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    • 专利摘要:
    The present invention (Meth) acrylate copolymers comprising 85 to 98% by weight of radically polymerized C1-C4 alkyl esters of acrylic or methacrylic acid and 15 to 2% by weight of (meth) acrylate monomers having quaternary ammonium groups in the alkyl radicals. Melting and mixing with 10 to 25 weight percent plasticizer, 10 to 50 weight percent antitack agent and / or 0.1 to 3 weight percent release agent, and optionally together with other pharmaceutical standard additives or auxiliaries and / or pharmaceutically active ingredients (a ) (B) degassing the mixture at a temperature of at least 120 ° C. to reduce the content of low boiling point components having a vapor pressure of at least 1.9 bar at 120 ° C. to 0.5% by weight or less; and And (c) injecting the degassed mixture into the mold of the injection molding unit at a temperature of 80 to 160 ° C. and removing the resulting molded body from the mold.
    公开号:KR20030022359A
    申请号:KR10-2003-7001616
    申请日:2002-05-08
    公开日:2003-03-15
    发明作者:페테라이트한스-울리히；벡케르트토마스；아쓰무스만프레트；회쓰베르너；푸흐스볼프강；쉬코브스키하르트무트
    申请人:룀 게엠베하 운트 콤파니 카게；
    IPC主号:
    专利说明:

    Method for injection molding molded bodies consisting of (meth) acrylate copolymers}
    [1] The present invention relates to a method for producing a molded article by injection molding and the molded article itself.
    [2] Prior art
    [3] (Meth) acrylate copolymers containing monomers with quaternary ammonium groups (e.g. trimethylammonium methylmethacrylate chloride) and their use as sustained-release pharmaceutical coatings have long been known. See EP-A 181. 515 or DE-C 1 617 751. It is processed in an organic solution or in an aqueous dispersion, for example by spraying on a pharmaceutical core, or without solvent by application in a melt in the presence of a flow aid.
    [4] EP 0 704 207 A2 describes thermoplastics for pharmaceutical coatings which are soluble in gastric juice. It is a copolymer made from 16 to 40% by weight acrylic or methacrylic acid, 30 to 80% by weight methyl acrylate and 0 to 40% by weight other alkyl (meth) acrylates.
    [5] In the examples, a suitable copolymer is melted at 160 ° C. and 6% by weight of glycerol monostearate is added and mixed. The mixture is broken up and crushed to give a powder. The powder is filled into an antechamber of an injection molding machine and injected into the mold cavity through a 0.5 mm wide vent under 170 bar pressure. After cooling, a bubble-free, slightly opaque, thin-walled pharmaceutical capsule is obtained. No special means of removing low boiling point components immediately before processing by injection molding is described.
    [6] Purpose and Achievement
    [7] It is an object of the present invention to provide a process by which injection molding of known (meth) acrylate copolymers containing monomers having quaternary ammonium groups is possible. This is to ensure that the obtained molded article has sustained release and meets high mechanical requirements, so that it can be used as a capsule (hard capsule), for example, provided as a container for pelletized pharmaceutically active ingredients.
    [8] This purpose is
    [9] (Meth) acrylate copolymer comprising 85 to 98% by weight of C1-C4 alkyl (meth) acrylate capable of free radical polymerization and 15 to 2% by weight of (meth) acrylate monomer having a tertiary ammonium group in the alkyl radical. Melted and mixed with 10 to 25% by weight plasticizer and 10 to 50% by weight desiccant and / or 0.1 to 3% by weight release agent and, where appropriate, other conventional pharmaceutical additives or auxiliaries and / or one or more pharmaceutically active ingredients. Step (a)
    [10] (B) degassing the mixture at a temperature of at least 120 ° C. to reduce the content of low boiling point components having a vapor pressure of at least 1.9 bar at 120 ° C. to 0.5% by weight or less; and
    [11] Injecting the degassed mixture into a mold of an injection molding system at a temperature of 80 to 160 ° C. and removing the resulting molded article from the mold (c).
    [12] The process of the present invention can be used to obtain novel injection molded articles that meet high mechanical requirements.
    [13] Implementation of the Invention
    [14] The process of the invention for producing a molded article by injection molding is divided into process steps (a), (b) and (c).
    [15] Process step (a)
    [16] (Meth) acrylate copolymer comprising 85 to 98% by weight of C1-C4 alkyl (meth) acrylate capable of free radical polymerization and 15 to 2% by weight of (meth) acrylate monomer having a tertiary ammonium group in the alkyl radical. 10-25 wt% plasticizer and 10-50 wt% desiccant and 0.1-3 wt% release agent, and, where appropriate, melted and mixed with other conventional pharmaceutical additives or auxiliaries and / or one or more pharmaceutically active ingredients. step.
    [17] Weight percent data is in each case based on the (meth) acrylate copolymer. The (meth) acrylate copolymer in pellet or powder form is preferably melted in an extruder under a temperature of 70 to 140 ° C. Desiccants and / or release agents and plasticizers may be introduced simultaneously or sequentially in any desired order. In addition, it applies to any conventional conventional other pharmaceutical adjuvant or additive, and to existing pharmaceutically active ingredients.
    [18] (Meth) acrylate copolymer
    [19] Examples of suitable (meth) acrylate copolymers are known from EP-A 181 515 or DE-C 1 617 751. It is a copolymer with pH dependent solubility or swellability and is suitable for pharmaceutical coatings. A possible preparation method that may be mentioned is the bulk polymerization process in the presence of free radical generating initiators dissolved in the monomer mixture. The polymer may also be prepared by solution or precipitation polymerization. Thus, the polymer may be obtained in finely divided form, for example by grinding in the case of bulk polymerization and by spray drying in the case of solution or precipitation polymerization.
    [20] The (meth) acrylate copolymer consists of 85 to 98% by weight of C1-C4 alkyl (meth) acrylate capable of free radical polymerization and 15 to 2% by weight of (meth) acrylate monomer having a tertiary ammonium group in the alkyl radical. .
    [21] Preferred C1-C4 alkyl (meth) acrylates are methyl acrylate, ethyl acrylate, butyl acrylate, butyl methacrylate and methyl methacrylate.
    [22] Particularly preferred (meth) acrylate monomers having quaternary ammonium groups are 2-trimethylammoniummethyl methacrylate chloride.
    [23] Examples of suitable copolymers may have a structure consisting of 50 to 70% by weight methyl methacrylate, 20 to 40% by weight ethyl acrylate and 7 to 2% by weight 2-trimethylammoniummethyl methacrylate chloride.
    [24] Certain suitable copolymers have a structure consisting of 65% methyl methacrylate, 30% ethyl acrylate and 5% by weight 2-trimethylammoniummethyl methacrylate chloride (EUDRAGIT R RS).
    [25] Another suitable (meth) acrylate copolymer is, for example, from 85 to 93% by weight of C1-C4 alkyl (meth) acrylate and from 7 to 15% by weight of (meth) acrylate monomer having tertiary ammonium groups in the alkyl radical. It may have a structure composed of%. This type of (meth) acrylate monomer is commercially available and has been used for a long time for sustained release coatings.
    [26] Certain suitable copolymers contain, for example, 60% by weight methyl methacrylate, 30% by weight ethyl acrylate and 10% by weight 2-trimethylammoniummethyl methacrylate chloride (EUDRAGIT R RL).
    [27] mixture
    [28] The (meth) acrylate copolymer is present in a mixture of a plasticizer and a desiccant and / or release agent. In a known manner, it may also be other conventional pharmaceutical adjuvant and / or pharmaceutically active ingredients conventional.
    [29] Adding a plasticizer reduces the brittleness of the molded article. As a result, the proportion of shattered articles after demolding is reduced. In the absence of plasticizers, the proportion of molded articles that have been satisfactorily removed is typically about 85% for most mixtures. The addition of plasticizers can reduce the proportion of demolding breakage, mainly increasing the overall yield to 95 to 100%.
    [30] The molecular weight of materials suitable as plasticizers is usually from 100 to 20,000 and contains one or more hydrophilic groups, such as hydroxy groups, ester groups or amino groups, in the molecule. Suitable materials are citrate, phthalate, sebacate and castor oil. Examples of suitable plasticizers are alkyl citrate, glycerol esters, alkyl phthalates, alkyl sebacates, sucrose esters, sorbitan esters, dibutyl sebacates and polyethylene glycols 4000 to 20,000. Preferred plasticizers are tributyl citrate, triethyl citrate, triethyl acetyl citrate, dibutyl sebacate and diethyl sebacate. The amount used is 10 to 25% by weight, preferably 12 to 22% by weight, particularly preferably 12 to 18% by weight, based on the (meth) acrylate copolymer.
    [31] Desiccant (Anti-stick):
    [32] Desiccants may be present alone or in combination with release agents in the mixture. The desiccant in the mixture has the property of having a large specific surface area, chemically inertness, good fluidity and fine particles. Due to this property, the desiccant can advantageously reduce the adhesion of the polymer containing polar comonomers which are homogeneously dispersed in the melt and act as functional groups. The desiccant (anti-sticking agent) may be added in an amount of 1 to 50% by weight, preferably 10 to 40% by weight, based on the copolymer.
    [33] Examples of desiccants are aluminum oxide, magnesium oxide, kaolin, talc, silica, barium sulfate, carbon black and cellulose.
    [34] Release agent
    [35] The release agent may be present alone in the mixture or together with a desiccant. The release agent should be added in an amount of 0.1 to 3% by weight, preferably 0.2 to 2.5% by weight, based on the copolymer.
    [36] In contrast to the desiccant, the release agent has the property of reducing the adhesion between the molded article and the mold surface from which the molded article is produced. For this reason, the molded article which is not broken and is not demolded geometrically can be manufactured. Release agents are, for the most part, partially miscible or immiscible with polymers in which they are particularly active. When the melt is injected into the mold cavity, partial miscibility or immiscibility causes a shift to the interface of the transition zone between the mold wall and the molded article. In order for the release agent to move particularly advantageously, the melting point of the release agent should be 20-100 ° C. below the processing temperature of the polymer.
    [37] Examples of release agents are esters of fatty acids or fatty amides, aliphatics, long chain carboxylic acids, fatty alcohols, as well as esters thereof, montan or paraffin waxes and metal soaps, glycerol monostearate, stearyl alcohol, glycerol esters of behenic acid, cetyl Particular mention is made of alcohols, palmitic acid, stearic acid, carnauba wax, beeswax and the like.
    [38] Additives or auxiliaries
    [39] The mixture may comprise from 0 to 100% by weight, based on the (meth) acrylate copolymer, an adjuvant or additive conventional to the agent.
    [40] Examples thereof which may be mentioned are stabilizers, dyes, antioxidants, wetting agents, pigments, brighteners and the like. They are mainly used as processing aids, for reliable and reproducible manufacturing processes and can ensure excellent long term storage stability.
    [41] An example of another adjuvant for the purposes of the present invention is a polymer. The mixture may comprise from 0 to 20% by weight of other polymers or copolymers, based on the (meth) acrylate copolymer.
    [42] In order to control the release of the active ingredient, in certain cases it may be advantageous to mix different polymers. However, the proportion of other polymers in the mixture is 20% by weight or less, preferably 10% by weight or less, in particular 0 to 5% by weight, based on the (meth) acrylate copolymer.
    [43] Examples of such other polymers include polyvinyl-pyrrolidone; Polyvinyl alcohol; Cationic (meth) acrylate copolymers prepared from methyl methacrylate and / or ethyl acrylate and 2-dimethylaminoethylmethacrylate (EUDRAGIT R E100); Carboxymethylcellulose salts; Hydroxypropyl cellulose (HPMC); Neutral (meth) acrylate copolymers prepared from methyl methacrylate and ethyl acrylate (anhydrides from EUDRAGIT R NE 30 D); Copolymers prepared from methyl methacrylate and butyl methacrylate (PLASTOID R B).
    [44] In addition, anionic (meth) acrylate copolymers and alkyls consisting of 40 to 100% by weight, preferably 45 to 99% by weight, in particular 85 to 95% by weight, of C1-C4 alkyl (meth) acrylates capable of free radical polymerization Suitable are anionic (meth) acrylate copolymers of up to 60% by weight, preferably 1 to 55% by weight, in particular 5 to 15% by weight, of (meth) acrylate monomers having anionic groups in the radicals.
    [45] Examples of suitable materials are natural (meth) acrylate copolymers consisting of 20 to 40% by weight ethyl acrylate and 60 to 80% by weight methyl methacrylate (EUDRAGIT R NE).
    [46] Other suitable materials are anionic (meth) consisting of 40 to 60% by weight of methacrylic acid and 60 to 40% by weight of methyl methacrylate, or 60 to 40% by weight of ethyl acrylate (EUDRAGIT R L or EUDRAGIT R L100-55) Acrylate copolymer.
    [47] Another suitable material is an anionic (meth) acrylate copolymer consisting of 20-40% by weight of methacrylic acid and 80-60% by weight of methylmethacrylate (EUDRAGIT R S).
    [48] Particularly good compatibilities are (meth) acrylate copolymers consisting of 10-30% by weight methyl methacrylate, 50-70% by weight methyl acrylate and 5-15% by weight methacrylic acid (EUDRAGIT R FS).
    [49] Pharmaceutically active ingredients
    [50] The mixture may comprise 0 to 200% by weight of one or more pharmaceutically active ingredients based on the (meth) acrylate copolymer. Pharmaceutically active ingredients as used herein include those that do not degrade at processing temperatures.
    [51] Pharmaceuticals (pharmaceutically active ingredients) used for the purposes of the present invention
    [52] 1.To treat, alleviate, prevent or detect a disease, injury, physical injury or pathological condition,
    [53] 2. to identify a situation, condition or function of a physical or mental condition,
    [54] 3. to replace body fluids or active ingredients produced by the human or animal body,
    [55] 4. To eradicate or eliminate pathogens, parasites or foreign objects or to be harmful to the human body, or
    [56] 5. For use in or administered to a human or animal body in order to affect the situation, condition or function of a physical or mental state.
    [57] For conventional medications, reference should be made to Rote Liste or Merck Index.
    [58] According to the invention, all active ingredients can be used which fulfill the desired therapeutic action and have suitable thermal stability and skin penetration within the meanings defined above.
    [59] While not fully claimed, important examples (group and individual substances) are:
    [60] painkiller,
    [61] Anti-allergic agents, antiarrhythmic drugs,
    [62] Antibiotics, chemotherapy, diabetes treatment, antidote,
    [63] Antiepileptic drugs, antihypertensives, antihypertensives,
    [64] Anticoagulants, antifungal drugs, anti-inflammatory drugs,
    [65] Beta receptor blockers, calcium antagonists and ACE inhibitors,
    [66] Broncholytics / anti-asthma drugs, cholinergic drugs, corticosteroids (Interna),
    [67] Dermatological drugs, diuretics, enzyme inhibitors, enzyme preparations and transport proteins,
    [68] Expectorant, geriatric medicine, gout medicine, cold medicine,
    [69] Hormones and inhibitors thereof, hypnotics / sedatives, cardiovascular agents, lipid lowering drugs,
    [70] Parathyroid hormone / calcium metabolism modulators,
    [71] Psychopharmaceuticals, sex hormones and inhibitors thereof,
    [72] Antispasmodic, sympathetic blockers, sympathetic drugs, vitamins
    [73] Wounds, cell growth inhibitors.
    [74] Process step (b)
    [75] Prior to processing, the (meth) acrylate copolymers actually have a content of at least 1% by weight, mostly about 2% by weight, of low boiling point components, which always have a vapor pressure of at least 1.9 bar at 120 ° C. The low boiling point component is mainly water absorbed from atmospheric moisture.
    [76] Step (b) of the process degass the mixture from step (a) at a temperature of at least 120 ° C., preferably 125 to 155 ° C., particularly preferably 130 to 140 ° C., so that the vapor pressure at 120 ° C. is 1.9 bar. The content of the above low boiling point component is 0.5% by weight or less, preferably 0.2% by weight or less, and particularly preferably 0.1% by weight or less. In this way, undesired sudden degassing, which forms bubbles or causes foaming in the obtained molded article, to be useless, does not occur during step (c) of the injection molding process.
    [77] Since the glass transition temperature of the (meth) acrylate copolymer is in the range of 50 ° C., the low boiling point component cannot be removed simply by drying at a high temperature, since the copolymer may perform undesired sintering or film formation in the meantime. .
    [78] Therefore, the degassing step (b) is preferably carried out by extrusion drying in an extruder with a degassing zone or through degassing in an injection molding system with an upstream vent. In the case of extrusion drying in an extruder with a degassing zone, the degassed extrudate is either introduced directly into the injection molding machine or into the injection molding. When degassing in an injection molding system with an upstream vent, the degassing process is carried out in a waiting room before the polymer is injected into the injection mold.
    [79] The mixture may immediately enter the molten form into the injection molding system, or may preferably be first cooled and pelletized. The pellets should be stored under conditions that permit little resorption of water, ie for short periods of time and / or only under anhydrous storage conditions.
    [80] Process step (c)
    [81] The degassed mixture is injected into the mold of the injection molding system at a temperature of 80 to 160 ° C., preferably 90 to 150 ° C., particularly preferably 115 to 145 ° C., and the molded article obtained is removed from the mold. The predetermined temperature refers to the maximum temperature reached in the hottest zone of the injection molding system used.
    [82] The thermoplastic processing is carried out in a manner known per se using an injection molding machine at a temperature of 80 to 160 ° C., in particular 100 to 150 ° C. and a pressure of 60 to 400 bar, preferably 80 to 120 bar.
    [83] When the glass transition temperature range of the (meth) acrylate copolymer used is, for example, 40 to 60 ° C., the mold temperature is correspondingly low, for example, 30 ° C. or less or 20 ° C. or less, so that the existing mixture The silver may already solidify in the mold immediately after the injection process to remove or release the final molded product from the mold.
    [84] The molded article can be removed from the mold cavity of the injection mold without breaking, and its surface is uniform, dense and flawless. Molded articles are characterized by mechanical strength, elasticity and breaking strength, respectively.
    [85] In particular, the impact strength according to ISO 179 measured on the test piece is at least 15 KJ / m 2 , preferably at least 18 KJ / m 2 , particularly preferably at least 20 KJ / m 2 .
    [86] The VST (A10) proximity heat deformation temperature measured on the test piece according to ISO 306 is 30 to 60 ° C.
    [87] Molded articles obtained according to the invention can be, for example, in the form of capsules, parts of capsules, for example half of capsules, or hard capsules used as containers for pharmaceutically active ingredients. The active ingredient contained in the binder can be filled in, for example in the form of pellets, after which the two capsule portions are bonded with an adhesive, welded with a laser, ultrasonic or microwave, or joined via a snap action connection. .
    [88] According to the invention, capsules made from different materials, such as gelatin, partially hydrolyzed starch, HPMC or other methacrylates, may also be incorporated into one another by this process. Thus, the molded article may also be part of the dosage unit.
    [89] Other forms such as tablets or lenses are also possible. The compounds used for injection molding already contain pharmaceutically active ingredients. In the final form, it is present in the form of maximally uniform dispersion in crystalline form (solid dispersion) or dissolved amorphous (solid solution).
    [90] Molded article
    [91] Due to step (b) of the process, the moisture content of the injection molded article obtained in step (c) of the process is very low, at least immediately after manufacture. The range of moisture content measurable by the Karl Fischer method for the test piece is less than 0.5% by weight. For example, the subsequent change in moisture content through the relatively long storage of the molded article in a wet atmosphere is above the corresponding limit for the present invention, which is mainly 120 ° C. for the smooth operation of the process step (c). This is because a small boiling point component, mainly water, with a vapor pressure of 1.9 bar or more is required.
    [92] The measurement of the quality of the molded article obtained is known as the alkali value. The definition of alkali value is similar to that of acid value. This indicates how many kilograms of potassium hydroxide (KOH) corresponds to 1 g of the basic group in the polymer. This is described in Ph. Eur. 2.2.20 Measure by potentiometric titration as in "Potentiometric Titration" or USP <541>. The starting weight is the amount corresponding to 1 g of copolymer having 10% by weight of trimethylammoniummethyl methacrylate chloride, which is dissolved in a mixture of 96 mL of glacial acetic acid and 4 mL of purified water and titrated with 0.1 N perchloric acid for mercury acetate (5% in glacial acetic acid). 5 mL of concentration solution). The alkali value of the pyrolyzed polymer in the mixture is lower than the alkali value of the non-pyrolyzed mixture.
    [93] Even if the small difference in alkali value as small as 0.5 exceeds 0.5, it may indicate thermal decomposition. If this type of degradation is present, there is a risk of modification to such an extent that sustained release is not acceptable.
    [94] The method of the present invention may directly comprise a pharmaceutically active ingredient or may provide an injection molded article in which subsequent filling of the pharmaceutically active ingredient may be contained, for example, in capsule form.
    [95] Examples of active ingredients suitable for injection into the molded article (capsules) or suitable for ingress into the molded article are acetylsalicylic acid, lantidine, simvastatin, enalapril, fluoxetine, amlodipine, amoxicillin, sertalin, nipididipine, ciprofloxacin, acichol Vir, lovastatin, epoetin, paroxetine, captopril, nabumethone, granisetrone, cimetidine, ticarcillin, triamterene, hydrochlorothiazide, verapamil, paracetamol, morphine derivatives, topotecan or pharmaceutically used Salts thereof.
    [96] The formulations of the invention are usually any desired pharmaceutically active ingredient, preferably those that can be administered in a sustained release, for example for the treatment of diabetes, analgesics, preferably for release to the gastrointestinal and / or mucous membranes. , Anti-inflammatory drugs, antirheumatic drugs, antihypertensive drugs, antihypertensive drugs, psychiatric drugs, neurostabilizers, antiseptics, muscle relaxants, glucocorticoids, ulcerative colitis or Crohn's disease, antibiotics, antiepileptic drugs, anticoagulants Antifungals, antitussives, atherosclerosis, diuretics, enzymes, enzyme inhibitors, gout, hormones and inhibitors, cardiac glycosides, immunotherapy, cytokines, constipation, lipid lowering drugs, migraine medications, mineral preparations, ocular therapies, antiperkines Antiseptics, thyroid drugs, antispasmodics, platelet coagulation inhibitors, vitamins, cell growth inhibitors, mutation inhibitors, phytopharmaceuticals, chemotherapeutic agents and amino Suitable for administering the.
    [97] Examples of suitable active ingredients include acarbose, beta receptor blockers, nonsteroidal antirheumatic drugs, cardiac glycosides, acetylsalicylic acid, virus growth inhibitors, aclarubicin, acyclovir, cisplatin, actinomycin, alpha sympathetic nerves Stimulant, beta sympathetic stimulant, demeprazole, allopurinol, alprostadil, prostaglandin, amantadine, ambroxol, amlodipine, methotrexate, S-aminosalicylic acid, amitriptyline, amoxicillin, anastrozole, athenol, Azathioprine, valsalazide, beclomethasone, betahistin, bezafibrate, bicalutamide, diazepam, diazepam derivatives, budesonide, bufexa film, buprenorphine, methadone, calcium salt, potassium salt, magnesium salt , Candesartan, carbamazepine, captopril, cephalosporin, cetirizine, cenodeoxycholic acid, ursodeoxycholic acid, theophylline, theophylline oil Conductors, trypsin, cimetidine, clarithromycin, claburanic acid, clindamycin, clobutinol, clonidine, cortimoxazole, codeine, caffeine, vitamin D, vitamin D derivatives, cholestyramine, chromoglylic acid, coumarin, coumarin derivatives , Cysteine, cytarabine, cyclophosphamide, cyclosporine, cyproterone, cytarabine, dapiprazole, desogestrel, desonide, dihydralazine, diltiazem, erkot alkaloids, dimenhydrinate, dimethyl Sulfoxide, dimethicone, dipyridarnoi, domperidone, domperidone derivatives, dopamine, doxazosin, doxorubicin, doxylamine, dapiprazole, benzodiazepines, diclofenac, glycoside antibiotics, decipramine, echoazoles, ACE inhibitors, e Nalapril, ephedrine, epinephrine, epoetin, epoetin derivatives, morphinane, calcium antagonists, irinotecan, modafinil, orlistat, Peptide antibiotics, phenytoin, rilusol, risedronate, sildenafil, topiramate, macrolide antibiotics, oestrogens, oestrogen derivatives, gestagens, gestagen derivatives, testosterone, testosterone derivatives, androgens, androgen derivatives, ethene Mead, etofenamate, etofibrate, fenofibrate, etophylline, etoposide, famcyclovir, famotidine, felodipine, fenofibrate, fentanyl, penticonazole, gyrase inhibitors, fluconazole, fludarabine, fluna Lysine, fluorouracil, fluoxetine, flubiprofen, ibuprofen, flutamide, fluvastatin, polytropin, formoterol, phosphomicin, furosemide, fusidic acid, galopamil, gancyclovir , Gemfibrozil, gentamicin, ginkgo, St John's wort, gleebenclamide, urea derivatives as oral diabetes treatment, glucagon, Glucosamine, Glucosamine Derivatives, Glutathione, Glycerol, Glycerol Derivatives, Hypotalamus Hormone, Goserelin, Girase Inhibitors, Guanetidine, Halopantrin, Haloperidol, Heparin, Heparin Derivatives, Hyaluronic Acid, Hydralazine, Hydrochlorothiazide, Hydrochlorochlorozide Thiazide derivatives, salicylates, hydroxyzin, idarubicin, isophosphamide, imipramine, indomethacin, indoramine, insulin, interferon, iodine, iodine derivatives, isoconazole, isoprenin, glutis Tols, glutathol derivatives, itraconazole, ketoconazole, ketoprofen, ketotifen, laccidipine, lansoprazole, levodopa, levometadon, thyroid hormones, lipoic acid, lipoic acid derivatives, lisinopril, lisuride, lofepramine, Lomustine, loperamide, loratadine, maprotiline, mebendazole, mebeberine, meclozin, mefenamic acid, mefloquine, meroc Cycam, Mepindolol, Meprobamate, Meropenem, Mesalazine, Mesuccimid, Metamizol, Metformin, Methotrexate, Methylphenidate, Methylprednisolone, Meticenme, Metoclopramide, Metoprolol, Metronidazole, Mianserine, Myconazole, Minocycline, Minoxidil, Misoprostol, Mitomycin, Mizolastin, Moexipril, Morphine, Morphine Derivatives, Evening Primrose, Nalbuphine, Naloxone, Tilidine, Naproxen, Narcotin, Natamycin, Neostigmine, Nisergoline, nicetamide, nifedipine, niflumic acid, nimodipine, nimorazol, nimusstin, nisoldipine, adrenaline, adrenaline derivatives, norfloxacin, novaminsulphone, noscapine, nistatin, oploxacin, olazapyne , Olsalazine, omeprazole, omoconazole, ondansetron, oxacerol, oxacillin, oxyconazole, oxymethazolin, pentoprazole, paracetamol, paroxetine, pensi Lovir, oral penicillin, pentazosin, pentipilin, pentoxifylline, perfenazine, fetidine, botanical extract, phenazone, peniamine, barbituric acid derivatives, phenylbutazone, phenytoin, pimozide, pindolol, Piperazine, Piracetam, Pyrenzepine, Pyribedil, Pyroxycam, Pramipexole, Pravastatin, Prazosin, Procaine, Promazine, Propibrine, Propranolol, Propapezone, Prostaglandin, Prothiamide, Propoxy Filin, quetiapine, quinapril, quinapril, ramipril, lantidine, leproterol, reserpin, ribavarin, rifampicin, risperidone, ritonavir, lopinirol, roxatidine, roxythromycin, Ruscogenin, rutoside, rutoside derivatives, sabadilla, salbutamol, salmeterol, scopolamine, sereglin, sertaconazole, sertindol, sertralion, silicate, simvastatin, cytostolitol, sotalol , Spagroom mountains, sea Parfloxacin, spectinomycin, spiramycin, spirapril, spironolactone, stavudine, streptomycin, sucralate, sufentanil, sulbactam, sulfonamide, sulfasalazine, sulfide, sulfamicillin, sultiam, thermima Tryptan, MS Metonium Chloride, Tacrine, Tacrolimus, Taliolol, Tamoxifen, Taurolidine, Tazarotene, Temezepam, Teniposide, Tenoxycam, Terrazosin, Terbinafine, Terbutalin, Terpenadine , Terypressin, tertatolol, tetracycline, tetrizoline, theobromine, theophylline, butyzin, thiazole, phenothiazine, thiotepa, thiagabin, thiapriide, priopionic acid derivatives, ticlopidine, thymolol, tiniida Sol, Thioconazole, Thioguanine, Thioxolone, Tyropramide, Tizanidine, Tolazoline, Tolbutamide, Tolcapone, Tolnaphate, Tolperison, Topotecan, Torasemide, Antistrogen, Tramadol , Tra Sleepy, transdolapril, tranilycypromine, trapidyl, trazodone, triamcinolone, triamcinolone derivatives, triamterene, trifluperidol, trifluridine, trimetoprim, trimipramine, tripelinamine, tri Prolidine, Triphosphamide, Tromantadine, Trometamol, Trofalpin, Troxertin, Tolubuterol, Tyramine, Tyrotricin, Urapidyl, Ursodeoxycholic acid, Kenodeoxycholic acid, Valacyclosis , Valproic acid, vancomycin, becuronium chloride, viagra, venlafaxine, verapamil, vidarabine, vigatrine, biloxazine, vinblastine, vincarmine, vincristine, bisdesin, vinorelbine, vinpocetin, biquidyl, Warfarin, xanthinol, nicotinate, xipamide, zafirlukast, zalcitabine, zidovudine, zolmitriptan, zolpidem, zuplicone, zeopepine and the like.
    [98] Examples of particularly preferred active ingredients include analgesics such as tramadol or morphine; Ulcerative colitis or Crohn's disease therapeutic agent such as 5-aminosalicylic acid; Corticosteroids such as budesonide; Quantum pump inhibitors such as omeprazole; Viral therapeutics such as acicolvir; Lipid lowering drugs such as simvastatin or pravastatin; H2 blockers, such as lantidine or pamotidine; Antibiotics such as amoxicillin and / or clavulanic acid; And ACE inhibitors such as enalapril or amlodipine.
    [99] If desired, the active ingredient may also be used in the form of a pharmaceutically acceptable salt or derivative thereof, and in the case of chiral active ingredients, optically active isomers or racemide or diastereomeric mixtures may be used. If desired, the compositions of the present invention may also comprise two or more pharmaceutically active ingredients.
    [100] Comparative Example 1: (Excessive High Temperature)
    [101] Degassing and Preparation of Mixtures (Compounds)
    [102] 3.25 kg of EUDRAGIT R RL 100 pellets and 1.0 kg of talc are weighed and placed in a 10 L stainless steel mixing vessel and mixed for 5 minutes with a tumbling mixer.
    [103] The prepared mixture is fed to a 30.34 twin screw extruder (Leistritz) to prepare a compound of the present invention. The set melting temperature is 140 ° C. and the screw rotational speed is 120 rpm. At 50% downstream of the total length of the extruder screw, triethyl citrate plasticizer is added by means of a membrane pump through the vent in the barrel wall, the amount of which is 15% based on the copolymer. Downstream of the mixing zone for homogenizing the mixture is degassed to the exhaust port in the extruder barrel. Four extrudate are molded into a die at the end of the extruder, recovered into a cooled metal plate and cut to produce pellets. The moisture content of the obtained pellets was 0.09% by weight by Karl Fischer titration.
    [104] Injection molding
    [105] The obtained mixture (compound) is supplied to a hopper of an injection molding machine (Arburg Allrounder 250-125), and the molded article is injection molded. The following temperatures are set for the injection molding machine: Zone 1 (feed zone): 70 ° C., Zone 2: 120 ° C., Zone 3: 160 ° C., Zone 4: 160 ° C., Zone 5 (die): 130 ° C. Injection pressure: 60 bar, Cooling pressure: 50 bar, Rear pressure: 5 bar. Mold temperature: 17 ° C. (cooling).
    [106] The molded injection molded article is a plaque of 65 × 40 × 1 mm. A smooth plaque is obtained without streaks and with a flawless surface. The plaque demolds without difficulty and is geometrically stable. However, decomposition of the polymer is expected due to the high temperature.
    [107] Comparative Example 2: (No Plasticizer)
    [108] Degassing
    [109] Prepared as in Example 1 but without the addition of triethyl citrate plasticizer.
    [110] Injection molding
    [111] It is performed as described in Example 1. The temperature in Zone 3 and Zone 4 is set to 120 ° C.
    [112] Result: It is not possible to produce uniform molded parts that are geometrically accurate. This is because of the too low flowability of the EUDRAGIT R RL 100 polymer.
    [113] Example 3: (Invention)
    [114] Degassing and Preparation of Compounds
    [115] Prepare as in Example 1.
    [116] Injection molding
    [117] The obtained mixture (compound) is supplied to a hopper of an injection molding machine (Arburg Allrounder 250-125), and the molded article is injection molded. However, the temperature in zone 3 and zone 4 of the injection molding machine is set to 120 ° C. The injection molded molded article is a plaque of 65 × 40 × 1 mm.
    [118] A smooth plaque is obtained without streaks and with a flawless surface. The plaque demolds without difficulty and is geometrically stable.
    [119] The alkali value of the obtained molded article is measured. The definition of alkali value is similar to that of acid value. It indicates how many kg of potassium hydroxide (KOH) corresponds to 1 g of the basic group in the polymer. This is described in Ph. Eur. 2.2.20 Measure by potentiometric titration as in "Potentiometric Titration" or USP <541>. The starting weight corresponds to 1 g of EUDRAGIT R RL 100, which is dissolved in a mixture of 96 mL glacial acetic acid and 4 mL of purified water and titrated with 0.1 N perchloric acid to mercury acetate (5 mL of 5% solution in glacial acetic acid). The alkali value obtained (mg KOH per gram of polymer) is 23.1. Compared to EUDRAGIT R RL 100 subjected to thermal stress in the injection molding process, the result is relatively good and the alkali value is 22.9.
    [120] Comparative Example 4: (No Desiccant or Release Agent)
    [121] Degassing and Preparation of Compounds
    [122] Using a weighing device, 10 kg of EUDRAGIT R RL 100 per hour is weighed and provided to the feed zone of the twin screw extruder. Using a screw rotation speed of 120 rpm, the pellets are recovered by an extruder and plasticized. The melting temperature is set at 140 ° C.
    [123] At 50% downstream of the total length of the twin screw extruder, perforations are made in the barrel wall and used to introduce triethyl citrate by means of a membrane pump, the amount of which is 20% based on the copolymer.
    [124] Downstream of the mixing zone for homogenizing the mixture is degassed through another vent in the barrel wall. Four extrudate are molded into a die at the end of the extruder, recovered into a cooled metal plate and cut to produce pellets. The moisture content of the obtained pellets is 0.1% by weight, as determined by Karl Fischer titration.
    [125] Injection molding
    [126] The obtained mixture (compound) is supplied to a hopper of an injection molding machine (Arburg Allrounder 250-125), and the molded article is injection molded. However, the temperature in Zone 3 and Zone 4 of the injection molding machine is set to 140 ° C. The injection molded injection molded article is a plaque of 65 × 40 × 1 mm.
    [127] The injection molded molded article is a plaque of 65 × 40 × 1 mm. After hitting as little as two times, the molded article was observed to increase cracking and separation from the mold, making it more difficult. As a result, the experiment was terminated.
    [128] Comparative Example 5: (Excessive High Temperature)
    [129] Degassing and Preparation of Compounds
    [130] From a degassed compound as in Example 1, comprising EUDRAGIT R RL 100
    [131] Injection molding
    [132] The obtained mixture (compound) is supplied to a hopper of an injection molding machine (Arburg Allrounder 250-125), and the molded article is injection molded. However, the temperature in Zone 3 and Zone 4 of the injection molding machine is set to 170 ° C. The injection molded molded article is a plaque of 65 × 40 × 1 mm.
    [133] A smooth plaque can be obtained without streaks and with a flawless surface. The plaques can demold without difficulty and are geometrically stable.
    [134] Using the method described in Example 3, the alkali value of the obtained molded article is measured by the potential difference.
    [135] In the results obtained, the alkali value (mg KOH per gram of polymer) is 22.3. For comparison, EUDRAGIT R RL 100 polymers that are not subjected to thermal stress during the injection molding process are tested. In the obtained result, the alkali value is 22.9. Even if the value is close to the limit of analytical accuracy, it shows a problem of thermal decomposition at 160 ° C or higher. Even at this temperature, a marked drop is expected, especially during continuous operation.
    [136] Example 6: (Invention)
    [137] Degassing and Preparation of Mixtures
    [138] 3.25 kg of EUDRAGIT R RL 100 pellets and 1.0 kg of talc are weighed and placed in a 10 L stainless steel mixing vessel and mixed for 5 minutes with a tumbling mixer.
    [139] The prepared mixture is fed to a 30.34 twin screw extruder [Rystreettsu] to prepare a compound of the present invention. The set melting temperature is 140 ° C. and the screw rotational speed is 120 rpm. At 50% downstream of the total length of the extruder screw, triethyl citrate plasticizer is added by means of a membrane pump through the vent in the barrel wall, the amount of which is 20% based on the total amount of material. Downstream of the mixing zone for homogenizing the mixture is degassed to the exhaust port in the extruder barrel. Four extrudate are molded into a die at the end of the extruder, recovered into a cooled metal plate and cut to produce pellets. The moisture content of the obtained pellets is 0.1% by weight, as determined by Karl Fischer titration.
    [140] Injection molding
    [141] The obtained mixture (compound) is supplied to a hopper of an injection molding machine (Arburg Allrounder 250-125), and the molded article is injection molded. However, in zones 3 and 4 of the injection molding machine the temperature is set to 140 ° C. The injection molded molded article is a plaque of 65 × 40 × 1 mm.
    [142] A smooth plaque is obtained without streaks and with a flawless surface. The plaque demolds without difficulty and is geometrically stable.
    [143] Example 7: (Invention)
    [144] Degassing and Preparation of Mixtures
    [145] 3.25 kg of EUDRAGIT R RL 100 pellets and 0.03 kg of stearic acid are weighed into a 10 L stainless steel mixing vessel and mixed for 5 minutes with a tumbling mixer.
    [146] The prepared mixture is fed to a 30.34 twin screw extruder [Rystreettsu] to prepare a compound of the present invention. The set melting temperature is 140 ° C. and the screw rotational speed is 120 rpm. At 50% downstream of the total length of the extruder screw, triethyl citrate plasticizer is added by means of a membrane pump through the vent in the barrel wall, the amount of which is 10% based on the total amount of material. Downstream of the mixing zone for homogenizing the mixture is degassed to another vent in the barrel wall. Four extrudate are molded into a die at the end of the extruder, recovered into a cooled metal plate and cut to produce pellets. The moisture content of the obtained pellets is 0.15% by weight, as determined by Karl Fischer titration.
    [147] Injection molding
    [148] The obtained mixture (compound) is supplied to a hopper of an injection molding machine (Arburg Allrounder 250-125), and the molded article is injection molded. However, in zones 3 and 4 of the injection molding machine the temperature is set to 140 ° C. The injection molded molded article is a plaque of 65 × 40 × 1 mm.
    [149] A smooth plaque is obtained without streaks and with a flawless surface. The plaque demolds without difficulty and is geometrically stable.
    [150] Example 8: (Invention)
    [151] Degassing and Preparation of Compounds
    [152] 3.25 kg of EUDRAGIT R RL 100 pellets and 0.01 kg of stearic acid are weighed into a 10 L stainless steel mixing vessel and mixed for 5 minutes with a tumbling mixer.
    [153] The prepared mixture is fed to a 30.34 twin screw extruder [Rystreettsu] to prepare a compound of the present invention. The set melting temperature is 140 ° C. and the screw rotational speed is 120 rpm. At 50% downstream of the total length of the extruder screw, triethyl citrate plasticizer is added by means of a membrane pump through the vent in the barrel wall, the amount of which is 12.5% based on the total amount of material. Downstream of the mixing zone for homogenizing the mixture is degassed to another vent in the barrel wall. Four extrudate are molded into a die at the end of the extruder, recovered into a cooled metal plate and cut to produce pellets. The moisture content of the obtained pellets was 0.13% by weight by Karl Fischer titration.
    [154] Injection molding
    [155] The obtained mixture (compound) is supplied to a hopper of an injection molding machine (Arburg Allrounder 250-125), and the molded article is injection molded. However, in zones 3 and 4 of the injection molding machine the temperature is set to 140 ° C. The injection molded molded article is a plaque of 65 × 40 × 1 mm.
    [156] A smooth plaque is obtained without streaks and with a flawless surface. The plaque demolds without difficulty and is geometrically stable.
    [157] Example 9: (invention)
    [158] Degassing and Preparation of Compounds
    [159] 3.25 kg of EUDRAGIT R RL 100 pellets and 0.003 kg of stearic acid are weighed into a 10 L stainless steel mixing vessel and mixed for 5 minutes with a tumbling mixer.
    [160] The prepared mixture is fed to a 30.34 twin screw extruder [Rystreettsu] to prepare a compound of the present invention. The set melting temperature is 140 ° C. and the screw rotational speed is 120 rpm. At 50% downstream of the total length of the extruder screw, triethyl citrate plasticizer is added by means of a membrane pump through the vent in the barrel wall, the amount of which is 10% based on the total amount of material. Downstream of the mixing zone for homogenizing the mixture is degassed to another vent in the barrel wall. Four extrudate are molded into a die at the end of the extruder, recovered into a cooled metal plate and cut to produce pellets. The water content of the obtained pellets was 0.04% by weight by Karl Fischer titration.
    [161] Injection molding
    [162] The obtained mixture (compound) is supplied to a hopper of an injection molding machine (Arburg Allrounder 250-125), and the molded article is injection molded. However, in zones 3 and 4 of the injection molding machine the temperature is set to 140 ° C. The injection molded molded article is a plaque of 65 × 40 × 1 mm.
    [163] A smooth plaque is obtained without streaks and with a flawless surface. The plaque demolds without difficulty and is geometrically stable.
    权利要求:
    Claims (9)
    [1" claim-type="Currently amended] (Meth) acrylate copolymer comprising 85 to 98% by weight of C1-C4 alkyl (meth) acrylate capable of free radical polymerization and 15 to 2% by weight of (meth) acrylate monomer having a quaternary ammonium group in the alkyl radical. 10-25 wt% plasticizer and 10-50 wt% desiccant and 0.1-3 wt% release agent, and, where appropriate, melted and mixed with other conventional pharmaceutical additives or auxiliaries and / or one or more pharmaceutically active ingredients. Step (a)
    (B) degassing the mixture at a temperature of at least 120 ° C. to reduce the content of low boiling point components having a vapor pressure of at least 1.9 bar at 120 ° C. to 0.5% by weight or less; and
    And (c) injecting the degassed mixture into a mold of an injection molding system at a temperature of 80 to 160 ° C. and removing the resulting molded article from the mold.
    [2" claim-type="Currently amended] The process according to claim 1, wherein the degassing step (b) is carried out by extrusion drying in an extruder having a degassing zone or by degassing in an injection molding system equipped with an upstream vent.
    [3" claim-type="Currently amended] An injection molded article which can be produced by the method according to claim 1.
    [4" claim-type="Currently amended] 4. A molded article according to claim 3, wherein the impact strength according to ISO 179 is at least 15 KJ / m 2 .
    [5" claim-type="Currently amended] The molded article according to claim 3 or 4, wherein at least one pharmaceutically active ingredient is directly present or contained in the molded article.
    [6" claim-type="Currently amended] The molded article according to claim 5, which is a capsule containing one or more pharmaceutically active ingredients.
    [7" claim-type="Currently amended] 7. A molded article according to any one of claims 3 to 6, which is a component in the form of a larger medicament or is present in the medicament.
    [8" claim-type="Currently amended] 8. The molded article according to claim 3, wherein one or more pharmaceutically active ingredients present directly or contained in the molded article can be sustained release in the gastrointestinal tract of an animal or human. 9.
    [9" claim-type="Currently amended] The pharmaceutical active ingredient according to any one of claims 3 to 8, acetylsalicylic acid, lantidine, simvastatin, enalapril, fluoxetine, amlodipine, amoxicillin, sertalin, nipidipine, ciprofloxacin, acicolvir , Lovastatin, epoetin, paroxetine, captopril, nabumethone, granisetrone, cimetidine, ticarcillin, triamterene, hydrochlorothiazide, verapamil, paracetamol, morphine derivatives, topotecan or those used pharmaceutically Molded article characterized in that the salt of which is present directly or contained in the molded article.
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    同族专利:
    公开号 | 公开日
    EP1392485A1|2004-03-03|
    JP4713830B2|2011-06-29|
    IL153650D0|2003-07-06|
    WO2002098625A1|2002-12-12|
    JP2004519370A|2004-07-02|
    PL358720A1|2004-08-09|
    EP1392485B1|2006-04-19|
    CA2418316C|2010-10-26|
    DE10127134A1|2002-12-12|
    PT1392485E|2006-08-31|
    DK1392485T3|2006-08-21|
    US20100239666A1|2010-09-23|
    HU0300757A2|2004-06-28|
    ES2262814T3|2006-12-01|
    HU0300757A3|2005-10-28|
    CA2418316A1|2003-02-03|
    DE50206478D1|2006-05-24|
    MXPA03001061A|2003-06-30|
    US20040104501A1|2004-06-03|
    BG107512A|2003-07-31|
    BR0205512A|2003-06-24|
    KR100854256B1|2008-08-26|
    PL202610B1|2009-07-31|
    SK1162003A3|2004-01-08|
    BG66251B1|2012-09-28|
    SK287705B6|2011-07-06|
    AT323579T|2006-05-15|
    HU225242B1|2006-08-28|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2001-06-05|Priority to DE10127134.4
    2001-06-05|Priority to DE10127134A
    2002-05-08|Application filed by 룀 게엠베하 운트 콤파니 카게
    2002-05-08|Priority to PCT/EP2002/005041
    2003-03-15|Publication of KR20030022359A
    2008-08-26|Application granted
    2008-08-26|Publication of KR100854256B1
    优先权:
    申请号 | 申请日 | 专利标题
    DE10127134.4|2001-06-05|
    DE10127134A|DE10127134A1|2001-06-05|2001-06-05|Production of injection molded shaped articles, especially for retarded drug release, by blending acrylate copolymer with plasticizer and other additives, degassing and molding|
    PCT/EP2002/005041|WO2002098625A1|2001-06-05|2002-05-08|Method for injection moulding moulded bodies consisting of acrylate copolymers|
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