• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    The present invention provides a mixture of A) at least one active compound, B) B1) from 10 to 90% by weight of thermoplastic polymer, and B2) from 10 to 90% by weight of low substituted hydroxypropylcellulose, and C) Solid formulations which can be obtained by melt extrusion from 0 to 50% by weight of conventional pharmaceutical auxiliaries based on the total amount of the formulation.
    公开号:KR19980702193A
    申请号:KR1019970705588
    申请日:1996-02-01
    公开日:1998-07-15
    发明作者:스펜 그라보브스키；죄르크 브라이텐바흐；죄르크 로젠베르크；악셀 잔너
    申请人:페라 스타르크;요헨 카르크；바스프 악티엔게젤샤프트；
    IPC主号:
    专利说明:

    Solid Active Compound Formulations
    The present invention
    A) at least one active compound,
    B) a mixture of B1) from 10 to 90% by weight of one or more thermoplastically processable water soluble polymers, and B2) from 10 to 90% by weight of a low substituted water insoluble hydroxypropylcellulose, and
    C) solid formulations which can be obtained by melt extrusion together from 0 to 50% by weight of one or more pharmaceutical auxiliaries based on the total amount of the formulation.
    Moreover, the present invention relates to a process for the preparation of the formulation and its use as a medicament.
    Active compound-containing formulations prepared by melt extrusion are known.
    Extrusion of active compound-containing melts of water-soluble polymers, preferably copolymers of vinylpyrrolidone, is described in EP 240 904 and EP 240 906.
    JP-A-58-192817 and JP-A-58-79915 describe melt extrusion of active compound-containing formulations based on thermoplastic polymers such as hydroxypropylcellulose as binders.
    Low-substituted hydroxypropylcellulose (L-HPC), prepared by partial esterification of cellulose and propylene oxide, is insoluble in water but swells upon contact with water. Due to this swelling, L-HPC is used as a disintegrant which promotes the decomposition of tablets. L-HPC can also be used as a binder in tablets to increase tablet hardness.
    Kawashima et al., Chem. Pharm. Bull. 41 (1933), 1827-31, describe the use of L-HPC in granules for tableting mainly depends on the particle size of L-HPC, while the active compound release profile is determined to be critically affected by the compressive force during compression. have.
    However, unlike hydroxypropyl cellulose having a high degree of substitution, L-HPC does not exhibit thermoplastic processability.
    It is an object of the present invention to find active compound formulations which can be prepared by melt extrusion of a polymer-active compound and which can specifically adjust the degree of release of the active compound.
    The inventors have found that this object can be achieved by the formulations first defined, the process for their preparation and their use as medicaments.
    Suitable active compounds as component A) are compounds which do not decompose under the processing conditions during melt extrusion.
    Suitable active compounds are, for example, acebutolol, acetylcysteine, acetylsalicylic acid, acyclovir, alprazolam, albumin, alpha calcidol, allantoin, allopurinol, ambroxol, amikacin, amylolide, amino Acetic acid, amiodarone, amitriptyline, amlodipine, amoxicillin, ampicillin, ascorbic acid, aspartame, asemizol, atenolol, beclomethasone, benserazide, benzalkonium hydroxide, benzocaine, benzoic acid, betamethasone , Benzafibrate, biotin, biferdene, bisoprolol, bromazepam, brohexine, bromocriptine, butesonide, bufecsa film, buplomedil, buspyrone, caffeine, camphor, captopril, car Bamzepine, Carbidopa, Carboplatin, Sephaclo, Cephalexin, Sepaderoxil, Sephazoline, Sepiksim, Cytotaxime, Ceftazidine, Ceftriaxone, Sepuroxime Axetyl, Chloramphenicol, Chlorhexidine, Chlorphecidin Laminin, Chlorthalidone, Choline, Cyclosporine, Cilastatin, Cimetidine, Ciproproxacin, Cisapride, Cisplatin, Clarithromycin, Clavulanic Acid, Clomipramine, Clonazepam, Clonidine, Clotrimazole, Clozapine , Codeine, cholestyramine, chromoglymic acid, cyanocobalamin, cyproterone, desogestrel, dexamethasone, dexpanthenol, dextrometophan, dextropropoxyphene, diazepam, diclofenac, digoxin, dihydrocodeine, digoxin Hydroergotamine, diltiazem, diphenhydramine, dipyridamole, dipyrone, disopyramid, domperidone, dopamine, enalapril, epheadrin, epinephrine, ergocalciferol, ergotamine, erythromycin, estradiol, Ethynylestradiol, etoposide, eucalyptus globulus, famotidine, ferodipine, fenofbrate, phenoterol, fentanyl, flavin mononucleotide, flu Nazol, flunarizine, fluorouracil, pulluloxetine, flurbiprofen, folic acid, furosemide, gemfibrozil, gemtamycin, ginco biloba, glybenclamide, glycizide, glycyr Hyzaglabra, Guapefenin, Haloperidol, Heparin, Hyaluronic Acid, Hydrochlorothiazide, Hydrocodone, Hydrocortisone, Hydromorphone, Ipratropium hydroxide, Ibuprofen, Imiphenem, Indomethacin, Iohexol, Iopamidol, isosorbide dinitrate, isosorbide mononitrate, isotretinoin, tetotifen, ketoconazole, ketoprofen, tetorolac, labetalol, lactulose, lecithin, levocarnitine, levodopa, levoglutamide , Levonorgestrel, levothyroxine, lidocaine, lipase, ricinopril, loperamide, lorazepam, lovastatin, methoxyprogesterone, menthol, methotrexate, methyldopa, methylprepa Nisolone, metoclopramide, metoprolol, myconazole, midazolam, minocycline, minoxidil, misoprostol, morphine, multivitamin and, minerals, nystatin, N-methylphedrine, naphthydrofuryl, naproxen, neo Mycin, Nicardidipine, Nisergoline, Nicotinamide, Nicotine, Nicotinic Acid, Nifedipine, Nimodipine, Nitridipine, Nizatidine, Noretysterone, Norproxacin, Norgestrel, Nortriptyline, Ofloxacin, Omeprazole, ondansetron, pancreatin, panthenol, pantothenic acid, paracetamol, penicillin G, penicillin V, phenobarbital, pentoxifylline, phenyllephrine, phenylpropanolamine, phenytoin, pyricampam, polymic B, povidone-iodine, pravastatin , Prazosin, prednisolone, propaphenone, propranolol, pseudoephedrine, pyridoxine, quinidine, ramipril, ranitidine, reserpin, retinol, riboflavin, rifampicin, rutoside, Saccharin, Salbutamol, Salkatonin, Salicylic Acid, Selegiline, Simvastatin, Somatropin, Sotalol, Apironolactone, Sucralate, Sulbactam, Sulfamtoxazole, Sulpyrid, Tamoxifen, Tegapur, Tef Lennon, terrazosin, terbutalin, terpenadine, theophylline, thiamine, ticlopidine, timolol, tranexamic acid, tretinoin, triamcinolone acetonide, triamterene, trimetapririm, troxeroutine, uracil, valproic acid, vancomycin, Verapamil, vitamin E, and zidovudine.
    Moreover, suitable active compounds are vitamins such as vitamin C, β-carotene and other carotenoids or crop protectants.
    The active compound is preferably present in solid solution form, ie in the form of molecular dispersion in the matrix, or in the form of a solid dispersion.
    The amount of active compound component A) in the total formulation can vary over a wide range depending on activity and release rate. In other words, the active compound content is from 0.1 to 90% by weight, preferably from 0.5 to 60% by weight, based on the total formulation. One condition is that the formulation can be thermoplastically processed.
    As polymerizable component B), the preparations according to the invention comprise B1) 10 to 90% by weight, preferably 20 to 80% by weight, of water-soluble thermoplastic polymer, and B2) 10 to 90% by weight, preferably 20 to 80 A weight percent water insoluble mixture of low substituted hydroxypropylcellulose is included and the quantitative value is based on the total amount of B1) and B2).
    Water-soluble polymers B1) to be mentioned are alkylcelluloses such as methylcellulose, hydroxymethyl-, hydroxyethyl-, hydroxypropyl- and hydroxyalkylcelluloses such as hydroxybutylcellulose, hydroxyethylmethyl- and hydroxypropyl Hydroxyalkylalkylcelluloses such as methylcellulose, polyvinylpyrrolidone, copolymers of N-vinylpyrrolidone and vinyl acetate containing up to 50% by weight of vinyl acetate, carboxyalkylcelluloses such as carboxymethylcellulose, Same polysaccharides and their alkali metal and ammonium salts, and mixtures of water-soluble polymers.
    Component B1) must be softened or melted in the entire mixture of all components in the range of 50 to 180 ° C., preferably 60 to 150 ° C., so that the material is extrudable.
    By water soluble it is meant that at least 0.5 g, preferably at least 2 g of the polymer should be dissolved even in colloidal form in 100 g of water at 20 ° C.
    Preferably, the polymer component A) used is hydroxypropylcellulose with a molar substitution of 3.0 to 4.4.
    According to the present invention, component B2) has a low substituted hydroxypropyl cellulose having a molar substitution of 0.5 to 2, preferably 1.5 to 1.8, low substituted hydroxypropyl cellulose described in US Pharmacopoeia NF XVII and Japanese Pharmacopoeia JP XI. (L-HPC) and this form of L-HPC is water insoluble but can swell in water and is not thermoplastic.
    Within the aforementioned ranges, the amount of component B2) used is preferably dependent on the required rate of active compound release. For fast release, smaller amounts, such as 5-30% by weight, are preferred. If the release of the active compound needs to be delayed, it is preferred to use 30 to 90% by weight of B2).
    According to the invention, the particle diameter of the L-HPC used is not critical.
    As component C), the preparations according to the invention may comprise up to about 50% by weight of conventional pharmaceutical auxiliaries such as fillers, lubricants, shaped release agents, flow control agents, plasticizers, colorants and stabilizers. These amounts and the following amounts are each based on the total amount of the formulation (100%).
    Notable fillers are, for example, oxides of magnesium, aluminum, silicon and titanium, and lactose, mannitol, sorbitol, xylitol, pentaerythritol and derivatives thereof, the amount of filler being about 0.02 to 50% by weight, preferably 0.2 to 20 wt%.
    Notable flow regulators include, for example, mono-, di- and triglycerides of long chain fatty acids such as C 12- , C 14- , C 16 -and C 18 -fatty acids and waxes such as carnova wax and lecithin, with an amount of about 0.1 To 30% by weight, preferably 0.1 to 5% by weight.
    Plasticizers which may be mentioned are for example low molecular weight polyalkylene oxides such as polyethylene glycol, polypropylene glycol and polyethylene propylene glycol, propylene glycol, polyhydric alcohols such as glycerol, pentaerythritol and sorbitol, and sodium diethylsulfosuccinate, glycerol Mono-, di- and triacetate and polyethylene glycol stearic acid esters. In this case, the amount of plasticizer is about 0.5 to 15% by weight, preferably 0.5 to 5% by weight.
    Notable lubricants are, for example, stearates and talc and silicon of aluminum or calcium, the amount of which is about 0.1 to 5% by weight, preferably about 0.1 to 3% by weight.
    Notable stabilizers are, for example, light stabilizers, antioxidants, radical scavengers, and stabilizers against microbial attack, the amount of which is preferably about 0.01 to 0.05% by weight.
    To prepare the preparations according to the invention, the active compound component is directly fused with Polymer B in the form of a physical mixture or mixed with an existing polymer melt.
    Otherwise, component A) and the melt are mixed in a known manner at 50 to 200 ° C. in an extruder, preferably a single- or double-screw extruder. The active compound-containing polymer melts for the preparation of the preparations according to the invention are calendered and extruded, for example, according to the process described in EP 240 906 and the process disclosed in DE 38 30 355. The water was divided into equal volumes with a solid surface moldable with a rotary knife, and molded by compression into tablets in a conventional tableting machine.
    Adjuvants may be mixed with the active compound and a melt or solution of Polymer B. Adjuvants can also be incorporated into the polymer melt together with the active compound. It is also possible to directly fuse mixtures of auxiliaries, active compounds and polymer B. Generally, a physical mixture of an adjuvant, active compound and polymer B is fused.
    The preparations according to the invention can be used as medicaments and in the form of tablets, pellets, granules or capsules. Preferably, pharmaceutical forms in which the release of the active compound is delayed are prepared using the preparations according to the invention.
    If desired, solid pharmaceutical forms can be provided with conventional coatings to enhance the (coated tablets) appearance and / or taste or to further delay the release of the active compound. If the tablet is administered orally such that the release of the active compound is delayed, the tablet is prepared in a closed cell porous form according to one of the known methods and spreads in the stomach and remains for longer.
    According to the present invention, the active compound release profile of the solid pharmaceutical form according to the invention can be specifically adjusted in particular in the preparation of a solid pharmaceutical form, in which the release of the active compound is delayed.
    Examples 1 to 3
    The active compounds, polymers B1) and B2), in the amounts shown in the table, were mixed, introduced into a double-screw extruder (ZSK 30, Werner Pfleiderer) and extruded in five temperature ranges. The temperature of each temperature range (batch 1-5) is shown in Table I, respectively. The melt extrudate appearing through the extruder nozzle lip was pelletized using a knife roll granulator to reduce air cooling heat.
    Release of the active compounds was determined by the paddle method according to USP XXI, US Pharmacopoeia. This in vitro method was used to determine the rate of solution of shaped articles containing active compounds (eg, tablets, pellets, etc.).
    To do this, the phosphate buffer with a pH of 6.8 was temperature controlled at 37 ° C. with 0.1% by weight sodium lauryl sulfate in a 1 L round bottom container and pellets with 300 g particle size of 1.25 to 1.60 mm were added. The active compound release from the pellet was measured after 1, 2, 3, 4, 5, 6, 7 and 8 hours at 100 rpm paddle rotation speed with UV spectroscopy in each case.
    The test results are shown in Table II below.
    ExampleNifedipine Weight%Polymer B1) 1) Weight%Polymer B2) 2) Weight%Temperature batch 1-5 One205030700,120,110,100,100 220404060,120,120,110,120 320305060,120,120,120,1301) Hydroxypropyl cellulose with molar substitution of 3.0 to 4.4 (Klucel EF, Hercules, USA) 2) Hydroxypropyl cellulose with molar substitution of 1.5 to 1.8 (LH 31, Shin-Etsu Chemical Comp. Ltd., Japan)
    Example% Release after One2345678 One32709199100100100100 23160778996100100100 32443576975818791
    权利要求:
    Claims (6)
    [1" claim-type="Currently amended] A) at least one active compound,
    B) a mixture of B1) from 10 to 90% by weight of one or more thermoplastically processable water soluble polymers, and B2) from 10 to 90% by weight of a low substituted water insoluble hydroxypropylcellulose, and
    C) Solid formulations which can be obtained by melt extrusion together from 0 to 50% by weight of one or more pharmaceutical auxiliaries based on the total amount of the formulation.
    [2" claim-type="Currently amended] The formulation according to claim 1, comprising hydroxypropyl cellulose having a molar substitution of 1.5 to 1.8 as component B2).
    [3" claim-type="Currently amended] The formulation according to claim 1 or 2, comprising water-soluble hydroxypropylcellulose as component B1).
    [4" claim-type="Currently amended] The active compound A) is processed with a polymerizable component B) and suitably an adjuvant C) to obtain a melt, extruding the melt and further shaping the preparation of the formulation according to any one of claims 1 to 3. Manufacturing method.
    [5" claim-type="Currently amended] Use of a formulation according to any one of claims 1 to 3 as a medicament.
    [6" claim-type="Currently amended] Solid pharmaceutical forms prepared from the formulation according to any one of claims 1 to 3.
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    同族专利:
    公开号 | 公开日
    FI973320D0|
    NO973730D0|1997-08-13|
    US5939099A|1999-08-17|
    FI973320A|1997-10-13|
    CN1174503A|1998-02-25|
    WO1996025151A1|1996-08-22|
    BR9606957A|1997-10-28|
    FI973320A0|1997-08-13|
    ZA9601137B|1997-09-16|
    CZ239497A3|1998-01-14|
    TR199700786T1|1998-02-21|
    NZ302243A|1999-01-28|
    BG101781A|1998-03-31|
    HU9702424A2|1998-06-29|
    DK809488T3|
    ES2180738T3|2003-02-16|
    PL321755A1|1997-12-22|
    EP0809488A1|1997-12-03|
    JP4049810B2|2008-02-20|
    CN1177584C|2004-12-01|
    CA2211033C|2005-04-26|
    IL117112D0|1996-06-18|
    DK0809488T3|2002-09-02|
    EP0809488B1|2002-07-17|
    PT809488E|2002-11-29|
    SK104397A3|1998-04-08|
    AU4786096A|1996-09-04|
    JPH10513477A|1998-12-22|
    AT220541T|2002-08-15|
    HU9702424A3|2001-03-28|
    CA2211033A1|1996-08-22|
    NO973730L|1997-08-13|
    DE19504832A1|1996-08-22|
    ZA961137B|1997-09-16|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1995-02-14|Priority to DE19504832.6
    1995-02-14|Priority to DE1995104832
    1996-02-01|Application filed by 페라 스타르크;요헨 카르크, 바스프 악티엔게젤샤프트
    1998-07-15|Publication of KR19980702193A
    优先权:
    申请号 | 申请日 | 专利标题
    DE19504832.6|1995-02-14|
    DE1995104832|DE19504832A1|1995-02-14|1995-02-14|Solid drug preparations|
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