CN1056508C - 连续制片法 - Google Patents
连续制片法 Download PDFInfo
- Publication number
- CN1056508C CN1056508C CN87102755A CN87102755A CN1056508C CN 1056508 C CN1056508 C CN 1056508C CN 87102755 A CN87102755 A CN 87102755A CN 87102755 A CN87102755 A CN 87102755A CN 1056508 C CN1056508 C CN 1056508C
- Authority
- CN
- China
- Prior art keywords
- polymer
- tablet
- vinyl pyrrolidone
- mixture
- weight
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 238000011437 continuous method Methods 0.000 title abstract description 3
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- 238000000034 method Methods 0.000 claims description 29
- 229920000642 polymer Polymers 0.000 claims description 28
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- 239000000463 material Substances 0.000 description 15
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 12
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- 239000002202 Polyethylene glycol Substances 0.000 description 2
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
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- 230000000968 intestinal effect Effects 0.000 description 2
- LDHQCZJRKDOVOX-IHWYPQMZSA-N isocrotonic acid Chemical compound C\C=C/C(O)=O LDHQCZJRKDOVOX-IHWYPQMZSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
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- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
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- 238000002360 preparation method Methods 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- GNSFRPWPOGYVLO-UHFFFAOYSA-N 3-hydroxypropyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OCCCO GNSFRPWPOGYVLO-UHFFFAOYSA-N 0.000 description 1
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 1
- 229920002126 Acrylic acid copolymer Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010023126 Jaundice Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
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- CDQSJQSWAWPGKG-UHFFFAOYSA-N butane-1,1-diol Chemical compound CCCC(O)O CDQSJQSWAWPGKG-UHFFFAOYSA-N 0.000 description 1
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Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
- A61J3/06—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of pills, lozenges or dragees
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
- A61J3/10—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of compressed tablets
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- 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
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29B—PREPARATION OR PRETREATMENT OF THE MATERIAL TO BE SHAPED; MAKING GRANULES OR PREFORMS; RECOVERY OF PLASTICS OR OTHER CONSTITUENTS OF WASTE MATERIAL CONTAINING PLASTICS
- B29B9/00—Making granules
- B29B9/02—Making granules by dividing preformed material
- B29B9/06—Making granules by dividing preformed material in the form of filamentary material, e.g. combined with extrusion
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B30—PRESSES
- B30B—PRESSES IN GENERAL
- B30B11/00—Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses
- B30B11/16—Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses using pocketed rollers, e.g. two co-operating pocketed rollers
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B30—PRESSES
- B30B—PRESSES IN GENERAL
- B30B15/00—Details of, or accessories for, presses; Auxiliary measures in connection with pressing
- B30B15/30—Feeding material to presses
- B30B15/302—Feeding material in particulate or plastic state to moulding presses
- B30B15/308—Feeding material in particulate or plastic state to moulding presses in a continuous manner, e.g. for roller presses, screw extrusion presses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
用连续法压制可挤出的药剂混合物片剂,此法是先将药剂混合物挤出,然后再将仍然可变形的挤出料在两个辊筒之间进行压制,这两个辊筒的转动方向相反并在辊筒壳上有相互对着的凹型的模子,这些凹型模子的型式即决定片剂的形状。
Description
本发明是关于一种简单、连续的制备片剂的方法。
常规的制片压机是应用冲头和冲模来进行循环操作。此法需要将制片材料进行彻底预混合,因此,总的说来,是一种昂贵的多级操作方法。
本发明的目的是提供一种简单、连续的制片方法。我们发现本发明的目的可通过将可挤出的药剂混合物连续制片的方法来达到,该方法是先将药剂混合物挤出,然后再将仍然可变形的挤出料在两个辊筒之间进行压制,此二辊筒的转动方向相反并在辊筒壳上有相互对着的凹型的模子,这些凹型模子的型式即决定片剂的形状。如果要制备半球形片剂或其他的一面平的片剂,则可用一个筒壳是平滑的辊筒。本发明的方法可将含有活性化合物的聚合物熔体挤出并压制。
本发明的方法所用的设备包括一台混料挤出机(1),此挤出机有一个或多个进料口(2)和一个或多个模头(3)以及两个后续辊筒(4),此二辊筒的转动方向相反并在沿着每一辊筒的圆柱面上与辊筒轴成直角的平面上,有许多成对的相互对着的凹模(5),每一个模头与一组凹模相关联,从而在两支辊筒互相接触的线上制出片型药剂。
虽然,可能先进行预混合是有利的,在此种情况下,用一台简单的挤出机即可满足要求,但是,如果应用常规的单螺杆或多螺杆混料挤出机,一般来说,实际上是更有利的,因此,也就不需要再进行预混合。如果药剂混合物的固体组份和液体组分需要分别加入,混料挤出机(1)可具有多个进料口(2)和一个通入惰性氧体(一般是氮氧)和(或)排气的管接头。为了增加挤出量,挤出机可具有一个以上的模头(3)。
为了保证可靠地运送挤出料和防止从模头流出的向下物流断开,按向下倾斜的方向进行挤出是有利的。在具体的情况下,最有利的角度,取决于产品的性质和制备产品的操作条件(例如,挤出温度和挤出速度)。
成型过程是在紧接着挤出过程后进行的。将仍然具有塑性的挤出料馈送通过一对辊筒(4),必要时可借助适当的导槽,在这两个辊筒的壳上,有成对地相互对着的凹型模子(5),从而在两支辊筒互相接触的线上制出片型药剂。
在一优选的实施方案中,尤其是对于模壁(凹型模5)具有一定程度的粘着力的粘性材料,可用一明槽将凹模互相连接起来,从而使成型后的片剂(6)通过一短片(称为断裂点7)仍然互相连接在一起。根据片剂材料的揉曲性,此法可制出一条由许多片剂构成的硬质的或象一串珍珠的药片带。
此种好象一串珍珠的药片带可卷起来并可用相当简单的机械设备以经济便宜的方式进行包装。
如果压制出来的片剂对模壁(辊筒壳上的凹模)的粘着力是相当低的,以致于单个片剂(末通过短片来连接)也不会粘在模壁上,而是全部自由地从凹模中掉出来,则上述连接片即可省去。在此种情况下,将长形凹模(压制椭圆形片剂或栓剂)按辊筒的纵向轴平行排列是有利的。
通常,空气冷却对于辊筒来说已足以满足要求。但是,在特殊情况下,将辊筒加热或另外再对其进行冷却可能是有利的。因此,对于这类情况来说,辊筒应该是能够进行加热的,即,具有可通过冷却液或加热介质的传统结构。
如果挤出机有一个以上的模头时,则每一个模头分别与一组成型凹模(5)相关联,此组凹模沿着每支辊筒圆周并在与辊筒轴成直角的一个平面上。
此种新方法是首创的连续压制药剂混合物片剂的方法。此法不仅比较简单、有效、比用常规的制片压机进行的常规制备方法更经济,而且还具有下列其他重要优点:
1.在设计片剂形状方面具有更大的活动余地(例如球形)。
2.由于连接在一起的片剂的重量可克服片剂与半凹模之间的粘着力,所以本法可压制只有克服了极大的困难才能用传统的制片压机压制的粘性和(或)高粘性材料。
可挤出的药剂混合物是由一种或几种药物活性化合物和按常规用于制备药片的一种或几种助剂组成的混合物;在升温(不低于70℃)情况下,例如用水将其调成糊状或将其中一种或几种组份熔融或软化,上述混合物为可挤出的药剂混合物。上面所讨论的混合物尤其是指那些含有医药上可接受的聚合物的混合物(混合物的玻璃化转变温度低于混合物中所有组份的分解温度),例如聚乙烯基吡咯烷酮(PVP)、N-乙烯基吡咯烷酮(NVP)与乙酸乙烯酯的共聚物、乙酸乙烯酯与巴豆酸的共聚物、部分水解的聚乙酸乙烯酯、聚乙烯醇、乙烯/乙酸乙烯酯共聚物、聚甲基丙烯酸羟乙酯、甲基丙烯酸甲酯与丙烯酸的共聚物、纤维素酯、纤维素醚、聚乙二醇或聚乙烯。聚合物的K值(根据H.Fikentscher,纤维素化学13(1932年)58-64及71和74页)由10至100,较好的是12至70,尤其是12至35,而PVP的K值,较好的是10至35,尤其是12至17。
在所有组份的总混合物中,聚合物粘合剂应在50至180℃,较好的是在60至130℃软化或熔融,从而使混合物可挤出。因此,混合物的玻璃化转变温度在任何情况下均必须低于180℃,最好的是低于130℃。必要时,可用惯用的医药上可接受的增塑剂,例如长链醇、乙二醇、丙二醇、三羟甲基丙烷、三甘醇、丁二醇、戊醇、己醇、聚乙二醇、聚硅氧烷、芳香羧酸酯(例如,邻苯二甲酸二烷酯、偏苯三酸酯、苯甲酸酯或对苯二甲酸酯)、脂肪二羧酸酯(例如,己二酸二烷酯、癸二酸酯、壬二酸酯、柠檬酸酯和酒石酸酯)或脂肪酸酯来降低混合物的玻璃化转变温度。
在有活性化合物和NVP聚合物,在适当的情况下,有惯用的药物助剂,以及有或最好是没有加增塑剂的混合物中,NVP聚合物最好是在所需的温度范围内熔融或软化。鉴于热量和(或)氧化作用不仅可能破坏活性化合物,而且还可能破坏NVP聚合物,因此NVP聚合物可能必须在低于某一温度下熔融或软化。否则,在挤出过程中可能会使药剂混合物发黄,这就是为什么到目前为止一般不用NVP聚合物来挤出的原因。但是,如果NVP聚合物不是在水溶液中,应用过氧化氢作为引发剂,而是在有机溶剂中或水中,应用有机过氧化物作为引发剂,例如,根据德国专利申请第3642633.4号或按美国专利第4,520,179和4,520,180号所述的方法来制备,则在挤出温度低于180℃,尤其是低于130℃下,几乎是没有危害的。
如果K值大于17,尤其是大于30或甚至40(直到最大值70),同时未加入强增塑剂,则唯一适用的NVP聚合物是那些玻璃化转变温度Tg低于120℃,较好的是低于100℃的聚合物,或者是该NVP聚合物(包括均聚物)必须不是在水中应用HO作为引发剂来制备的聚合物。否则,实际上,会在聚合物中产生在升温下可导致发黄的端基。
根据预计的用途,NVP聚合物可通过其共聚单体的类型和数量来提供足够强的或弱的亲水性,使用该聚合物制备的片剂可于口中溶解(口腔片)、在胃中或在片剂进入肠道之前溶解(迅速地或逐渐地)或膨胀,以便它们释放出活性化合物。这些聚合物当它们吸收了10%(重)的水或储于90%相对湿度下,可充分地膨胀。如果希望含羧基的粘合剂只在肠道的碱性介质中才释放出活性化合物,则只有该聚合物的中和形式(盐形式),其中羧基的部分或全部质子被铵、钠、钾离子所替代,才具有上述吸水性。
适合作NVP的共聚单体是不饱和羧酸,例如,甲基丙烯酸、巴豆酸、顺式丁烯二酸或亚甲基丁二酸、它们与1至12个碳原子、较好的是1至8个碳原子的醇形成的酯、丙烯酸羟乙酯和丙烯酸羟丙酯、甲基丙烯酸羟乙酯和甲基丙烯酸羟丙酯、(甲基)丙烯酰胺、顺式丁烯二酸和亚甲基丁二酸的酐和半酯(半酯在聚合作用完成之前不形成为好)、N-乙烯基己内酰胺和丙酸乙烯酯。较好的共聚单体是丙烯酸而尤其是乙酸乙烯酯。因此,NVP均聚物或含有乙酸乙烯酯作为唯一的共聚单体的NVP聚合物是优选的。乙酸乙烯酯和丙酸乙烯酯可在聚合作用完成后才全部或部分水解。
惯用的药物助剂,按聚合物重量计算,其总用量可达100%,它们是,例如,象硅酸盐或硅藻土、硬脂酸或其盐,例如与镁或钙形成的盐、甲基纤维素、羧基甲基纤维素钠、滑石、蔗糖、乳糖、谷类淀粉或玉米淀粉、土豆粉或聚乙烯醇一类的增量剂,润湿剂,防腐剂,崩解剂,吸附剂,染料和香料(参阅例如H.Sucker等人所著Pharmazeutisc-he Technologie Thieme Verlag,Stuttgart 1978年)。
需要时,根据本发明制备的片剂还可有惯用的包衣以改进外观和(或)味道(包衣片剂)或同时又延迟释放活性化合物。对于持续释放活性化合物的口服剂来说,用常规技术生产密眼多孔型的片剂可能是有利的,以便它浮在胃中从而在胃中停留一段较长的时间。此种新方法还可用于生产非常小的片剂,此种小片剂可取代惯用的粒剂有助于装入胶囊。对于本发明来说,片剂一词并不只限于某一形状或口服投药。而是还包括直肠投药的栓剂(在体温下不会熔化)。
对于本发明来说,药物活性化合物是指在加工条件下不会分解的所有具药物作用而副作用又非常小的物质。根据药物的活性和释放速度,活性化合物的浓度和每单位剂量的含量可在较宽的范围内变化。唯一的条件是,其用量和浓度能充分达到所期望的效果。例如,活性化合物的浓度可从0.1%至95%(重),较好的是从20%至80%(重),尤其是从30%至70%(重)。也可以应用活性化合物的组合物。对于本发明来说,活性化合物包括维生素。
在下列实例中,份数或百分数均按重量计算。
实施例1
将45份由60%(重)N-乙烯基吡咯烷酮和40%(重)乙酸乙烯酯制成的并具有K值为30的共聚物、5份十八烷醇和50份茶碱在一台双螺杆挤出机中混合并挤出。挤出机机筒的六段注料温度为30℃、60℃、60℃、60℃、60℃、60℃;将模头加热至100℃。将获得的挤出料,用权利要求中所述的设备,直接压制成椭圆形片剂。所得到的硬质片剂带很容易断裂成单个的片剂。用此法制成的片剂具有机械稳定性,在运输和包装过程中设有磨耗。
实施例2
将50份实例1的共聚物和50份茶碱在一台双螺杆挤出机中混合并挤出。与实例1不同之处是,将六段注料的温度调至30℃、60℃、60℃、60℃、90℃和120℃。将模头亦加热至120℃。将获得的挤出料,用权利要求中所述的设备,压制成类似于实例1的椭圆形片剂。这些片剂亦具有机械稳定性。
实施例3
将47.5份由60%(重)N-乙烯基吡咯烷酮和40%(重)乙酸乙烯酯制成的并具有K值为30的共聚物,2.5份作为片剂崩解剂的交联PVP和50份茶碱在一台双螺杆挤出机中混合并挤出。5段注料温度均为120℃,模头温为130℃。将仍然具有塑性的挤出料,按实例1中所述的方法,压制成椭圆形片剂。制得的片剂具有机械稳定性。
实施例4
将50份由30%(重)N-乙烯基吡咯烷酮和70%(重)乙酸乙烯酯制成的并具有K值为52的共聚物和50份茶碱在一台双螺杆挤出机中混合并挤出。5段注料温度为30℃、60℃、100℃、100℃和120℃。将模头亦加热至120℃。将仍然具有塑性的挤出料,按实例1中所述的方法,压制成具在有机械稳定性的椭圆形片剂。
实施例5至8
将具有下表中所列的各种K值的50%(重)N-乙烯基吡咯烷酮均聚物(PVP)与50%(重)茶碱的混合物,在表中所规定的温度下,在一台单螺杆挤出机中熔融、挤出并按实例1中所述的方法压制片剂。
温度〔℃〕实 例 K值 1 2 3 4 5 模头
注料5 12 115 125 135 145 135 1456 17 125 125 135 145 145 1557 25 145 155 165 175 175 1758 30 150 160 160 170 180 1808a 60 150 160 160 170 180 180
实施例9
将40份由60%(重)N-乙烯基吡咯烷酮和40%(重)乙酸乙烯酯制成的并具有K值为30的共聚物,10份聚甲基丙烯酸羟乙酯和50份茶碱,按类似于实例1中所述的方法,加工成具有机械稳定性的片剂。5段注料的温度为70℃、80℃、80℃、80℃和80℃,而模头温度为90℃。
实例施10
将50份市售的水解度为80%的聚乙酸乙烯酯和50份茶碱,按类似于实例1中所述的方法加工。5段注料的温度为100、100、110、120和130℃,而模头温度为150℃。
实施例11
将50份K值为30的聚甲基丙烯酸羟乙酯和50份茶碱,按类似于实例1中所述的方法加工。5段注料的温度为120℃、130℃、150℃、160℃和160℃,而模头温度为170℃。
实施例12至14
将36份由60%(重)N-乙烯基吡咯烷酮和40%(重)乙酸乙烯酯制成的并具有K值为30的共聚物、4份十八烷醇、40份茶碱和20份淀粉(实例12)、乳糖(实例13)或蔗糖(实例14),在一台6段注料的双螺杆挤出机中混合,并按类似于实例1中所述的方法压成片剂。6段注料的温度为90℃、100℃、110℃、120℃、120℃和130℃,而模头温度为135℃。
实施例15至17
将50份实例12至14的共聚物和50份戊脉安,按实例12至14中所述的方法压成片剂。
下列实例按类似于上述实例中所述的方法进行。加工条件和在半变化试验中的释放速率(参阅R.Voigt著Lehrbuch der pharmazeutisch-en Technolgie,第5版Verl、Chemie Weinheim;Deerfield Beach,Flo-rida;Basle,1984年,第627页,以及根据usp 21的浆式法)均列于下表。
表
重量比 T1 T2 T3 T4 T5 T6 模头 释放速率实例号 活性化合物 聚合物 助剂 活性化合物/
(温度 ℃)
聚合物/助剂18 假麻黄碱47,5 A ./. 50/50/0 60 80 100 120 120 120 120 100% 1小时
二苯基羟基胺2,519 Propafenone A starch 40/40/20 60 70 90 110 110 110 110 100% 1小时20 Propafenone A StA 60/35/5 80 90 100 120 140 140 140 100% 2小时21 Propafenone A StA 60/30/10 80 90 100 120 130 130 140 52% 6小时22 Propafenone A StS 60/35/5 70 90 100 110 115 115 115 42% 6小时23 Propafenone B StA 50/40/10 65 80 95 110 110 110 110 100% 6小时24 Propafenone A MgSt 60/35/5 60 70 80 80 95 100 100 95% 6小时25 Propafenone A MgSt 50/40/10 60 70 80 80 95 100 100 80% 6小时26 Anipamil A MgSt 50/40/10 30 30 40 40 60 60 60 100% 2小时27 维生素B B ./. 50/50/0 40 40 50 60 80 80 80 100% 1小时28 烟酸 A ./. 50/50/0 60 70 80 95 95 100 100 100% 1小时29 Biperiden A StA 50/45/5 80 90 100 120 120 130 135 100% 4小时30 Biperiden A ./. 50/50/0 80 90 110 120 140 140 140 100% 1小时31 Canthaxanthin B ./. 50/50/0 30 30 40 40 60 60 60 100% 1小时32 Canthaxanthin A ./. 50/50/0 40 40 55 60 60 80 80 100% 1小时
表(续)
重量比
活性化合物/ T1 T2 T3 T4 T5 T6 模头实例号 活性化合物 聚合物 聚合物 (温度 ℃)33 消炎痛 A 25/75 50 60 70 80 80 80 8034 消炎痛 B 25/75 60 80 100 120 120 120 12035 Anipamil A 25/75 30 30 40 50 50 60 6036 Anipamil A 25/75 30 30 40 50 50 60 6037 苯佐卡因 D 25/75 60 80 95 100 120 120 14038 苯佐卡因 D 25/75 60 80 95 100 120 130 14039 苯佐卡因 F 25/75 30 30 40 50 50 60 6040 苯佐卡因 B 25/75 60 80 100 120 120 120 12041 5.5-二苯基羟基胺 8 25/75 60 80 100 120 120 120 12042 醋酰胺 B 25/75 60 80 100 120 120 120 12043 磺胺噻唑 B 25/75 70 90 100 100 100 100 12044 磺胺噻唑 E 25/75 70 90 100 100 100 110 12045 苯佐卡因 A 25/75 30 30 40 50 60 70 7046 5.5-二苯基羟基胺 A 25/75 60 80 100 120 120 120 13047 醋氨酚 A 25/75 60 80 100 120 120 120 13048 磺胺噻唑 A 50/50 70 90 100 100 100 100 13049 维生素C C 50/50 75 95 95 120 120 120 120
表(续)
重量比
活性化合物/ T1 T2 T3 T4 T5 T6 模头实例号 活性化合物 聚合物 聚合物 (温度 ℃)50 苯佐卡因 E 25/75 60 70 80 120 130 130 13051 苯佐卡因 G 25/75 60 70 70 80 80 80 12052 苯佐卡因 H 25/75 50 60 60 60 80 90 11053 苯佐卡因 I 25/75 50 60 70 70 75 75 80A =60%(重)NVP和40%(重)乙酸-乙烯酯的共聚物,K值约为33B =PVP,K值为12C =PVP,K值为17D =Mowiol30-92(92%水解的聚乙烯醇)E =Mowlol 4-80(80%水解的聚乙烯醇)F =重量比为30/40/30的NVP、乙酸乙烯酯和丙烯酸羟丙酯的共聚物K值约为18G =乙酸纤维素H =乙酸邻苯二甲酸纤维素I =乙酸乙烯酯/巴豆酸共聚物,K值约为30StA =十八烷醇StS =硬脂酸MgSt=硬脂酸镁
Claims (2)
1.一种将可挤出的药剂混合物制片的连续方法,包括下列步骤:
在挤出机中,混合药物活性化合物和含有30-100重量%的N-乙烯基吡咯烷酮-2的N-乙烯基吡咯烷酮-2聚合物,形成熔体,所述聚合物具有10-100的K值,所述混合物具有低于180℃的玻璃化转变温度,
将熔体挤出,并将仍然可变形的挤出料在转动方向相反的两个辊筒的表面之间进行压制,这两个辊筒的表面有相互对着的凹型的模子,由此形成具有相对的凹型的形状的单个片剂。
2.根据权利要求1的方法,其特征在于应用有机过氧化剂作为引发剂,在有机溶剂中或在水中制成所述含有所述药物活性化合物的N-乙烯基吡咯烷酮-2聚合物的熔体,并且将所述含有药物活性化合物的N-乙烯基吡咯烷酮-2聚合物熔体挤出并压制。
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DEP3612211.4 | 1986-04-11 | ||
DE19863612211 DE3612211A1 (de) | 1986-04-11 | 1986-04-11 | Kontinuierliches verfahren zum tablettieren |
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-
1986
- 1986-04-11 DE DE19863612211 patent/DE3612211A1/de not_active Withdrawn
-
1987
- 1987-03-31 AT AT87104731T patent/ATE63056T1/de not_active IP Right Cessation
- 1987-03-31 ES ES87104731T patent/ES2022188B3/es not_active Expired - Lifetime
- 1987-03-31 DE DE8787104731T patent/DE3769687D1/de not_active Expired - Lifetime
- 1987-03-31 EP EP87104731A patent/EP0240906B1/de not_active Expired - Lifetime
- 1987-04-03 YU YU590/87A patent/YU45412B/xx unknown
- 1987-04-08 FI FI871538A patent/FI88577C/fi not_active IP Right Cessation
- 1987-04-08 CS CS872531A patent/CS270222B2/cs not_active IP Right Cessation
- 1987-04-09 JP JP62085890A patent/JPH078293B2/ja not_active Expired - Fee Related
- 1987-04-09 AR AR87307264A patent/AR241630A1/es active
- 1987-04-10 PT PT84660A patent/PT84660B/pt not_active IP Right Cessation
- 1987-04-10 HU HU871623A patent/HUT55218A/hu unknown
- 1987-04-10 CA CA000534439A patent/CA1303501C/en not_active Expired - Lifetime
- 1987-04-10 NO NO871512A patent/NO173588C/no not_active IP Right Cessation
- 1987-04-10 AU AU71400/87A patent/AU590697B2/en not_active Ceased
- 1987-04-11 CN CN87102755A patent/CN1056508C/zh not_active Expired - Lifetime
- 1987-04-11 KR KR1019870003528A patent/KR940005302B1/ko not_active IP Right Cessation
-
1988
- 1988-12-22 US US07/289,407 patent/US4880585A/en not_active Expired - Lifetime
-
1991
- 1991-06-03 GR GR91400710T patent/GR3002559T3/el unknown
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105073362A (zh) * | 2013-02-22 | 2015-11-18 | 马格奥托马蒂克公司 | 碾压辊造粒机及其使用 |
CN105073362B (zh) * | 2013-02-22 | 2017-11-21 | 马格奥托马蒂克公司 | 碾压辊造粒机及其使用 |
US11925915B2 (en) | 2014-11-05 | 2024-03-12 | Maag Automatik Gmbh | Squeezing-roll granulator, granulating system comprising same, and use of the squeezing-roll granulator |
Also Published As
Publication number | Publication date |
---|---|
CS253187A2 (en) | 1989-10-13 |
KR870009705A (ko) | 1987-11-30 |
FI88577B (fi) | 1993-02-26 |
NO173588C (no) | 1994-01-05 |
CA1303501C (en) | 1992-06-16 |
CN87102755A (zh) | 1987-10-28 |
EP0240906A2 (de) | 1987-10-14 |
YU59087A (en) | 1989-12-31 |
AU7140087A (en) | 1987-10-15 |
GR3002559T3 (en) | 1993-01-25 |
CS270222B2 (en) | 1990-06-13 |
NO871512D0 (no) | 1987-04-10 |
JPH078293B2 (ja) | 1995-02-01 |
US4880585A (en) | 1989-11-14 |
KR940005302B1 (ko) | 1994-06-16 |
NO871512L (no) | 1987-10-12 |
NO173588B (no) | 1993-09-27 |
ES2022188B3 (es) | 1991-12-01 |
AR241630A1 (es) | 1992-10-30 |
JPS62240061A (ja) | 1987-10-20 |
PT84660B (pt) | 1989-11-30 |
HUT55218A (en) | 1991-05-28 |
DE3769687D1 (de) | 1991-06-06 |
FI871538A (fi) | 1987-10-12 |
YU45412B (en) | 1992-05-28 |
PT84660A (en) | 1987-05-01 |
EP0240906B1 (de) | 1991-05-02 |
FI871538A0 (fi) | 1987-04-08 |
AU590697B2 (en) | 1989-11-09 |
EP0240906A3 (en) | 1988-08-03 |
ATE63056T1 (de) | 1991-05-15 |
FI88577C (fi) | 1993-06-10 |
DE3612211A1 (de) | 1987-10-15 |
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