• 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 invention contains, in addition to at least one active substance, A) from 10 to 90% by weight of thermoplastically treatable water soluble polymer, B) from 5 to 85% by weight of isomeric malt, and C) from 0 to 5% by weight of lecithin. The sum of the constituents relates to a solid medicament obtained by extrusion and subsequent molding of a solvent free melt of 100% by weight.
    公开号:KR19990063853A
    申请号:KR1019980702324
    申请日:1996-09-30
    公开日:1999-07-26
    发明作者:위르겐 차이들러；요에르그 로젠베르그；외르그 노이만；외르그 브라이텐바흐
    申请人:스타르크, 카르크；바스프 악티엔게젤샤프트；
    IPC主号:
    专利说明:

    Solid medicaments obtained by extrusion of a heterogeneous malt-containing polymer-active material melt
    The present invention is based on the total amount of the pharmaceutical form in addition to the one or more active ingredients
    A) 2 to 90% by weight of a water-soluble polymer capable of melt treatment,
    B) 5 to 89.9 weight percent of heterogeneous malt, and
    C) 0 to 5% by weight of lecithin
    It relates to a solid pharmaceutical form obtainable by extrusion and subsequent molding of a solvent-free melt comprising a.
    The invention also relates to a method of making such a pharmaceutical form.
    Formulations containing the active ingredient and prepared by melt extrusion are generally known.
    Extrusion of the melt of a water-soluble polymer, preferably a copolymer of vinylpyrrolidone, containing the active ingredient is described, for example, in EP-A 240 904 and EP-A 240 906.
    The melt extrusion method can be used for a number of active ingredients. Specifically, it is possible to influence the properties of the formulations prepared using different auxiliaries, for example the rate of dissolution of the pharmaceutical form in the gastrointestinal tract.
    If it is desired to produce a rapidly released solid pharmaceutical form, it is necessary to use auxiliaries which have a high dissolution rate consistent with a correspondingly high water solubility and furthermore do not adversely affect the meltability of the polymer melt containing the active ingredient. In general, sugar alcohols such as mannitol or sorbitol, or sugars such as lactose have been used for this purpose to date.
    However, a disadvantage of known compositions is that they are in some cases poorly processable due to the high tack during molding, especially during rolling. In addition, these compositions are often still unsatisfactory in terms of release rate. Another factor is the lack of tablet-like mechanical strength due to large embrittlement and consequent cracking, which means that it still needs to be improved.
    It is an object of the present invention to develop a pharmaceutical form which exhibits rapid release of the active ingredient, which simultaneously has very good processability and high stability of the pharmaceutical form.
    The inventors have finally discovered that this object is achieved by the pharmaceutical form defined at the outset.
    Suitable active ingredients according to the invention are those which have sufficient thermal stability under the conditions of the melt extrusion process.
    Examples of suitable active ingredients are
    Acebutolol, acetylcysteine, acetylsalicylic acid, acyclovir, albrazolam, alpha calcidol, allantoin, allopurinol, ambroxol, amikacin, amylolide, aminoacetic acid, amiodarone, amitriptyline, Amlodipine, Amoxicillin, Ampicillin, Ascorbic Acid, Aspartame, Astimazole, Athenolol, Beclomethasone, Bencerazide, Benzalkonium hydrodrochloride, Benzocaine, Benzoic acid, Betamethasone, Bezafibrate, Biotin, Biferri Den, bisoprolol, bromasephemine, brominehexine, bromocriptine, budesonide, bupecsamak, buflomedil, buspyrone, caffeine, camphor, captopril, carbamazepine, carbidopa, carboplatin, Sephachlor, cephalexin, cepharoxil, cefazoline, sepicsim, cephataxime, ceftazine, ceftriaxone, cefuroxime, celedillin, chloramphenicol, chlorhexidine, chlorpheniramine, chlortalidone , Choline, cyclosporin, cilastatin, cimetidine, ciprofloxacin, cisapride, cisplatin, clarithromycin, clavulanic acid, clomibramine, clonazepam, clonidine, clotrimazole, codeine, cholestyramine, chromoglyg Lic acid, cyanocobalamin, cyproterone, desogestrel, dexamethasone, dexpanthenol, dextromethorphan, dextropropoxyphene, diazepam, diclofenac, digoxin, dihydrocodeine, dihydroergotamine, dihydroergotoxin , Diltiazem, diphenhydramine, dipyridamole, dipyrone, disopyramid, domperidone, dopamine, doxocycline, enalapril, ephedrine, epinephrine, ergocalciferol, ergotamine, erythromycin, estradiol, Ethinylestradiol, etoposide, Eucalyptus Globulus, famotidine, felodipine, fenofibrate, fenterolol, fentanyl, flavin Mononucleotides, fluconazole, flunarizine, fluorouracil, fluoxetine, flurbiprofen, furosemide, galopamil, gemfibrozil, gentaminecin, Ginkgo Biloba, glybenclamide, glycopy Gide, Glozapine, Glycyrrhiza Glabra, Griseofulvin, Guapenesine, Haloperidol, Heparin, Hyaluronic Acid, Hydrochlorothiazide, Hydrocodone, Hydrocortisone, Hydromorphone, Ibrax Hydroxide Rofume, ibuprofen, imipenem, indomethacin, iohexol, iopamidol, isosorbate dinitrogen, isosorbate nitrate, isotrethionine, ketotifen, ketoconazole, ketoprofen, ketorolac, rabatalone, Lactulose, Lecithin, Levocarnitine, Levodopa, Levoglutamide, Levonorgestrel, Levothyroxine, Lidocaine, Lipase, Replamin, Ricinopril, Loperamide, Lorazepam, Lovastatin, Doxyprogesterone, menthol, methotrexate, methyldopa, methylprednisolone, metoclopramide, metoprolol, myconazole, midazolam, minocycline, minoxidil, misoprostol, morphine, multivitamin and minerals, N-methylephedrine, naphthyl Drupuril, Naproxen, Neomycin, Nicardipine, Nisergoline, Nicotinamide, Nicotine, Nicotinic Acid, Nifedipine, Nimodipine, Nitrazepam, Nitridipine, Nizatidine, Norethysterone, Norfloxacin, Norgest Reel, nortriptyline, nystatin, opfloxacin, omeprazole, ondansetron, pancreatin, panthenol, pantothenic acid, paracetamol, penicillin G, penicillin V, phenobarbital, phenoxyphylline, phenoxymethylphenicillin, phenylephrine, phenylpropa Nolamin, Phenytoin, Pyroxycam, Polymyxin B, Povidone-iodine, Pravastatin, Prazepam, Prazosin, Prednisolone, Prednason, Pro Mocliptin, propaphenone, propranolol, propoxyphylline, pseudoephedrine, pyridoxine, quinidine, ramipril, ranitidine, reserpin, retinol, riboflavin, rifampicin, rutoside, saccharin, salbutamol, salcatonin, salicylic acid, Simvastatin, somatropin, sotalol, spironolactone, sucralate, sulbactam, sulfamethoxazole, sulfasalazine, sulfide, tamoxifen, tegapur, teprenon, terazosine, terbutalin, terpenadine, tetra Cyclin, theophylline, thiamine, ticlopidine, timolol, tranexamic acid, tretinoin, triamcinolone, acetonide, triamterene, trimetapririm, troxerectin, uracil, valproic acid, vancomycin, verapamil, vitamin E, bolonic acid There is a lead bud.
    Particularly suitable active ingredients according to the invention are those suitable for the preparation of quick-release (immediate-release) forms.
    Preferred active ingredients are verapamil or its physiologically resistant salts, particularly preferably verapamil hydrochloride. Paracetamol is also preferred.
    Meltable water-soluble polymer component A) that may be mentioned
    Alkylcelluloses, for example methylcellulose,
    Hydroxymethylcellulose, for example hydroxymethyl-, hydroxyethyl-, hydroxypropyl- and hydroxybutylcellulose,
    Hydroxyalkylmethylcelluloses, for example hydroxyethylmethyl- and hydroxypropylmethylcellulose,
    Polyvinylpyrrolidone,
    Copolymers of N-vinylpyrrolidone with vinyl acetate, having up to 50% by weight vinyl acetate,
    Carboxyalkylcelluloses, for example carboxymethylcellulose,
    Polysaccharides, for example alginic acid and its alkali metal and ammonium salts,
    Polyethylene glycol, and
    There is a mixture of such water-soluble polymers.
    In a complete mixture of all the components, component A) must be softened or melted at 50 to 180 ° C, preferably 80 to 140 ° C, so that the composition can be extruded. If appropriate, workability at these temperatures can be achieved by adding a plasticizer.
    By "water soluble" is meant colloidally soluble, where appropriate, at least 0.5 g, preferably at least 2 g, of the polymer is dissolved in 100 g of water at 20 ° C.
    Preferred polymer components A) besides polyvinylpyrrolidone are polyethylene glycols and particularly preferably copolymers obtained by free-radical polymerization of 60% by weight of N-vinylpyrrolidone with 40% by weight of vinyl acetate. Hydroxypropyl cellulose is also preferred.
    The pharmaceutical form contains, as an adjuvant, heterogeneous malt, also known under the trade name Palatinit®. Isomer malt isomers 1-O-α-D-glucopyranosyl-D-mannitol dihydrate (1,1-GPM dihydrate) and 6-O-α-D-glucopyranosyl-D-sorbitol (1,6 -Hydrogenated maltose consisting of approximately equivalent parts of -GPS).
    The particle size of the heterogeneous malt can vary within a wide range, but the preferred particle size is 0.1 to 0.8 mm.
    Commercially obtainable isomeric is enzymatic rearrangement of sucrose to isomeric maltose (6-O-α-D-glucopyranosyl-D-fructose) in a first step, which is then hydrogen / rane Prepared by hydrogenation with nickel.
    The pharmaceutical form according to the invention comprises the polymer component A) in an amount of 2 to 90% by weight, preferably 10 to 90% by weight, particularly preferably 10 to 50% by weight. Heterogeneous malt is used in amounts of 5 to 89.9% by weight, preferably 10 to 70% by weight, particularly preferably 20 to 60% by weight.
    The amount of active ingredient also depends on the efficacy of the treatment. It is incorporated in amounts of 0.1 to 70% by weight, preferably 10 to 60% by weight, particularly preferably 20 to 50% by weight.
    The amounts stated are in each case based on the total amount of the pharmaceutical form (= 100% by weight).
    In addition, in order to further improve processability, the pharmaceutical form may include 5% by weight or less of lecithin, preferably 2-5% by weight.
    Formulations according to the invention may further comprise conventional pharmaceutical auxiliaries such as fillers, lubricants, mold release agents, flow rate regulators, plasticizers, dyes and stabilizers in amounts of up to about 50% by weight.
    To prepare a pharmaceutical form according to the invention, the active ingredient can be directly melted in the form of a physical mixture with polymer A) or mixed with a pre-made polymer melt.
    Alternatively, the active ingredient is mixed in a conventional manner with the melt in an extruder, preferably a single or twin screw extruder at a temperature of 50 to 180 ° C, preferably 80 to 140 ° C. The molding of the polymer melt containing the active ingredient for providing the blend according to the invention is carried out, for example, by rolling the extrudate by the method described in EP-A 240 906, and by DE-A 38 30 355 By the method disclosed in the invention, the extrudate can be carried out using a rotary cutter to convert into blanks having the same volume, which can be further deformed and have a solidified surface, which is then compressed into tablets in a conventional purifier. have.
    The pellets obtained in this way can be filled into hard gelatin capsules after rounding.
    It is possible to admix the adjuvant into the melt or solution of the active ingredient with polymer A). It is also possible for the auxiliary to be incorporated into the polymer melt together with the active ingredient. Mixtures of auxiliaries, active ingredients and polymers may also be directly melted. In general, it is common for the physical mixture of the auxiliary, active ingredient and polymer to melt together.
    The combinations according to the invention are used as medicaments and in tablet, pellet, granule or capsule form or in other pharmaceutical forms which can be administered orally. Pharmaceutical forms in which the active ingredient is rapidly released are preferably prepared using the combinations according to the invention.
    If desired, solid pharmaceutical forms may be provided with conventional coatings to improve appearance and / or taste (sugar-coated tablets), or methods of film coating by spraying solutions or dispersions of aqueous or organic polymers. It can provide a film-coated tablet form.
    It is possible by the composition of the pharmaceutical form according to the invention to achieve good processability as well as rapid release of the active ingredient.
    In the handling and shaping of the melt, the problems caused by the particularly vulnerable active ingredient, eg verapamil hydrochloride, are avoided by the formulations according to the invention.
    The pharmaceutical forms described in the examples below were obtained by the rolling method described in EP-B 240 906. They showed good resistance to mechanical stress and did not tend to stick.
    <Examples 1 to 7>
    Extrusion / Rolling-Common Method:
    Extruder Type: Twin Screw Extruder
    Number of bands: 4 + head (die)
    Tablet: round, lenticular, weight 300 mg
    Melt flow rate: 20-25 kg / h
    Release measurement of active ingredient
    USP XXIII Paddle Method (Verapamil HCl Tablet) Page 1625
    Speed: 50 rpm
    Paddle Medium: 0.1 mol / l HCl
    Polymer A) used was a copolymer prepared from 60% by weight of N-vinylpyrrolidone and 40% by weight of vinyl acetate (“Copolyvidon” according to the German Pharmacopoeia).
    The stated amounts refer to the weight percent in each case.
    Example 1 (Comparative Example)
    Verapamil HCl26.67% Copolyvidone40.00% Mannitol28.33% lecithin5.00% Total weight363 mg
    Extrusion condition:Band 1Band 2Band 3Band 4head Temperature (℃)80100115115115
    The release test of the active ingredient showed that 52.4% of the active ingredient was released after 30 minutes.
    <Example 2>
    Verapamil HCl26.67% Copolyvidone40.00% Heterogeneous malt28.33% lecithin5.00% Total weight368 mg
    Extrusion condition:Band 1Band 2Band 3Band 4head Temperature (℃)100120130130130
    The release test of the active ingredient showed that 91.5% of the active ingredient was released after 30 minutes.
    <Example 3>
    Verapamil HCl33.33% Copolyvidone31.67% Heterogeneous malt32.00% lecithin3.00% Total weight242 mg
    Extrusion condition:Band 1Band 2Band 3Band 4head Temperature (℃)80100110110110
    The release test of the active ingredient showed that 65.4% of the active ingredient was released after 20 minutes.
    <Example 4>
    Verapamil HCl33.33% Copolyvidone23.67% Heterogeneous malt40.00% lecithin3.00% Total weight246 mg
    Extrusion condition:Band 1Band 2Band 3Band 4head Temperature (℃)80100110110110
    The release test of the active ingredient showed that 77.0% of the active ingredient was released after 20 minutes.
    Example 5
    Verapamil HCl33.33% Copolyvidone13.67% Heterogeneous malt50.00% lecithin3.00% Total weight252 mg
    Extrusion condition:Band 1Band 2Band 3Band 4head Temperature (℃)80100110110110
    The release test of the active ingredient showed that 85.8% of the active ingredient was released after 20 minutes.
    <Example 6>
    Verapamil HCl33.33% Copolyvidone13.67% Heterogeneous malt50.00% lecithin3.00% Total weight252 mg
    Extrusion condition:Band 1Band 2Band 3Band 4head Temperature (℃)80100110110110
    The release test of the active ingredient showed that 93.2% of the active ingredient was released after 30 minutes.
    Example 7 (Comparative Example)
    Verapamil HCl30.00% Copolyvidone70.00%
    Extrusion condition:Band 1Band 2Band 3Band 4head Temperature (℃)90130130140140
    The release test of the active ingredient showed that 93.7% of the active ingredient was released after 30 minutes.
    <Example 8>
    Verapamil HCl32% Heterogeneous malt41.5% Copolyvidone24% Hydrogenated castor oil2.00% Highly disperse silica0.5%
    Band 1Band 2Band 3Band 4head Temperature (℃)80100110110110
    Release testing of the active ingredient revealed that at least 96.7% of the active ingredient was released after 30 minutes.
    <Examples 9 and 10>
    Paracetamol tablet type
    Extrusion / Rolling-General Method
    Extruder Type: Twin Screw Extruder
    Tablet type: oval, weight 700 mg
    Melt flow rate: 20-25 kg / h
    Paddle Method: USP 23 (Pacetamol Tablets)
    The stated amounts refer to the weight percent in each case.
    Example 9
    Paracetamol72% Polyvinylpyrrolidone, K value 304% Heterogeneous malt17.25% Highly disperse silicaOne% Sodium starch glycolate5% Sodium Lauryl Sulfate0.75%
    Band 1Band 2Band 3Band 4head Temperature (℃)80120120130145
    Release testing of the active ingredient revealed that 100% of the active ingredient was released after 30 minutes. Paddle way.
    <Example 10>
    Paracetamol72% Copolyvidone4% Heterogeneous malt17.25% Highly disperse silica1.00% Sodium starch glycolate5% Sodium Lauryl Sulfate0.75%
    Band 1Band 2Band 3Band 4head Temperature (℃)80120120130145
    The release test of the active ingredient showed that 98% of the active ingredient was released after 30 minutes.
    <Examples 11 to 13>
    Vitamin B Complex Tablets
    Extrusion / Rolling-Common Method:
    Extruder Type: Twin Screw Extruder
    Number of bands: 4 + head
    Tablet, round, lenticular, weight about 240 mg
    Melt flow rate: 20-25 kg / h
    The stated amounts refer to the weight percent in each case.
    <Example 11>
    Thiamine mononitrate0.572% Riboflavin0.704% Pyridoxine HCl0.748% Cyanocobalamin (0.1% incorporation into maltodextrin)1.32% Calcium D-pantothenate2.64% Nicotinic acid7.26% Folic acid0.066% Biotin0.02% Heterogeneous malt31.67% Hydroxypropylcellulose (Klucel® EF)50.00% lecithin5.00%
    Band 1Band 2Band 3Band 4head Temperature (℃)80100105105110
    <Example 12>
    Thiamine mononitrate0.65% Riboflavin0.8% Pyridoxine HCl0.85% Cyanocobalamin (0.1% incorporation into maltodextrin)1.5% Calcium D-pantothenate3.00% Nicotinic acid8.25% Folic acid0.075% Biotin0.015% Heterogeneous malt45.86% Hydroxypropyl cellulose35.00% lecithin4%
    Band 1Band 2Band 3Band 4head Temperature (℃)809090100115
    Example 13
    Thiamine mononitrate0.3575% Riboflavin0.44% Pyridoxine HCl0.4583% Calcium D-pantothenate1.65% Nicotinamide4.537% Biotin0.0178% Heterogeneous malt74.538% Hydroxypropylmethylcellulose10.00% Collidone K 305% lecithin3%
    Band 1Band 2Band 3Band 4head Temperature (℃)80120130133133
    权利要求:
    Claims (8)
    [1" claim-type="Currently amended] In addition to one or more active ingredients,
    A) 2 to 90% by weight of a water-soluble polymer capable of melt treatment,
    B) 5 to 89.9 weight percent of heterogeneous malt, and
    C) 0 to 5% by weight of lecithin
    Wherein the sum of all components is 100% by weight, obtainable by extrusion and subsequent molding of the solvent-free melt.
    [2" claim-type="Currently amended] The method of claim 1,
    A) 10 to 90% by weight of a water-soluble polymer capable of melt treatment,
    B) 5 to 89.9 weight percent of heterogeneous malt, and
    C) 0 to 5% by weight of lecithin
    A pharmaceutical form comprising a sum of all components of 100% by weight.
    [3" claim-type="Currently amended] The solid pharmaceutical form according to claim 1 or 2, comprising as polymer A) a homopolymer or copolymer of N-vinyllactam.
    [4" claim-type="Currently amended] 4. The solid pharmaceutical form according to claim 3 comprising a copolymer of N-vinylpyrrolidone with vinyl acetate.
    [5" claim-type="Currently amended] The solid pharmaceutical form according to claim 1 or 2, comprising hydroxypropylcellulose as polymer A).
    [6" claim-type="Currently amended] The solid pharmaceutical form according to any one of claims 1 to 4, comprising verapamil or a physiologically resistant salt thereof as an active ingredient.
    [7" claim-type="Currently amended] The solid pharmaceutical form according to any one of claims 1 to 5, further comprising a conventional pharmaceutical adjuvant.
    [8" claim-type="Currently amended] A method for producing a pharmaceutical form according to any one of claims 1 to 6, comprising converting the components to a melt at 50 to 180 ° C.
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    同族专利:
    公开号 | 公开日
    AU7282896A|1997-04-28|
    DK854707T3|
    DE59609923D1|2003-01-09|
    DK0854707T3|2002-12-16|
    EP0854707A1|1998-07-29|
    HU9903384A3|2001-04-28|
    ES2187678T3|2003-06-16|
    CN1198094A|1998-11-04|
    ZA9608130B|1998-03-27|
    AT228355T|2002-12-15|
    US6187342B1|2001-02-13|
    JPH11512729A|1999-11-02|
    IL123250D0|1998-09-24|
    BR9610799A|1999-07-13|
    EP0854707B1|2002-11-27|
    NO981394L|1998-03-27|
    CA2230950A1|1997-04-10|
    NO981394D0|1998-03-27|
    IL123250A|2000-08-31|
    HU9903384A2|2000-10-28|
    DE19536394A1|1997-04-03|
    MX9801988A|1998-08-30|
    RU2197228C2|2003-01-27|
    CN1200694C|2005-05-11|
    CA2230950C|2007-12-04|
    WO1997012603A1|1997-04-10|
    CZ95998A3|1998-08-12|
    JP4041163B2|2008-01-30|
    BG102346A|1998-10-30|
    TW438599B|2001-06-07|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1995-09-29|Priority to DE1995136394
    1995-09-29|Priority to DE19536394.9
    1996-09-30|Application filed by 스타르크, 카르크, 바스프 악티엔게젤샤프트
    1996-09-30|Priority to PCT/EP1996/004262
    1999-07-26|Publication of KR19990063853A
    优先权:
    申请号 | 申请日 | 专利标题
    DE1995136394|DE19536394A1|1995-09-29|1995-09-29|Solid pharmaceutical forms, obtainable by extrusion of a polymer-active substance melt containing isomalt|
    DE19536394.9|1995-09-29|
    PCT/EP1996/004262|WO1997012603A1|1995-09-29|1996-09-30|Solid medicaments obtained by extrusion of an isomalt-containing polymer-active substance melt|
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