CN1320887C - Methotrexate oral disintegrating tablet and its preparation method - Google Patents

Methotrexate oral disintegrating tablet and its preparation method Download PDF

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CN1320887C
CN1320887C CN 200410035779 CN200410035779A CN1320887C CN 1320887 C CN1320887 C CN 1320887C CN 200410035779 CN200410035779 CN 200410035779 CN 200410035779 A CN200410035779 A CN 200410035779A CN 1320887 C CN1320887 C CN 1320887C
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methotrexate
orally disintegrating
mannitol
tablet
microcrystalline cellulose
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CN1754538A (en )
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马晶
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马晶
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本发明涉及一种在口腔内不需水即能迅速崩解的甲氨蝶呤口腔崩解片,是先把甲氨蝶呤、羧甲基淀粉钠、微晶纤维素、甘露醇、硬脂酸镁分别粉碎过100目筛,混合均匀,采用粉末直接压片法制得口腔崩解片。 The present invention relates to orally disintegrating tablets of methotrexate within the oral cavity without water A rapidly disintegrating i.e., a first methotrexate, sodium carboxymethyl starch, microcrystalline cellulose, mannitol, stearic magnesium were crushed through a 100 mesh sieve, mixed using direct powder compression method to obtain an orally disintegrating tablet. 该口腔崩解片在口腔内的崩解时间在15秒以内,其体外的崩解时间小于1分钟,药物溶出速度快,生物利用度高,其15分钟的溶出度达90.1%以上,相当于普通片60分钟的溶出度。 The orally disintegrating tablets in the buccal cavity disintegration time of 15 seconds or less, in vitro disintegration time less than 1 minute, faster drug dissolution rate, bioavailability, its dissolution 15 minutes of more than 90.1%, corresponding to Common dissolution sheet 60 minutes.

Description

一种甲氨蝶呤口腔崩解片及其制备方法 One kind of methotrexate orally disintegrating tablet and preparation method

所属技术领域 Those of skill

:本发明涉及含有甲氨蝶呤的药物组合物,是关于一种甲氨蝶呤口服制剂的改进技术。 : The present invention relates to a pharmaceutical composition comprising methotrexate, methotrexate relates to a technique to improve oral formulations.

技术背景:甲氨蝶呤在临床上应用已有几十年的历史,开始用于治疗白血病和用作抗肿瘤药物,包括各型急性白血病,特别是急性淋巴细胞白血病、恶性淋巴瘤、非何杰金氏淋巴瘤和蕈样肉芽肿、多发性骨髓病、头颈部癌、肺癌、各种软组织肉瘤、银屑病;乳腺癌、卵巢癌、宫颈癌、恶性葡萄胎、绒毛膜上皮癌、睾丸癌等。 Background: Methotrexate has been in clinical use for several decades, used to treat leukemia and began to be used as anticancer drugs, including various types of acute leukemia, particularly acute lymphoblastic leukemia, malignant lymphoma, non-HE Hodgkin's lymphoma and mycosis fungoides, multiple myeloma, head and neck cancer, lung cancer, soft tissue sarcoma, psoriasis; breast cancer, ovarian cancer, cervical cancer, malignant mole, choriocarcinoma, testicular cancer. 近年来,甲氨蝶呤作为一种免疫抑制剂,广泛用于活动性类风湿关节炎等自身免疫性疾病的治疗。 In recent years, as an immunosuppressant, methotrexate, widely used to treat autoimmune diseases and other active rheumatoid arthritis.

甲氨蝶呤难溶于水,其体内生物利用度和体外溶出特性有一定的相关性。 Methotrexate insoluble in water, their bioavailability in vivo and in vitro dissolution profile has a certain correlation. 目前临床上使用的甲氨蝶呤口服制剂为甲氨蝶呤片,其生物利用度在50mg/m2剂量为20-50%,更大剂量(200mg/m2)降至25%。 Methotrexate oral formulation currently used clinically methotrexate sheet, its bioavailability in 50mg / m2 dose of 20 to 50%, higher doses (200mg / m2) to 25%. 甲氨蝶呤普通片剂生物利用度较低的原因与其崩解速度慢、溶出度低的缺点有关。 Methotrexate reasons for the low bioavailability of the tablet normal to its slow disintegration rate, the disadvantages related to a low dissolution rate.

发明内容 SUMMARY

:本发明的目的在于提供一种服用方便、吸收快、生物利用度高的甲氨蝶呤口腔崩解片制剂。 : Object of the present invention is to provide an easy to take, rapid absorption, high bioavailability methotrexate oral disintegrating tablet formulation.

对于难溶于水的药物,其体内生物利用度和体外溶出特性有一定的相关性。 For poorly water soluble drug bioavailability in vivo and in vitro dissolution profile has a certain correlation. 由于甲氨蝶呤难溶于水,因此,本发明以缩短片剂崩解时间、提高其溶出度速度入手,来促进人体对甲氨蝶呤的吸收,使甲氨蝶呤能快速达到有效血药浓度,迅速起效。 Since methotrexate insoluble in water, therefore, the present invention is to shorten the disintegration time of tablets, to improve the dissolution-rate start to improve the absorption of methotrexate, methotrexate enable to quickly reach effective blood concentration, rapid onset. 此外,甲氨蝶呤用于肿瘤化疗过程中,病人常见的不良反应为呕吐,本发明的解决方案是把甲氨蝶呤配制成一种在口腔内不需要水即可迅速崩解的甲氨蝶呤口腔崩解片,既可加快溶出速度,又适用于见水即呕的肿瘤化疗患者,以及老年人和特殊不能得到水的环境下的患者。 In addition, methotrexate for cancer chemotherapy, the patient is vomiting common adverse reactions, solution of the invention is to be formulated into a methotrexate does not need water to disintegrate rapidly in the oral cavity methotrexate MTX orally disintegrating tablets, can accelerate the dissolution rate, but also for the patient to see the water i.e. emesis cancer chemotherapy patients, and the elderly can not be obtained and special water environment.

口腔崩解片是一种在口腔内不需水即能崩解或溶解的片剂。 It is an orally disintegrating tablet that can disintegrate without water or dissolve the tablet in the oral cavity. 服用该类制剂时不需用水或只需用少量水,也无需咀嚼,片剂置于舌面遇唾液迅速崩解,借吞咽动作入胃起效。 Such formulations when administered without water or with only a small amount of water, without chewing, the tablet rapidly disintegrating saliva case disposed tongue, stomach by swallowing onset. 将甲氨蝶呤制成口腔崩解片,可使崩解时间明显缩短,溶出速度提高,吸收快,生物利用度高,提高临床用药的顺应性。 Methotrexate is made orally disintegrating tablet, the disintegration time can be shortened significantly, increase dissolution rate, rapid absorption, high bioavailability, improve compliance of clinical medicine.

制备口腔崩解片的技术要点是既能使片剂快速崩解,又具有良好的口感。 Techniques Preparation of orally disintegrating tablets of the tablet is both rapid disintegration, but also has good taste.

甲氨蝶呤在临床使用上的特点是剂量规格较小,常用量是每次口服5~10mg,一日1次,市售的普通片的规格剂量为2.5mg/片。 Methotrexate characteristics clinically used dosage strengths are smaller, the amount used is oral administration of 5 ~ 10mg, day 1, standard commercial tablets in dose of 2.5mg / sheet. 甲氨蝶呤为橙黄色结晶性粉末,无臭、无味,将其微粉化后,在口腔中并无沙砾感,无特殊气味和味道。 Methotrexate orange yellow crystalline powder, odorless, tasteless, after micronized, not gritty in the mouth, no special smell and taste. 根据甲氨蝶呤原料的特点,选用粉末直接压片法的制备工艺。 The material characteristics of methotrexate, selection of powder process of direct compression method.

采用粉末直接压片法制备片剂的要点是保证混合粉末的流动性和可压性好。 Points directly prepared by powder tablet to ensure the tablet is a flow and pressure of the mixed powder may be good. 由于甲氨蝶呤在每片中的含量为2.5mg,在整个片剂中药物占的比例不大,原料本身的流动性和可压性对直接压片的影响较小;而填充剂占较大比例,混合粉末的流动性和可压性主要决定于填充剂的性能。 Since the content of methotrexate per tablet to 2.5mg, not in the whole pharmaceutical tablet proportion, less raw materials themselves affect flowability and compressibility of direct compression; the filler accounts for more a large proportion, and the fluidity of mixed powder may be pressure mainly determined by the properties of the filler. 因此,选用合适的辅料种类和比例,使口腔崩解片的崩解速度快,有合适的硬度,制备过程易于规模化生产。 Thus, the choice of suitable auxiliaries kinds and proportions of the fast disintegrating oral disintegrating time of the tablet, a suitable hardness, easy preparation of large-scale production.

本发明所述的口腔崩解片是由甲氨蝶呤、崩解剂羧甲基淀粉钠、干燥粘合剂微晶纤维素、润滑剂硬脂酸镁及矫味剂甘露醇等组分组成。 Orally disintegrating tablets according to the present invention is a methotrexate, a disintegrating agent sodium carboxymethyl starch, microcrystalline cellulose, dry binders, lubricants, flavoring agents and magnesium stearate, mannitol, etc. constituents . 其组分含量,以重量百分数计为:3.5-7.5wt%的甲氨蝶呤,20.0-24.0wt%的羧甲基淀粉钠,55.0-65.0wt%的微晶纤维素,1.0-2.0wt%的硬脂酸镁,10.0-20.0wt%的甘露醇。 Its component content, in weight percent of: 3.5-7.5wt% of methotrexate, 20.0-24.0wt% of sodium carboxymethyl starch, 55.0-65.0wt% of microcrystalline cellulose, 1.0-2.0% magnesium stearate, 10.0-20.0wt% mannitol.

口腔崩解片的崩解时限与崩解剂性能密切相关。 The disintegration time of the orally disintegrating tablet disintegrant is closely related to performance. 片剂之所以速崩是由于其崩解剂具有不溶于水(或不完全溶于水)与吸湿性强的特点,崩解剂通过毛细管作用使水分子容易渗透进入片剂之中,吸水后粉粒膨胀而不溶解,不形成胶体溶液,不至于阻碍水分子的继续渗入,使片剂进一步崩解。 The reason is because the rapidly disintegrating tablet disintegrating agents which have not dissolved in water (or not completely soluble in water) and Strong hygroscopic characteristics, disintegrants by capillary action into the water molecules easily penetrate into a tablet, after water absorption particles swell without dissolving, a colloidal solution is not formed, and will not hinder the continued penetration of water molecules, to further disintegrate the tablet. 本发明以羧甲基淀粉钠为崩解剂。 The present invention is sodium carboxymethyl starch as disintegrant. 选用的羧甲基淀粉钠其置换度通常为0.3-0.5左右,溶胀度为5ml/g,如市售商品Primojel、Explotab或DST等均可使用。 The sodium carboxymethyl starch selected degree of substitution thereof is usually about 0.3 to 0.5, the degree of swelling of 5ml / g, commercially available as Primojel, Explotab DST, or the like can be used.

微晶纤维素流动性和可压性好,适合于直接压片,在直接压片工艺中起着干燥粘合剂的作用。 Microcrystalline cellulose flowability and compressibility may be better suitable for direct compression, dry adhesive plays a role in the direct compression process. 其次,微晶纤维素还具有良好的崩解作用,在本品中也有助于崩解,但其溶胀度较低(3.4ml/g),而且随着微晶纤维素含量的增大,崩解时限呈延长的趋势。 Secondly, microcrystalline cellulose also has a good disintegration, in this product also contributes to disintegrate, but its low degree of swelling (3.4ml / g), and with microcrystalline cellulose content increased, collapse the solution was to extend the time limit of the trend. 原因可能是片剂内部结构发生了变化,微晶纤维素颗粒的凹凸形状相互嵌合形成了致密结构,孔隙被压力破坏,使片剂不易被湿润。 The reason may be the internal structure of the tablet changes, microcrystalline cellulose particles of irregular shape forming a dense structure are fitted together, the pore pressure is destroyed, so that the tablet can not easily be wetted. 微晶纤维素是由吡喃环D-葡萄糖构成的直链多糖,其聚合度为200,溶胀度为3.4ml/g,如市售Avicel、PH-101、PH-102等均可使用。 Microcrystalline cellulose is a linear polysaccharide composed of glucose, D- pyran ring, a polymerization degree of 200, the degree of swelling was 3.4ml / g, commercially available as Avicel, PH-101, PH-102 and the like can be used.

矫味剂可选用甘露醇,还可添加阿斯巴甜、 糖精钠、甜菊甙、香精等。 Flavoring agents can be selected mannitol may be added aspartame, saccharin sodium, stevioside, flavors and the like. 甘露醇是片剂中常用的矫味剂和填充剂,在口腔中迅速溶解,且在溶解时吸热,口感清凉甜爽。 Mannitol is commonly used in tablets flavoring agents and fillers, rapidly dissolves in the oral cavity, and upon dissolution endotherm, cool taste sweet and cool. 但本项研究的处方筛选数据表明,随着甘露醇用量的加大,崩解时间增加,通过综合评价崩解时间的口感,确定甘露醇的最适用量。 But the study of prescription screening data showed that with the increasing amount of mannitol, disintegration time increases, the time of disintegration taste through comprehensive evaluation, to determine the optimum amount of mannitol.

润滑剂可选用硬脂酸镁,微粉硅胶等,一般常用量为1-2%。 Optional lubricant, magnesium stearate, aerosil and the like, is generally used in an amount of 1-2%.

本发明做了崩解剂使用量的选择试验,以微晶纤维素为直接压片的干燥粘合剂,根据文献数据,选择55-80%的用量范围,在此基础上选择崩解剂的种类和用量。 The present invention is made of a disintegrating agent is used in an amount selected test, microcrystalline cellulose as dry binder in direct compression, according to literature data, select an amount of 55-80% range, on the basis of the selected disintegrant the type and amount.

低取代羟丙基纤维素和羧甲基淀粉钠均为优良的崩解剂,并有文献报道低取代羟丙甲基纤维素可以遮盖不良气味。 Low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch are excellent disintegrating agents, and has been reported that low-substituted hydroxypropylmethyl cellulose can cover the bad smell. 将低取代羟丙基纤维素和羧甲基淀粉钠用量设计在15-30%的范围内,并通过测定崩解时限进行比较,试验设计处方的用量见表1、表2。 The low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch in an amount within the design range of 15-30%, and compared to the amount of prescription experimental design shown in Table 1, Table 2 was measured by disintegration time.

以甘露醇为矫味剂,根据口感和崩解时限作为判断指标,进一步优化工艺。 Mannitol as flavoring agents, as determined according to taste and disintegration index, and further optimize the process. 试验设计处方的用量见表3。 The amount of formulation Table 3 experimental design.

试验方法:按设计处方的量称量原辅料,过筛,混匀,采用粉末直接压片法制备试验样品,分别测定各处方样品的崩解时间。 Test Method: according to the amount of prescription design weighed raw materials, sieving, mixing, using test samples prepared by the direct powder tabletting, disintegration time were measured for each formulation sample.

崩解时限的测定方法为:在10ml量筒中加入37℃±1℃的水2ml,取1片口腔崩解片,加入水中,片剂应在水中迅速崩解,崩解后的颗粒应能通过40目筛(内径为441um)。 A method for measuring disintegration time: graduated cylinder was added in 10ml of water of 37 ℃ ± 1 ℃ 2ml, an orally disintegrating tablet taken, added to water, the tablets should disintegrate rapidly in water, the disintegration of the particles should be able to 40 mesh sieve (inner diameter 441um). 重复检查6片,观察片剂的崩解情况,记录片剂完全崩解而且颗粒通过筛网的时间。 6 Repeat examination, observation disintegrating case of tablets, the tablet completely disintegrated and the recording time of the particles through the screen. 试验数据与结果见表1、表2。 Test data results in Table 1, Table 2.

表1崩解剂(低取代羟丙基纤维素)用量的筛选 Table 1 Screening of a disintegrant (low substituted hydroxypropyl cellulose) is used in an amount

表2崩解剂(羧甲基淀粉钠)用量的筛选 Table 2 Screening disintegrant (sodium carboxymethyl starch) in an amount

从表1、表2可以看出,低取代羟丙基纤维素与羧甲基淀粉钠比较,羧甲基淀粉钠作为崩解剂,试验批号9的崩解性能最好。 From Table 1, it can be seen in Table 2, compared with low-substituted hydroxypropylcellulose, sodium carboxymethyl starch, sodium carboxymethyl starch as a disintegrating properties disintegrant, preferably 9 test batch.

为改善口腔崩解片的口感,拟加入甘露醇作为矫味剂。 To improve the taste of the orally disintegrating tablet, to be added as a flavoring agent mannitol. 以试验批号9为基础,加入不同用量的甘露醇,试验数据及结果见表3。 9 to the test batch basis, different amounts of mannitol was added, the test data and results are shown in Table 3.

表3矫味剂(甘露醇)用量的筛选 Table 3 Screening amounts flavoring agent (mannitol)

从表3可以看出,甘露醇加入量的增大会改善口感,但也会延长崩解时间。 As can be seen from Table 3, it will increase in the amount of mannitol was added to improve the taste, but also increases the disintegration time. 综合两种因素,选择批号13最佳,制得的甲氨蝶呤口腔崩解片其崩解时限和口感均符合设计要求。 Comprehensive two factors, to select the best batches 13, resulting methotrexate orally disintegrating tablet disintegration time and mouth feel which are in line with the design requirements. 因此本发明通过试验选定羧甲基淀粉钠的组份含量为20-24wt%,微晶纤维素的组份含量为55-65wt%。 Thus, the present invention is selected by experiment ingredients sodium carboxymethyl starch content is 20-24wt%, the content of ingredients of microcrystalline cellulose is 55-65wt%.

在粉末直接压片工艺中,由于不经过制备颗粒的过程而直接进行压片,粉末的流动性和可压性是较为重要的指标,关系到进行工业化生产的可行性。 In the direct powder tabletting process, since during the preparation of granules without direct tableting, the powder flowability and compressibility index is more important, related to the feasibility of industrial production. 如果混合粉末的流动性不好,在生产中会影响到压片速度,或压制的片剂片重差异大等弊端;如果粉末的可压性不好,制成的片剂机械强度不高,在运输和贮藏过程中容易破损。 If the mixed powder flowability is not good, in the production of compression will affect the speed, or compressed tablet weight variation and large drawbacks; If the powder is not good compressibility, the mechanical strength of the tablet is not made high, easily damaged during transportation and storage. 本项研究中,对于混合粉末的流动性和可压性进一步试验的验证,以确保工业化生产产品质量的均一性、可控性,和产品运输中片剂的完整性。 In this study, to verify the flow and pressure of the mixed powder can be further tested to ensure uniformity of product quality industrial production, control, and transport the product tablet integrity.

通常以粉末的休止角作为作为表示粉末流动性的一种指标,粉末的休止角越小,表明粉末的流动性越好。 Angle of repose of a powder is generally used as an indicator of flowability of a powder as said powder is smaller angle of repose, the better the flowability of the powder showed that. 为进一步研究粉末的流动性,按照批号13制备了040101批样品,将批号13中硬脂酸镁的量提高1倍(占处方量的1.5%)制备040102批样品。 To further study flowability of the powder, the lot numbers of the 13 040 101 batch batch of samples to increase the amount of magnesium stearate in a 13-fold (1.5% of the prescribed amount) 040102 batches prepared samples were prepared. 比较2批样品的崩解时限和粉末的流动性,结果见表4。 Disintegration Comparative batches of samples 2 and fluidity of the powder, the results in Table 4.

表42批样品物理性能指标试验 Table 42 Physical performance test batches of samples

从表4可以看出,040102批的粉末休止角较小,表明混合粉末流动性较好,制得片剂的崩解时间也符合规定。 As can be seen from Table 4, 040,102 granted smaller angle of repose of the powder, the mixed powder showed good flowability, disintegration time of the tablets are also prepared compliance.

为验证各批次之间重复性,按照040102批的处方和压片压力,制备040103、040104、040105批样品,分别测定物料的流动性、可压性及崩解时限等指标,见表5。 To verify the reproducibility between batches, in accordance with the prescription and tableting pressure batch 040102, preparation 040103,040104,040105 batches of samples were measured in the flow of materials, compressibility and disintegration time and other indicators, are shown in Table 5.

表5 3批样品物理性能指标试验 Table 53 Physical performance test batches of samples

从表5可以看出,粉末直接压片的工艺进行样品的制备,原辅料的混合粉末具有良好的流动性,混合粉末的可压性好,在较小的压力下压制成的片剂具有良好的硬度,经脆碎度考察,减失重量在1.1-1.2%。 As can be seen from Table 5, sample preparation of direct compression process is performed, the mixed powder of raw materials has good flowability, good compressibility of the mixed powder, compressed into tablets at a pressure of less good hardness, friability by inspection, less weight loss at 1.1-1.2%.

为进一步验证物料的流动性,测定3批样品的片重差异,见表6。 To further verify the flow of materials, three batches of samples to measure the weight difference of the sheet are shown in Table 6.

表6甲氨蝶呤口腔崩解片重量差异检查结果 Table 6 methotrexate orally disintegrating tablet weight variation test results

从表6可以看出,混合粉末的流动性好,各批次之间重复性好,适合直接压片的工业化生产。 As can be seen from Table 6, the mixed powder of good flowability, good reproducibility between batches, suitable for industrial production of direct compression tableting.

为比较崩解时限的测定方法与口腔内崩解情况,将3个批号的口腔崩解片进行志愿者的口腔内崩解试验,以对照体外崩解时限的测定方法与口腔内崩解情况的相关性。 Determination of disintegration time comparison measurement method and disintegration in the oral cavity, the three batches of an oral disintegrating tablet for orally disintegrating test volunteers to control the in vitro disintegration time of the orally disintegrating situation Correlation.

表7体外崩解时限及口腔内崩解时限 Table 7 In vitro disintegration time and the disintegration time in the oral cavity

结果表明:三批样品均在1分钟内崩解,相当于在口腔内15秒以内崩解,可能是因为在体外为静态环境下崩解,而口腔内崩解有舌部运动所致。 The results showed that: all three batches disintegrate within 1 minute, 15 seconds or less equivalent to disintegrate in the oral cavity, it may be because in vitro disintegration under a static environment, the orally disintegrating portion tongue movement caused.

为表明本发明的进步性,我们还做了本发明甲氨蝶呤口腔崩解片的溶出度试验,并与普通片作了比较。 To show improvement of the present invention, we have made a dissolution test methotrexate orally disintegrating tablet of the present invention, and compared with the conventional tablets. 普通片选自市售上海信谊药业有限公司产的甲氨蝶呤片,产品批号:020917。 Common sheet is a commercial piece of methotrexate Shanghai Sine Pharmaceutical Co., Ltd. production, lot number: 020917. 测定方法采用中国药典2000年版二部附录XC第三法。 Determination of Chinese Pharmacopoeia 2000 edition of Appendix XC third law. 试验结果见表8。 The test results are shown in Table 8.

表8 甲氨蝶呤口腔崩解片溶出均一性试验测定结果(%) Table 8 Dissolution of methotrexate orally disintegrating tablets uniformity test assay results (%)

根据中国药典的规定,普通片溶出的合格限度为45分钟达标示量的75%。 According to the provisions of Chinese Pharmacopoeia, ordinary tablets dissolution eligibility threshold for 45 minutes 75% of the labeled amount. 从表3中可以看出,本发明三批样品的溶出度均一性良好,批内个体差异小,批间重现性好,三批口腔崩解片的溶出度均较市售普通片明显加快,5分钟溶出度即达90.1%以上,比普通片在5分钟时的溶出度提高了72.7 %。 As can be seen from Table 3, three batches of samples uniformity of the dissolution of the present invention is good, a small individual difference intra, inter-assay reproducibility is good, the dissolution of three batches of the commercially available orally-disintegrating tablet of the ordinary sheet significantly accelerated compared 5 minutes i.e., dissolution of more than 90.1%, a 72.7% increase over ordinary sheet dissolution at 5 minutes. 所以本发明的优点是很明显的,它服用方便,是一种在口腔内不需水即能崩解或溶解的片剂,吸收快,生物利用度高与口服混悬剂相当,对于吞咽困难的老年人和吞水即呕的癌症病人,以及特殊不能得到水的环境下的患者尤其适用。 There is an advantage of the invention is obvious, it is easy to take, that can be a water without disintegration or dissolution of the tablet in the oral cavity, rapid absorption, high bioavailability and oral suspensions rather, for dysphagia the elderly and cancer patients swallow the water that vomit, and special patient can not get under the water environment is particularly useful.

具体实施方式 detailed description

:下面再以实施例方式对本发明作进一步说明,给出本发明的实施细节,但并不是旨在限定本发明的保护范围。 : The following Example further embodiment of the present invention will be further described, are given details of the present embodiment of the invention, but not intended to limit the scope of the present invention.

甲氨蝶呤、微晶纤维素、羧甲基淀粉钠、硬脂酸镁、甘露醇均过100目筛。 Methotrexate, microcrystalline cellulose, sodium carboxymethyl starch, magnesium stearate, mannitol were over 100 mesh sieve.

称取甲氨蝶呤2.5克,先与15克羧甲基淀粉钠以等量递加法混匀,接着加入40克微晶纤维素充分混匀,然后依次10克甘露醇和1克硬脂酸镁混匀。 Weigh 2.5 g of methotrexate, first with 15 g sodium carboxymethyl starch mixed in equal amounts sliding scale method, 40 g of microcrystalline cellulose and then mixed well, followed by 10 g of mannitol and 1 g of magnesium stearate mix well. 检测混合粉中甲氨蝶呤的百分含量,计算片重后,压制成片。 Detecting the mixed powder percentage content of methotrexate, the tablet weight is calculated and compressed into tablets. 如此可压制出1000片甲氨蝶呤口腔崩解片。 Thus it can suppress a 1000 methotrexate orally disintegrating tablets.

其崩解时间为25秒,15分钟溶出度为92.8%。 Disintegration time was 25 seconds and 15 minutes was 92.8% dissolution.

下面再用几个实例进一步说明本发明。 Here again Several examples further illustrate the invention. 下述实例是以生产1000片口腔崩解片的配方例。 The following example is the production of 1000 Formulation Example orally disintegrating tablets.

实施例1甲氨蝶呤 2.5g羧甲基淀粉钠 13.5g微晶纤维素 42.5g甘露醇 6.7g硬脂酸镁 0.9g制成1000片甲氨蝶呤、微晶纤维素、羧甲基淀粉钠、硬脂酸镁、甘露醇均过100目筛。 Example 1 2.5g methotrexate sodium carboxymethyl starch 13.5g microcrystalline cellulose 42.5g Mannitol 6.7g magnesium stearate 0.9g embodiment 1000 made methotrexate, microcrystalline cellulose, carboxymethyl starch sodium, magnesium stearate, mannitol were over 100 mesh sieve.

称取甲氨蝶呤2.5克,先与14克羧甲基淀粉钠以等量递加法混匀,接着加入42克微晶纤维素充分混匀,然后依次与6.7克甘露醇和0.9克硬脂酸镁混匀。 Weigh 2.5 g of methotrexate, first with 14 g sodium carboxymethyl starch, mix in equal amounts sliding scale method, followed by sufficiently mixing 42 g of microcrystalline cellulose, followed by 6.7 g of mannitol and 0.9 grams of stearic acid magnesium mix. 检测混合粉中甲氨蝶呤的百分含量,计算片重后,压制成片。 Detecting the mixed powder percentage content of methotrexate, the tablet weight is calculated and compressed into tablets. 如此可压制出1000片甲氨蝶呤口腔崩解片。 Thus it can suppress a 1000 methotrexate orally disintegrating tablets.

其崩解时间为28秒,15分钟溶出度为91.9%。 Disintegration time is 28 seconds and 15 minutes was 91.9% dissolution.

实施例2甲氨蝶呤 5.0g羧甲基淀粉钠 16g微晶纤维素 38g甘露醇 7.8g硬脂酸镁 1.2g制成1000片甲氨蝶呤、微晶纤维素、羧甲基淀粉钠、硬脂酸镁、甘露醇均过100目筛。 Example 2 5.0g methotrexate sodium carboxymethyl starch 16g Magnesium stearate 7.8g microcrystalline cellulose 1.2g Mannitol 1000 made methotrexate, microcrystalline cellulose, sodium carboxymethyl starch 38g, magnesium stearate, mannitol were over 100 mesh sieve.

称取甲氨蝶呤5.0克,先与16克羧甲基淀粉钠以等量递加法混匀,接着加入38克微晶纤维素充分混匀,然后依次7.8克甘露醇和1.2克硬脂酸镁混匀。 Weigh 5.0 g of methotrexate, a sliding scale method first mixed in equal amounts and 16 g sodium carboxymethyl starch, followed by addition of 38 g of microcrystalline cellulose mixed well, followed by 7.8 g of mannitol and 1.2 g of magnesium stearate mix well. 检测混合粉中甲氨蝶呤的百分含量,计算片重后,压制成片。 Detecting the mixed powder percentage content of methotrexate, the tablet weight is calculated and compressed into tablets. 如此可压制出1000片甲氨蝶呤口腔崩解片。 Thus it can suppress a 1000 methotrexate orally disintegrating tablets.

其崩解时间为32秒,15分钟溶出度为93.1%。 Disintegration time of 32 seconds and 15 minutes was 93.1% dissolution.

实施例3甲氨蝶呤 2.5g羧甲基淀粉钠 13.5g微晶纤维素 37.5g甘露醇 13g硬脂酸镁 1.1g制成1000片甲氨蝶呤、微晶纤维素、羧甲基淀粉钠、硬脂酸镁、甘露醇均过100目筛。 Example 3 2.5g methotrexate sodium carboxymethyl starch 13.5g Magnesium stearate 1.1g Microcrystalline cellulose 13g 1000 made methotrexate, microcrystalline cellulose, sodium carboxymethyl starch, mannitol 37.5g Example , magnesium stearate, mannitol were over 100 mesh sieve.

称取甲氨蝶呤2.5克,先与13.5克羧甲基淀粉钠以等量递加法混匀,接着加入37.5克微晶纤维素充分混匀,然后依次13克甘露醇和1.1克硬脂酸镁混匀。 Weigh 2.5 g of methotrexate, first with 13.5 g sodium carboxymethyl starch mixed in equal amounts sliding scale method, followed by addition of 37.5 g of microcrystalline cellulose mixed well, followed by 13 g of mannitol and 1.1 g of magnesium stearate mix well. 检测混合粉中甲氨蝶呤的百分含量,计算片重后,压制成片。 Detecting the mixed powder percentage content of methotrexate, the tablet weight is calculated and compressed into tablets. 如此可压制出1000片甲氨蝶呤口腔崩解片。 Thus it can suppress a 1000 methotrexate orally disintegrating tablets.

其崩解时间为35秒,15分钟溶出度为92.9%。 Disintegration time of 35 seconds and 15 minutes was 92.9% dissolution.

Claims (3)

  1. 1.一种甲氨蝶呤口腔崩解片,由甲氨蝶呤、干燥粘合剂微晶纤维素、润滑剂硬脂酸镁、崩解剂羧甲基淀粉钠和矫味剂甘露醇组成,其特征在于所说口腔崩解片的组成含量,以重量百分数计为:3.5-7.5wt%的甲氨蝶呤,20.0-24.0wt%的羧甲基淀粉钠,55.0-65.0wt%的微晶纤维素,1.0-2.0wt%的硬脂酸镁,10.0-20.0wt%的甘露醇。 An orally disintegrating tablet of methotrexate, a methotrexate, dry binder microcrystalline cellulose, a lubricant, magnesium stearate, sodium carboxymethyl starch, disintegrants and flavoring agents mannitol wherein the content of said composition orally disintegrating tablets, in weight percent of: 3.5-7.5wt% of methotrexate, 20.0-24.0wt% of sodium carboxymethyl starch, 55.0-65.0wt% micro microcrystalline cellulose, 1.0-2.0wt% magnesium stearate, 10.0-20.0wt% mannitol.
  2. 2.依照权利要求1所述甲氨蝶呤口腔崩解片,其特征在于采用粉末直接压片法。 2. In accordance with claim 1 methotrexate orally disintegrating tablets, characterized in that a direct powder compression method.
  3. 3.依照权利要求1所述甲氨蝶呤口腔崩解片的配制方法,其特征在于包括以下主要配制步骤:(1)将甲氨蝶呤、微晶纤维素、羧甲基淀粉钠、硬脂酸镁、甘露醇分别粉碎过100目筛;(2)将甲氨蝶呤先与羧甲基淀粉钠进行混合过筛,混匀,再和微晶纤维素混匀,再加入甘露醇和硬脂酸镁,混合均匀,调节片重与压力压片制得权利要求1所述甲氨蝶呤口腔崩解片。 3. The method of claim 1 methotrexate orally disintegrating tablet formulation according to claim, wherein the formulation comprises the following major steps: (1) methotrexate, microcrystalline cellulose, sodium carboxymethyl starch, hard magnesium stearate, mannitol were sifted through a 100-mesh sieve; (2) to be methotrexate and sodium carboxymethyl starch are mixed and sieved, mixed, and microcrystalline cellulose and mix, then add the hard and mannitol magnesium stearate, mixed uniformly, and the pressure adjusting tablet weight to obtain tablets of claim 1 methotrexate orally disintegrating tablet.
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CN1208612A (en) * 1997-08-15 1999-02-24 安徽中人科技有限责任公司 Sustained release and implantation type methotrexate medicine and method for preparing same
WO2004002447A2 (en) * 2002-06-26 2004-01-08 Alza Corporation Dosage forms for increasing the solubility and extending the release of drugs such as e.g. topiramate and phenyton

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Publication number Priority date Publication date Assignee Title
CN1208612A (en) * 1997-08-15 1999-02-24 安徽中人科技有限责任公司 Sustained release and implantation type methotrexate medicine and method for preparing same
WO2004002447A2 (en) * 2002-06-26 2004-01-08 Alza Corporation Dosage forms for increasing the solubility and extending the release of drugs such as e.g. topiramate and phenyton

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