07 Acusphere, Inc. Matrices medicamenteuses poreuses et procedes de fabrication associes
WO2002045693A1 (fr) * 2000-12-07 2002-06-13 Altana Pharma Ag Preparation pharmaceutique comprenant un principe actif disperse sur une matrice

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008070072A2 (fr) * 2006-12-01 2008-06-12 Mutual Pharmaceutical Company, Inc. Formes, compositions de carvédilol, et leurs procédés de préparation
WO2008070072A3 (fr) * 2006-12-01 2009-04-16 Mutual Pharmaceutical Co Formes, compositions de carvédilol, et leurs procédés de préparation
WO2012090218A1 (fr) 2010-12-30 2012-07-05 Zota Health Care Ltd Effets synergiques de la combinaison de composés spécifiques avec le paracétamol et leurs effets sur diverses maladies
CN115702883A (zh) * 2021-08-05 2023-02-17 上海博志研新药物技术有限公司 布洛芬药物组合物、其制备方法及应用

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WO2005123138A9 (fr) 2006-04-06
KR20050093986A (ko) 2005-09-26
KR100681660B1 (ko) 2007-02-09

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