CN105476976B - The pharmaceutical composition and its preparation method and application - Google Patents

The pharmaceutical composition and its preparation method and application Download PDF

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CN105476976B
CN105476976B CN201510982014.2A CN201510982014A CN105476976B CN 105476976 B CN105476976 B CN 105476976B CN 201510982014 A CN201510982014 A CN 201510982014A CN 105476976 B CN105476976 B CN 105476976B
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cycloserine
pharmaceutical composition
amount
total
water
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CN105476976A (en
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陈日星
陈建豪
罗盛莲
范红银
陈万英
郝小妹
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广州瑞尔医药科技有限公司
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42Oxazoles

Abstract

本发明公开了种药物组合物及其制备方法和应用,该药物组合物由环丝氨酸和辅料组成,所述药物组合物的D粒径为75~380μm,所述辅料的用量占药物组合物总质量的9~45%。 The present invention discloses a drug composition and preparation method and application of the pharmaceutical composition and adjuvant composition cycloserine, D particle size of the pharmaceutical composition is 75 380μm ~, the materials used in an amount of total pharmaceutical composition 9 to 45% by mass. 本发明的药物组合物的稳定性与现有技术相比有较大的提升,最优例在常温条件(温度25℃,湿度60%)下密封存储180天,制剂标示量的百分含量的降解量<0.5%,加速条件(40℃,湿度75%)下密封存储180天,制剂标示量的百分含量的降解量<4.0%。 Stability of the pharmaceutical compositions of the present invention compared to the prior art are greatly improved, most cases at room temperature conditions (temperature 25 ℃, humidity 60%) seal 180 days storage, the percentage of the labeled amount of the formulation amount of degradation <0.5% accelerated conditions (40 deg.] C, 75% humidity) the lower seal 180 days storage, the percentage of the amount of degradation of the labeled amount of formulation <4.0%.

Description

药物组合物及其制备方法和应用 The pharmaceutical composition and its preparation method and application

技术领域 FIELD

[0001] 本发明涉及药物制剂技术领域,特别是涉及一种药物组合物及其制备方法和应用。 [0001] The present invention relates to the technical field of pharmaceutical formulation, in particular, relates to a pharmaceutical composition and its preparation method and application.

背景技术 Background technique

[0002] 肺结核是结核病中一种影响人民身体健康的疾病,随着链霉素和异烟肼等抗结核病药物的出现,使肺结核病成为一种可以治疗的疾病。 [0002] TB is TB that affects people's health diseases, with the advent of anti-TB drugs such as isoniazid and streptomycin, the TB has become a disease that can be treated. 但是由于相关知识的不足和治疗的不规范,使得结核杆菌耐药越来越严重。 However, due to the irregularities and lack of treatment-related knowledge, making Mycobacterium tuberculosis resistant to more and more serious.

[0003] 肺结核是一种由结核杆菌引起的传染性较强的疾病。 [0003] Tuberculosis is an infectious disease caused strong by Mycobacterium tuberculosis. 在世界卫生组织确定的三种需要重点控制的疾病中,肺结核仅次于艾滋病。 In the three kinds of disease the World Health Organization identified the need to focus control, second only to tuberculosis, AIDS. 中国是肺结核流行严重的国家,此外随着结核杆菌的耐药,中国的耐药病人也在不断增加。 China is a serious tuberculosis-endemic countries, in addition with the drug-resistant Mycobacterium tuberculosis, drug-resistant patients in China has also increased. 故开发抗肺结核病的药物,特别是抗结核耐药的药物是十分必要的。 Therefore, development of anti-TB drugs, especially anti-TB drug resistance is necessary.

[0004] 虽然环丝氨酸的抗结核杆菌的作用比链霉素的弱,但其不易产生耐药。 [0004] While the anti-TB cycloserine weaker effect than streptomycin, but not easy to produce drug resistance. 所以环丝氨酸主要用于治疗耐药结核杆菌引起的肺结核。 So cycloserine for the treatment of drug-resistant tuberculosis caused by Mycobacterium tuberculosis.

[0005] 环丝氨酸除了用于治疗结核杆菌引起的感染外,还可以用于治疗其它的一些疾病。 [0005] cycloserine addition to the treatment of infections caused by Mycobacterium tuberculosis, but may also be useful in the treatment of other diseases. 美国专利US2014018349,世界知识产权专利W02008118785,欧洲专利EP2338482以及欧洲专利EP0378134均公开了环丝氨酸可用于精神病、抑郁症或阿尔茨海默病的治疗。 US Patent US2014018349, the World Intellectual Property patent W02008118785, European patent EP2338482 and European Patent EP0378134 all disclose cycloserine can be used in the treatment of psychosis, depression or Alzheimer's disease. 美国专利US2014213621公开了环丝氨酸可用于慢性疼痛的治疗。 U.S. Patent No. US2014213621 discloses cycloserine may be used for treating chronic pain.

[0006] 在美国、欧洲、日本以及中国均有环丝氨酸的产品获批上市,用于治疗结核杆菌引起的肺结核。 [0006] In the United States, Europe, Japan and China have approved products on the market cycloserine for the treatment of tuberculosis caused by Mycobacterium tuberculosis.

[0007] 现有面世的环丝氨酸的制剂主要是速释类制剂,其组合物粒径很小,D9q粒度小于64μπι,制剂的稳定性比较差,在加速条件(温度40°C,湿度75%)下密封存储40天,制剂标示量的百分含量从99.1 %降到43.3%,加速40天降解量为56.3 %,加速条件下密封存储180 天,主药几乎已全部降解。 Cycloserine formulation [0007] The available conventional immediate release preparations is mainly that small particle size composition, D9q size of less than 64μπι, poor stability of the formulation, under accelerated conditions (a temperature of 40 ° C, 75% humidity ) lower seal 40 days storage, the percentage of the labeled amount of the formulation down to 43.3% from 99.1%, the amount of degradation accelerator 40 days 56.3%, under accelerated storage conditions of seal 180 days, almost all of the main drug degradation. 在常温条件(温度25°C,湿度60%)下密封存储180天,制剂标示量的百分含量从99.1 %降到86.4 %,常温条件180天降解量为12.8 %。 In (a temperature of 25 ° C, 60% RH) at room temperature storage conditions seal 180 days, the percentage of the labeled amount of the formulation down to 86.4% from 99.1%, the amount of degradation normal temperature 180 days 12.8%. 由于制剂比较不稳定, 因此会影响治疗效果以及使用的安全性。 Since the preparation relatively unstable, thus affecting the therapeutic effect and safety of use.

[0008] 俄罗斯专利RU2248205公开了在环丝氨酸中加入一些填充剂并填充于胶囊,来改善胶囊内容物的流动性和制剂的稳定性,其中加入的填充剂主要是二水合磷酸钙、微粉硅胶和硬脂酸钙。 [0008] Russian Patent RU2248205 discloses the stability of the added filler in some cycloserine and filled in a capsule, the capsule content to improve fluidity of the formulation and wherein the filler is added mainly calcium phosphate dihydrate, silica powder and Calcium stearate. 该胶囊剂增加了二水合磷酸钙来提高胶囊内容物的流动性,但由于二水合磷酸钙的摩擦力较大故容易磨损机器,长时间甚至导致粉末变色快的问题。 The capsule increases the calcium phosphate dihydrate to improve the fluidity of the contents of the capsule, but because it is larger friction calcium phosphate dihydrate is easy to machine wear, resulting in a long time even faster powder discoloration. 该专利没有具体的检测数值显示其稳定性的状况,按照该专利处方制得的制剂,其稳定性仍然较差,在加速条件(温度40°C,湿度75%)下密封存储180天,制剂标示量的百分含量从99.3%降到65.4%,加速180天降解量为34.1%。 This patent does not specifically detect the status of their stability numerical display, according to the patent the formulation prepared formulation, stability is still poor, at (a temperature of 40 ° C, 75% humidity) sealed storage under accelerated conditions for 180 days Formulation the percentage of the labeled amount of from 99.3% down to 65.4%, the amount of degradation accelerate 180 days was 34.1%. 在常温条件(温度25°C,湿度60%)条件下密封存储180 天,制剂标示量的百分含量从99.3 %降到94.8%,常温条件180天降解量为4.5 %。 Under normal conditions (temperature 25 ° C, 60% RH) conditions seal 180 days storage, the percentage of the labeled amount of the formulation down to 94.8% from 99.3%, the amount of degradation normal temperature 180 days was 4.5%. 另外该处方在稳定性试验中发现存在内容物变色的问题,原因可能与模具磨损中的金属微粒带入内容物,进而使有效成分加速降解有关,该专利并没有解决此类品种稳定性不好的问题,也没有发现有公开提高环丝氨酸制剂稳定性的专利。 Also found in this formulation stability test contents discoloration problem, possibly because the metal particles into the contents of the die wear, and thus accelerating the degradation of active ingredients, this patent does not address the poor stability of such species problem, but also found no patents disclose improved formulation stability cycloserine.

[0009] 因此,目前市场上需要开发一种稳定性更好的环丝氨酸制剂以满足临床的需求。 [0009] Therefore, there is a need to develop better stability cycloserine preparation for the market to meet the needs of clinical practice.

发明内容 SUMMARY

[0010] 基于此,本发明的目的是提供一种稳定性好的环丝氨酸的药物组合物。 [0010] Based on this, an object of the present invention is to provide a good stability of a pharmaceutical composition cycloserine.

[0011] 具体的技术方案如下: [0011] The specific technical solution as follows:

[0012] 一种药物组合物,该药物组合物包括环丝氨酸和辅料,所述的药物组合物的D90粒径为75〜380μπι,所述辅料的用量占药物组合物总质量的9〜45 %。 9~45% [0012] A pharmaceutical composition, the pharmaceutical composition comprising excipients and cycloserine, the particle diameter D90 of the pharmaceutical composition is 75~380μπι, the total mass of the excipients used in an amount of the pharmaceutical composition .

[0013] 在其中一些实施例中,所述辅料包括滑石粉,以及粘合剂和/或可压性辅料。 [0013] In some of these embodiments, the adjuvants include talc, a binding and / or compressible materials.

[00Μ]在其中一些实施例中,所述滑石粉的用量占药物组合物总量的9〜45%,所述粘合剂的用量占药物组合物总质量的〇〜6%,所述可压性辅料的用量占药物组合物总质量的0 〜16% 〇 [00Μ] In some of these embodiments, the total amount of 9~45% of the amount of the pharmaceutical composition of talc, 〇~6% of total mass of the binder is used in an amount of a pharmaceutical composition, said the total pressure of the mass of materials used in an amount of 0 ~ 16% pharmaceutical composition billion

[0015] 在其中一些实施例中,所述辅料包括滑石粉和粘合剂,所述滑石粉的用量占药物组合物总质量的23〜38 %,所述粘合剂的用量占药物组合物总质量的0.05〜2 %。 [0015] In some of these embodiments, the total mass of the excipients 23~38% and a binder include talc, the talc used in an amount of a pharmaceutical composition, said binder composition with an amount of a pharmaceutical 0.05~2% of total mass.

[0016] 在其中一些实施例中,所述辅料包括滑石粉和可压性辅料,所述滑石粉的用量占药物组合物总质量的23〜38%,所述可压性辅料的用量占药物组合物总质量的8〜14%。 [0016] In some of these embodiments, the adjuvants include talc and compressible excipients, 23~38% of the total mass of the talc used in an amount of the pharmaceutical composition, the pressure may be used in an amount of pharmaceutical excipients 8~14% of the total mass of the composition.

[0017] 在其中一些实施例中,所述粘合剂选自聚乙烯吡咯烷酮、羟丙甲纤维素、羟丙纤维素、乙基纤维素、甲基纤维素、羧甲基纤维素钠、羟乙纤维素、糊精中一种或几种;所述可压性辅料选自乳糖、淀粉、磷酸氢钙、微晶纤维素、甘露醇、糊精中一种或几种。 [0017] In some of these embodiments, the adhesive is selected from polyvinyl pyrrolidone, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, ethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose acetate, one or more dextrin; the compressible excipient selected from lactose, starch, dicalcium phosphate, microcrystalline cellulose, mannitol, one or more dextrin.

[0018] 在其中一些实施例中,该药物组合物的剂型为胶囊剂,所述胶囊剂的空心胶囊为明胶空心胶囊或羟丙甲纤维素空心胶囊,所述空心胶囊的干燥失重〈15.0%。 [0018] In some of these embodiments, the dosage form of the pharmaceutical composition is a capsule, the capsule hollow capsules are gelatin capsules or hollow hypromellose capsule hollow, said hollow capsule Loss on drying <15.0% .

[0019] 本发明的另一目的是提供上述药物组合物的制备方法。 [0019] Another object of the present invention is to provide a method for preparing the above pharmaceutical composition.

[0020] 具体的技术方案如下: [0020] The specific technical solution as follows:

[0021] 上述药物组合物的制备方法,包括如下步骤: [0021] The method of preparing the above pharmaceutical composition, comprising the steps of:

[0022] 将D9q粒径为75〜380μπι的环丝氨酸与辅料按所述质量百分比混合均匀,即得所述药物组合物; [0022] The particle size of 75~380μπι D9q cycloserine adjuvant and mixed by the mass percentage, i.e., to obtain the pharmaceutical composition;

[0023] 或,将环丝氨酸与辅料按所述质量百分比混合,然后进行湿法制粒、干法制粒或流化床制粒,干燥,过筛整粒,即得所述药物组合物; [0023] or, according to the cycloserine and the mass percentage of the mixed materials, and wet granulation, dry granulation or fluidized bed granulation, dried and sieved and sieved, to obtain the pharmaceutical composition;

[0024] 或,将辅料进行湿法制粒、干法制粒或流化床制粒,干燥,过筛整粒,得D9q粒径为75 〜380μπι的辅料颗粒,再与D9q粒径为75〜380μπι的环丝氨酸按所述质量百分比进行混合,即得所述药物组合物。 [0024] or the auxiliary wet granulation, dry granulation or fluidized bed granulation, dried and sieved and sieved to give a particle size of 75 ~380μπι D9q excipient particles, then the particle diameter 75~380μπι D9q cycloserine by the mass percentage were mixed, to obtain the pharmaceutical composition.

[0025] 在其中一些实施例中,所述药物组合物的干燥失重介于0.2〜2%,D9Q粒径介于120 〜380μπι〇 [0025] In some of these embodiments, the loss on drying of the pharmaceutical composition is between 0.2~2%, D9Q particle size between 120 ~380μπι〇

[0026] 本发明的另一目的是提供上述药物组合物的应用。 [0026] Another object of the present invention is the use of the aforementioned pharmaceutical compositions.

[0027] 具体的技术方案如下: [0027] The specific technical solution as follows:

[0028] 上述药物组合物在制备治疗结核杆菌引起的肺结核的药物中的应用。 [0028] Application of tuberculosis in the pharmaceutical preparation of the aforementioned pharmaceutical compositions in the treatment of tuberculosis caused.

[0029] 上述药物组合物在制备治疗精神病、抑郁症、阿尔茨海默病或慢性疼痛的药物中应用。 [0029] The preparation of the pharmaceutical composition in the treatment of psychosis, depression, Alzheimer's disease or chronic pain medicament.

[0030] 本发明的原理及优点如下: [0030] The principles and advantages of the present invention are as follows:

[0031] 本发明针对现有技术的不足,提供一种环丝氨酸的药物组合物,具体而言是一种含环丝氨酸的速释类胶囊剂。 [0031] The present invention addresses deficiencies in the prior art, there is provided a pharmaceutical composition cycloserine, particularly a class of immediate release capsules containing cycloserine.

[0032] 目前的环丝氨酸制剂主要是胶囊剂,但其制剂的稳定性较差,在常温条件(温度25 °C,湿度60%)和加速条件(40°C,湿度75%)下制剂主药的降解都较快,影响制剂的疗效和使用的安全性。 [0032] It is mainly cycloserine capsule formulation, but poor stability of the formulation, the primary formulation at room temperature conditions (temperature 25 ° C, 60% RH) and accelerated conditions (40 ° C, 75% humidity) drugs are rapidly degraded, affect the safety and efficacy of the formulation used.

[0033] 本发明通过提高辅料的粒径(进而提高药物组合物的粒径)和控制药物组合物的干燥失重的量不仅提高了制剂释放的速度,而且极大地提高了制剂的稳定性。 [0033] The present invention by increasing the particle size of the excipient (thereby increasing the particle diameter of the pharmaceutical composition) and a controlled amount of loss on drying of the pharmaceutical composition not only increases the speed of the release formulations, and greatly improve the stability of the formulation.

[0034] 本发明的药物组合物的Dgo粒径介于75〜380μηι,干燥失重介于0.2〜2%。 [0034] Dgo particle size of the pharmaceutical compositions of the present invention is between 75~380μηι, loss on drying is between 0.2~2%.

[0035] 本发明的药物组合物通过在环丝氨酸中加入辅料,或将环丝氨酸与辅料联合制粒的方式,将药物组合物的D9Q粒径控制在75〜380μπι,不仅使胶囊内容物具有良好的流动性以及润滑性,也提高了制剂的释放速度和制剂的稳定性。 The pharmaceutical composition of [0035] the present invention by adding the cycloserine adjuvant, and excipients or cycloserine granulation combined manner, the particle size of the pharmaceutical composition D9Q controlled 75~380μπι, not only the contents of the capsule have good fluidity and lubricity, but also improves the stability of the formulation and the release rate of the formulation. 处方中的辅料主要是滑石粉,以及粘合剂和/或可压性辅料。 The materials mainly prescription talc, and a binder and / or compressible materials.

[0036] 本发明的药物组合物的剂型为胶囊剂,所述胶囊剂的空心胶囊为明胶空心胶囊或羟丙甲纤维素空心胶囊,所述空心胶囊的干燥失重〈15.0%。 Dosage [0036] The pharmaceutical compositions of the present invention are capsules, the capsules hollow capsules are gelatin capsules or hollow hypromellose capsule hollow, said hollow capsule Loss on drying <15.0%.

[0037] 本发明的药物组合物的稳定性与现有技术相比有较大的提升,最优例在常温条件(温度25°C,湿度60%)下密封存储180天,制剂标示量的百分含量的降解量〈0.5%,加速条件(40°C,湿度75%)下密封存储180天,制剂标示量的百分含量的降解量〈4.0%。 Stability [0037] The pharmaceutical compositions of the present invention has a greatly improved compared to the prior art, the best embodiment at normal conditions (temperature 25 ° C, 60% RH) sealed storage 180 days, the labeled amount of the formulation amount of degradation percentage of <0.5% accelerated conditions (40 ° C, 75% humidity) the lower seal 180 days storage, the percentage of the amount of degradation of the labeled amount of formulation <4.0%.

具体实施方式 Detailed ways

[0038] 以下通过实施例对本发明做进一步阐述。 [0038] The following examples further illustrate the present invention do.

[0039] 对比例1 [0039] Comparative Example 1

[0040] 环丝氨酸占总量90.9%,环丝氨酸含量99.713%,滑石粉325目(粒径44μπι)。 [0040] 90.9% of the total cycloserine, cycloserine content of 99.713%, 325 mesh talc (particle size 44μπι).

[0041] 处方: [0041] Prescription:

[0042] [0042]

Figure CN105476976BD00051

[0043] 制备方法: [0043] Preparation:

[0044] 取处方量的环丝氨酸过200目筛,后与处方量的滑石粉混匀,按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊即可。 [0044] The formulation amount of a cycloserine through 200 mesh sieve, after mixing with formulation amounts of talc, according to specifications of each capsule containing 250mg of cycloserine filling a No. 1 gelatin capsules to hollow.

[0045] 上述方法制备的胶囊,其干燥失重为0.769%,在水中崩解时间为5分钟,在pH 1.2、?!14.0、?!16.8以及水中的15分钟的溶出度均大于90%。 Capsules prepared in [0045] the above-described method, the loss on drying was 0.769%, the disintegration time of 5 min in water, at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 90%.

[0046] 稳定性数据见表1。 [0046] The stability data are shown in Table 1.

[0047] 对比例2 [0047] Comparative Example 2

[0048] 环丝氨酸占总量64.1 %,环丝氨酸含量99.713 %,滑石粉325目。 [0048] 64.1% of the total cycloserine, cycloserine content of 99.713%, 325 mesh talc.

[0049] 处方: [0049] Prescription:

[0050] [0050]

Figure CN105476976BD00061

[0051] 制备方法: [0051] Preparation:

[0052] 取处方量的环丝氨酸过200目筛,后与处方量的滑石粉混匀,按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊即可。 [0052] The formulation amount of a cycloserine through 200 mesh sieve, after mixing with formulation amounts of talc, according to specifications of each capsule containing 250mg of cycloserine filling a No. 1 gelatin capsules to hollow.

[0053] 上述方法制备的胶囊,其干燥失重为0.521 %,在水中崩解时间为5分钟,在pH 1.2、 ?!14.0、?!16.8以及水中的15分钟的溶出度均大于90%。 Capsules prepared in [0053] the above-described method, the loss on drying was 0.521%, the disintegration time of 5 min in water, at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 90%.

[0054] 稳定性数据见表1。 [0054] The stability data are shown in Table 1.

[0055] 对比例3 [0055] Comparative Example 3

[0056] 环丝氨酸占总量55.6 %,环丝氨酸含量99.713 %,滑石粉325目。 [0056] 55.6% of the total cycloserine, cycloserine content of 99.713%, 325 mesh talc.

[0057] 处方: [0057] Prescription:

[0058] [0058]

Figure CN105476976BD00062

[0060] 制备方法: [0060] Preparation:

[0061] 取处方量的环丝氨酸过200目筛,后与处方量的滑石粉混匀,按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊即可。 [0061] The formulation amount of a cycloserine through 200 mesh sieve, after mixing with formulation amounts of talc, according to specifications of each capsule containing 250mg of cycloserine filling a No. 1 gelatin capsules to hollow.

[0062] 上述方法制备的胶囊,其干燥失重为0.672%,在水中崩解时间为5分钟,在pH 1.2、 ?!14.0、?!16.8以及水中的15分钟的溶出度均大于90%。 Capsules prepared in [0062] the above-described method, the loss on drying was 0.672%, the disintegration time of 5 min in water, at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 90%.

[0063] 稳定性数据见表1。 [0063] The stability data are shown in Table 1.

[0064] 对比例4 [0064] Comparative Example 4

[0065] 环丝氨酸占总量64.1 %,环丝氨酸含量99.668 %,滑石粉325目。 [0065] 64.1% of the total cycloserine, cycloserine content of 99.668%, 325 mesh talc.

[0066] 处方: [0066] Prescription:

[0067] [0067]

Figure CN105476976BD00063

[0068] 制备方法: [0068] Preparation:

[0069] 取处方量的环丝氨酸过200目筛,后与处方量的滑石粉混匀,按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊即可。 [0069] The formulation amount of a cycloserine through 200 mesh sieve, after mixing with formulation amounts of talc, according to specifications of each capsule containing 250mg of cycloserine filling a No. 1 gelatin capsules to hollow.

[0070] 上述方法制备的胶囊,其干燥失重为0.530%,在水中崩解时间为5分钟,在pH 1.2、 ?!14.0、?!16.8以及水中的15分钟的溶出度均大于90%。 Capsules prepared in [0070] the above-described method, the loss on drying was 0.530%, the disintegration time of 5 min in water, at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 90%.

[0071] 稳定性数据见表1。 [0071] The stability data are shown in Table 1.

[0072] 表1 [0072] TABLE 1

[0073] [0073]

Figure CN105476976BD00071

[0075] 实施例5 [0075] Example 5

[0076] 环丝氨酸占总量64.1 %,环丝氨酸含量99.713%,滑石粉200目(粒径75μπι)。 [0076] 64.1% of the total cycloserine, cycloserine content of 99.713%, 200 mesh talc (particle size 75μπι).

[0077] 处方: [0077] Prescription:

[0078] [0078]

Figure CN105476976BD00072

[0079] 制备方法: [0079] Preparation:

[0080] 取处方量的环丝氨酸过200目筛,后与处方量的滑石粉混匀,按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊即可。 [0080] The formulation amount of a cycloserine through 200 mesh sieve, after mixing with formulation amounts of talc, according to specifications of each capsule containing 250mg of cycloserine filling a No. 1 gelatin capsules to hollow.

[0081] 上述方法制备的胶囊,其干燥失重为0.496 %,在水中崩解时间为5分钟,在pH 1.2、 ?!14.0、?!16.8以及水中的15分钟的溶出度均大于90%。 Capsules prepared in [0081] the above-described method, the loss on drying was 0.496%, the disintegration time of 5 min in water, at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 90%.

[0082] 稳定性数据见表2。 [0082] The stability data are shown in Table 2.

[0083] 实施例6 [0083] Example 6

[0084] 环丝氨酸占总量64.1 %,环丝氨酸含量99.713 %,滑石粉200目。 [0084] 64.1% of the total cycloserine, cycloserine content of 99.713%, 200 mesh talc.

[0085] 处方: [0085] Prescription:

[0086] [0086]

Figure CN105476976BD00081

[0087] 制备方法: [0087] Preparation:

[0088] 取处方量的环丝氨酸过100目筛,后与处方量的滑石粉混匀,按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊即可。 [0088] The formulation amount of a cycloserine than 100 mesh, and after mixing prescribed amounts of talc, according to specifications of each capsule containing 250mg of cycloserine filling a No. 1 gelatin capsules to hollow.

[0089] 上述方法制备的胶囊,其干燥失重为0.583 %,在水中崩解时间为5分钟,在pH 1.2、 ?!14.0、?!16.8以及水中的15分钟的溶出度均大于90%。 Capsules prepared in [0089] the above-described method, the loss on drying was 0.583%, the disintegration time of 5 min in water, at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 90%.

[0090] 稳定性数据见表2。 [0090] The stability data are shown in Table 2.

[0091] 实施例7 [0091] Example 7

[0092] 环丝氨酸占总量64.1%,环丝氨酸含量99.713%,滑石粉100目(粒径150μπι)。 [0092] 64.1% of the total cycloserine, cycloserine content of 99.713%, 100 mesh talc (particle size 150μπι).

[0093] 处方: [0093] Prescription:

[0094] [0094]

Figure CN105476976BD00082

[0095] 制备方法: [0095] Preparation:

[0096] 取处方量的环丝氨酸过100目筛,后与处方量的滑石粉混匀,按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊即可。 [0096] The formulation amount of a cycloserine than 100 mesh, and after mixing prescribed amounts of talc, according to specifications of each capsule containing 250mg of cycloserine filling a No. 1 gelatin capsules to hollow.

[0097] 上述方法制备的胶囊,其干燥失重为0.578 %,在水中崩解时间为4分钟,在pH 1.2、 ?!14.0、?!16.8以及水中的15分钟的溶出度均大于90%。 Capsules prepared in [0097] the above-described method, the loss on drying was 0.578%, the disintegration time of 4 min in water at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 90%.

[0098] 稳定性数据见表2。 [0098] The stability data are shown in Table 2.

[0099] 实施例8 [0099] Example 8

[0100] 环丝氨酸占总量64.1 %,环丝氨酸含量99.619 %,滑石粉100目。 [0100] 64.1% of the total cycloserine, cycloserine content of 99.619%, 100 mesh talc.

[0101] 处方: [0101] Prescription:

[0102] [0102]

Figure CN105476976BD00083

[0103] 制备方法: [0103] Preparation:

[0104] 取处方量的环丝氨酸过100目筛,后与处方量的滑石粉混匀,按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊即可。 [0104] The formulation amount of a cycloserine than 100 mesh, and after mixing prescribed amounts of talc, according to specifications of each capsule containing 250mg of cycloserine filling a No. 1 gelatin capsules to hollow.

[0105] 上述方法制备的胶囊,其干燥失重为0.544%,在水中崩解时间为4分钟,在pH 1.2、 ?!14.0、?!16.8以及水中的15分钟的溶出度均大于90%。 Capsules prepared in [0105] the above-described method, the loss on drying was 0.544%, the disintegration time of 4 min in water at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 90%.

[0106] 稳定性数据见表2。 [0106] The stability data are shown in Table 2.

[0107] 表2 [0107] TABLE 2

[0108] [0108]

Figure CN105476976BD00091

[0110] 实施例9 [0110] Example 9

[0111] 环丝氨酸占总量64.1 %,环丝氨酸含量99.713 %,湿法制粒的辅料100目,溶剂为水,粘合剂占总量1. 〇%,粘合剂为聚乙烯吡咯烷酮K30。 [0111] 64.1% of the total cycloserine, cycloserine content of 99.713%, 100 mesh wet granulation excipient, solvent is water, the binder comprises 1 billion total%, the binder is polyvinyl pyrrolidone K30.

[0112] 处方: [0112] Prescription:

[0113] [0113]

Figure CN105476976BD00092

[0114] 制备方法: [0114] Preparation:

[0115] 将处方量的滑石粉与聚乙烯吡咯烷酮K30混匀,加入适量的水制软材,后过40目筛制湿颗粒,置于60°C下干燥2h,将干燥后的颗粒过100目筛整粒,得制粒后的辅料颗粒。 [0115] The formulation amounts of talc and polyvinylpyrrolidone K30 mixing, water was added q.s. made of soft material, made after the 40 mesh sieve wet granules, drying is placed 60 ° C for 2h, the dried granules through 100 mesh sieve, to obtain the granulated excipient particles. 将处方量的环丝氨酸过100目筛,再与制粒后的辅料混匀,按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。 The prescribed amount of a cycloserine through 100 mesh sieve, and then mixed with the granulated materials according to specifications of each capsule containing 250mg of cycloserine filled gelatin No. 1 empty capsules.

[0116] 上述方法制备的胶囊,其干燥失重为1.201%,在水中崩解时间为4分钟,在pH 1.2、 ?!14.0、?!16.8以及水中的15分钟的溶出度均大于90%。 Capsules prepared in [0116] the above-described method, the loss on drying was 1.201%, the disintegration time of 4 min in water at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 90%.

[0117] 稳定性数据见表3。 [0117] The stability data are shown in Table 3.

[0118] 实施例10 [0118] Example 10

[0119] 环丝氨酸占总量64.1 %,环丝氨酸含量99.713%,湿法制粒的辅料60目(粒径250μ m),溶剂为水,粘合剂占总量1.0%,粘合剂为聚乙烯吡咯烷酮Κ30。 [0119] accounted for 64.1% of the total amount of cycloserine, cycloserine content of 99.713%, 60 mesh wet granulation excipient (particle diameter 250μ m), the solvent is water, the binder comprises 1.0% of the total, the binder is a polyethylene pyrrolidone Κ30.

[0120] 处方: [0120] Prescription:

[0121] [0121]

Figure CN105476976BD00101

[0122] 制备方法: [0122] Preparation:

[0123] 将处方量的滑石粉与聚乙烯吡咯烷酮K30混匀,加入适量的水制软材,后过40目筛制湿颗粒,置于60°C下干燥2h,将干燥后的颗粒过60目筛整粒,得制粒后的辅料颗粒。 [0123] The formulation amounts of talc and polyvinylpyrrolidone K30 mixing, water was added q.s. made of soft material, made after the 40 mesh sieve wet granules, drying is placed 60 ° C for 2h, the dried granules through 60 mesh sieve, to obtain the granulated excipient particles. 将处方量的环丝氨酸过100目筛,再与制粒后的辅料混匀,按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。 The prescribed amount of a cycloserine through 100 mesh sieve, and then mixed with the granulated materials according to specifications of each capsule containing 250mg of cycloserine filled gelatin No. 1 empty capsules.

[0124] 上述方法制备的胶囊,其干燥失重为I . 015 %,在水中崩解时间为4分钟,在p H 1.2、 ?!14.0、?!16.8以及水中的15分钟的溶出度均大于90%。 Capsules prepared in [0124] the above-described method, the loss on drying I. 015%, the disintegration time of 4 min in water at p H 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 90 %.

[0125] 稳定性数据见表3。 [0125] The stability data are shown in Table 3.

[0126] 实施例11 [0126] Example 11

[0127] 环丝氨酸占总量64.1%,环丝氨酸含量99.713%,湿法制粒的辅料60目,溶剂为水,粘合剂占总量1. 〇%,粘合剂为聚乙烯吡咯烷酮K30。 [0127] cycloserine total 64.1%, 99.713% Cycloserine content, 60 mesh wet granulation excipient, solvent is water, the binder comprises 1 billion total%, the binder is polyvinyl pyrrolidone K30.

[0128] 处方: [0128] Prescription:

[0129] [0129]

Figure CN105476976BD00102

[0130] 制备方法: [0130] Preparation:

[0131] 将处方量的滑石粉与聚乙烯吡咯烷酮K30混匀,加入适量的水制软材,后过40目筛制湿颗粒,置于60°C下干燥2h,将干燥后的颗粒过60目筛整粒,得制粒后的辅料颗粒。 [0131] The formulation amounts of talc and polyvinylpyrrolidone K30 mixing, water was added q.s. made of soft material, made after the 40 mesh sieve wet granules, drying is placed 60 ° C for 2h, the dried granules through 60 mesh sieve, to obtain the granulated excipient particles. 将处方量的环丝氨酸过100目筛,再与制粒后的辅料混匀,按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。 The prescribed amount of a cycloserine through 100 mesh sieve, and then mixed with the granulated materials according to specifications of each capsule containing 250mg of cycloserine filled gelatin No. 1 empty capsules.

[0132] 上述方法制备的胶囊,其干燥失重为2.183%,在水中崩解时间为4分钟,在pH 1.2、 ?!14.0、?!16.8以及水中的15分钟的溶出度均大于90%。 Capsules prepared in [0132] the above-described method, the loss on drying was 2.183%, the disintegration time of 4 min in water at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 90%.

[0133] 稳定性数据见表3。 [0133] The stability data are shown in Table 3.

[0134] 实施例12 [0134] Example 12

[0135] 环丝氨酸占总量90.9 %,环丝氨酸含量99.713 %,湿法制粒的辅料40目(粒径380μ m),溶剂为水,粘合剂占总量0.25%,粘合剂为聚乙烯吡咯烷酮Κ30。 [0135] accounted for 90.9% of the total cycloserine, cycloserine content of 99.713%, wet granulation auxiliaries 40 mesh (particle diameter 380μ m), the solvent is water, accounting for 0.25% of the total binder, the binder is a polyethylene pyrrolidone Κ30.

[0136] 处方: [0136] Prescription:

[0137] [0137]

Figure CN105476976BD00111

[0139] 制备方法: [0139] Preparation:

[0140] 将处方量的滑石粉与聚乙烯吡咯烷酮K30混匀,加入适量的水制软材,后过20目筛制湿颗粒,置于60°C下干燥2h,将干燥后的颗粒过40目筛整粒,得制粒后的辅料颗粒。 [0140] The formulation amounts of talc and polyvinylpyrrolidone K30 mixing, water was added q.s. made of soft material, made after the 20 mesh sieve wet granules, drying is placed 60 ° C for 2h, the dried granules through 40 mesh sieve, to obtain the granulated excipient particles. 将处方量的环丝氨酸过100目筛,再与制粒后的辅料混匀,按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。 The prescribed amount of a cycloserine through 100 mesh sieve, and then mixed with the granulated materials according to specifications of each capsule containing 250mg of cycloserine filled gelatin No. 1 empty capsules.

[0141] 上述方法制备的胶囊,其干燥失重为0.627 %,在水中崩解时间为4分钟,在pH 1.2、 ?!14.0、?!16.8以及水中的15分钟的溶出度均大于90%。 Capsules prepared in [0141] the above-described method, the loss on drying was 0.627%, the disintegration time of 4 min in water at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 90%.

[0142] 稳定性数据见表3。 [0142] The stability data are shown in Table 3.

[0143] 实施例13 [0143] Example 13

[0144] 环丝氨酸占总量64.1 %,环丝氨酸含量99.713 %,湿法制粒的辅料60目,溶剂为乙醇,粘合剂占总量1. 〇%,粘合剂为聚乙烯吡咯烷酮K30。 [0144] cycloserine total 64.1%, 99.713% Cycloserine content, 60 mesh wet granulation excipient, solvent is ethanol, 1 billion% of the total binder comprises binder is povidone K30.

[0145] 处方: [0145] Prescription:

[0146] [0146]

Figure CN105476976BD00112

[0147] 制备方法: [0147] Preparation:

[0148] 将处方量的滑石粉与聚乙烯吡咯烷酮K30混匀,加入适量的乙醇制软材,后过40目筛制湿颗粒,置于60°C下干燥2h,将干燥后的颗粒过60目筛整粒,得制粒后的辅料颗粒。 [0148] A prescribed amount of talc mixed with polyvinylpyrrolidone K30, adding an appropriate amount of ethanol produced soft material, over a 40-mesh sieve made wet granules, drying is placed 60 ° C for 2h, the dried granules through 60 mesh sieve, to obtain the granulated excipient particles. 将处方量的环丝氨酸过100目筛,再与制粒后的辅料混匀,按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。 The prescribed amount of a cycloserine through 100 mesh sieve, and then mixed with the granulated materials according to specifications of each capsule containing 250mg of cycloserine filled gelatin No. 1 empty capsules.

[0149] 上述方法制备的胶囊,其干燥失重为0.756 %,在水中崩解时间为4分钟,在pH 1.2、 ?!14.0、?!16.8以及水中的15分钟的溶出度均大于90%。 Capsules prepared in [0149] the above-described method, the loss on drying was 0.756%, the disintegration time of 4 min in water at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 90%.

[0150] 稳定性数据见表3。 [0150] The stability data are shown in Table 3.

[0151] 实施例14 [0151] Example 14

[0152] 环丝氨酸占总量55.6 %,环丝氨酸含量99.713 %,湿法制粒的辅料60目,溶剂为乙醇,粘合剂占总量1. 〇%,粘合剂为聚乙烯吡咯烷酮K30。 [0152] cycloserine total 55.6%, 99.713% Cycloserine content, 60 mesh wet granulation excipient, solvent is ethanol, 1 billion% of the total binder comprises binder is povidone K30.

[0153] 处方: [0153] Prescription:

[0154] [0154]

Figure CN105476976BD00121

[0155] 制备方法: [0155] Preparation:

[0156] 将处方量的滑石粉与聚乙烯吡咯烷酮K30混匀,加入适量的乙醇制软材,后过40目筛制湿颗粒,置于60°C下干燥2h,将干燥后的颗粒过60目筛整粒,得制粒后的辅料颗粒。 [0156] A prescribed amount of talc mixed with polyvinylpyrrolidone K30, adding an appropriate amount of ethanol produced soft material, over a 40-mesh sieve made wet granules, drying is placed 60 ° C for 2h, the dried granules through 60 mesh sieve, to obtain the granulated excipient particles. 将处方量的环丝氨酸过100目筛,再与制粒后的辅料混匀,按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。 The prescribed amount of a cycloserine through 100 mesh sieve, and then mixed with the granulated materials according to specifications of each capsule containing 250mg of cycloserine filled gelatin No. 1 empty capsules.

[0157] 上述方法制备的胶囊,其干燥失重为0.701 %,在水中崩解时间为4分钟,在pH 1.2、?!14.0、?!16.8以及水中的15分钟的溶出度均大于90%。 Capsules prepared in [0157] the above-described method, the loss on drying was 0.701%, the disintegration time of 4 min in water at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 90%.

[0158] 稳定性数据见表3。 [0158] The stability data are shown in Table 3.

[0159] 实施例15 [0159] Example 15

[0160] 环丝氨酸占总量64.1 %,环丝氨酸含量99.713 %,流化床制粒的辅料60〜80目,溶剂为乙醇,粘合剂占总量1.0%,粘合剂为聚乙烯吡咯烷酮K30。 [0160] accounted for 64.1% of the total amount of cycloserine, cycloserine content of 99.713%, fluidized bed granulation excipients 60~80 mesh, the solvent is ethanol, 1.0% of the total binder comprises, as a binder polyvinylpyrrolidone K30 .

[0161] 处方: [0161] Prescription:

[0162] [0162]

Figure CN105476976BD00122

[0163] 制备方法: [0163] Preparation:

[0164] 将处方量的聚乙烯吡咯烷酮K30配置成聚乙烯吡咯烷酮K30乙醇溶液,将处方量的滑石粉置于流化床中喷加聚乙烯吡咯烷酮K30乙醇溶液制湿颗粒,并在流化状态下进行干燥,过60目到80目筛整粒,将处方量的环丝氨酸过100目筛后与制粒后的辅料混匀,再按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。 [0164] The formulation amounts of polyvinylpyrrolidone K30 configured polyvinylpyrrolidone K30 alcohol solution, the formulation amounts of talc was placed in a fluidized bed spray-adding an ethanol solution of polyvinylpyrrolidone K30 manufactured by wet granulation, fluidized state and after drying, 60 mesh to 80 mesh sieve, the prescribed amount of cycloserine than 100 mesh and granulated materials after mixing, then each capsule containing 250mg of cycloserine specifications hollow filled gelatin capsules No. 1 .

[0165] 上述方法制备的胶囊,其干燥失重为0.723 %,在水中崩解时间为4分钟,在pH 1.2、 ?!14.0、?!16.8以及水中的15分钟的溶出度均大于90%。 Capsules prepared in [0165] the above-described method, the loss on drying was 0.723%, the disintegration time of 4 min in water at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 90%.

[0166] 稳定性数据见表3。 [0166] The stability data are shown in Table 3.

[0167] 实施例16 [0167] Example 16

[0168] 环丝氨酸占总量64.1 %,环丝氨酸含量99.474 %,湿法制粒的辅料60目,溶剂为乙醇,粘合剂占总量1. 〇%,粘合剂为聚乙烯吡咯烷酮K30。 [0168] cycloserine total 64.1%, 99.474% Cycloserine content, 60 mesh wet granulation excipient, solvent is ethanol, 1 billion% of the total binder comprises binder is povidone K30.

[0169] 处方: [0169] Prescription:

[0170] [0170]

Figure CN105476976BD00131

[0171] 制备方法: [0171] Preparation:

[0172] 将处方量的聚乙烯吡咯烷酮K30配置成聚乙烯吡咯烷酮K30乙醇溶液,再加入处方量的滑石粉制软材,后过40目筛制湿颗粒,置于60°C下干燥2h,将干燥后的颗粒过60目筛整粒,得制粒后的辅料颗粒。 [0172] The formulation amounts of polyvinylpyrrolidone K30 configured polyvinylpyrrolidone K30 alcohol solution was added an amount of talcum powder made of soft material prescription, over 40 mesh wet granules prepared, placed in drying 60 ° C for 2h, the the dried granules were passed through a 60 mesh sieve to give granules after granulation excipients. 将处方量的环丝氨酸过100目筛,再与制粒后的辅料混匀,按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。 The prescribed amount of a cycloserine through 100 mesh sieve, and then mixed with the granulated materials according to specifications of each capsule containing 250mg of cycloserine filled gelatin No. 1 empty capsules.

[0173] 上述方法制备的胶囊,其干燥失重为0.635%,在水中崩解时间为4分钟,在pH 1.2、 ?!14.0、?!16.8以及水中的15分钟的溶出度均大于90%。 Capsules prepared in [0173] the above-described method, the loss on drying was 0.635%, the disintegration time of 4 min in water at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 90%.

[0174] 稳定性数据见表3。 [0174] The stability data are shown in Table 3.

[0175] 实施例17 [0175] Example 17

[0176] 环丝氨酸占总量64.1 %,环丝氨酸含量99.713 %,湿法制粒的辅料60目,溶剂为乙醇,粘合剂占总量〇. 1 %,粘合剂为聚乙烯吡咯烷酮K30。 [0176] accounted for 64.1% of the total amount of cycloserine, cycloserine content of 99.713%, 60 mesh wet granulation excipient, solvent is ethanol, the total square binder comprises 1% binder is polyvinylpyrrolidone K30.

[0177] 处方: [0177] Prescription:

[0178] [0178]

Figure CN105476976BD00132

[0179] 制备方法: [0179] Preparation:

[0180] 将处方量的聚乙烯吡咯烷酮K30配置成聚乙烯吡咯烷酮K30乙醇溶液,再加入处方量的滑石粉制软材,后过40目筛制湿颗粒,置于60°C下干燥2h,将干燥后的颗粒过60目筛整粒,得制粒后的辅料颗粒。 [0180] The formulation amounts of polyvinylpyrrolidone K30 configured polyvinylpyrrolidone K30 alcohol solution was added an amount of talcum powder made of soft material prescription, over 40 mesh wet granules prepared, placed in drying 60 ° C for 2h, the the dried granules were passed through a 60 mesh sieve to give granules after granulation excipients. 将处方量的环丝氨酸过100目筛,再与制粒后的辅料混匀,按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。 The prescribed amount of a cycloserine through 100 mesh sieve, and then mixed with the granulated materials according to specifications of each capsule containing 250mg of cycloserine filled gelatin No. 1 empty capsules.

[0181] 上述方法制备的胶囊,其干燥失重为〇. 697 %,在水中崩解时间为4分钟,在pH 1.2、 ?!14.0、?!16.8以及水中的15分钟的溶出度均大于90%。 Capsules prepared in [0181] the above-described method, the loss on drying billion. 697%, the disintegration time of 4 min in water at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 90% .

[0182] 稳定性数据见表3。 [0182] The stability data are shown in Table 3.

[0183] 实施例18 [0183] Example 18

[0184] 环丝氨酸占总量64.1 %,环丝氨酸含量99.713 %,湿法制粒的辅料60目,溶剂为乙醇,粘合剂占总量3%,粘合剂为聚乙烯吡咯烷酮K30。 [0184] accounted for 64.1% of the total amount of cycloserine, cycloserine content of 99.713%, 60 mesh wet granulation excipient, solvent is ethanol, 3% of the total binder comprises binder is povidone K30.

[0185] 处方: [0185] Prescription:

[0186] [0186]

Figure CN105476976BD00141

[0187] 制备方法: [0187] Preparation:

[0188] 将处方量的聚乙烯吡咯烷酮K30配置成聚乙烯吡咯烷酮K30乙醇溶液,再加入处方量的滑石粉制软材,后过40目筛制湿颗粒,置于60°C下干燥2h,将干燥后的颗粒过60目筛整粒,得制粒后的辅料颗粒。 [0188] The formulation amounts of polyvinylpyrrolidone K30 configured polyvinylpyrrolidone K30 alcohol solution was added an amount of talcum powder made of soft material prescription, over 40 mesh wet granules prepared, placed in drying 60 ° C for 2h, the the dried granules were passed through a 60 mesh sieve to give granules after granulation excipients. 将处方量的环丝氨酸过100目筛,再与制粒后的辅料混匀,按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。 The prescribed amount of a cycloserine through 100 mesh sieve, and then mixed with the granulated materials according to specifications of each capsule containing 250mg of cycloserine filled gelatin No. 1 empty capsules.

[0189] 上述方法制备的胶囊,其干燥失重为0.640 %,在水中崩解时间为4分钟,在pH 1.2、 ?!14.0、?!16.8以及水中的15分钟的溶出度均大于90%。 Capsules prepared in [0189] the above-described method, the loss on drying was 0.640%, the disintegration time of 4 min in water at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 90%.

[0190] 稳定性数据见表3。 [0190] The stability data are shown in Table 3.

[0191] 实施例19 [0191] Example 19

[0192] 环丝氨酸占总量64.1 %,环丝氨酸含量99.713 %,湿法制粒的辅料40目,溶剂为乙醇,粘合剂占总量6%,粘合剂为聚乙烯吡咯烷酮K30。 [0192] accounted for 64.1% of the total amount of cycloserine, cycloserine content of 99.713%, a 40 mesh wet granulation excipient, solvent is ethanol, 6% of the total binder, the binder is povidone K30.

[0193] 处方: [0193] Prescription:

[0194] [0194]

Figure CN105476976BD00142

[0195] 制备方法: [0195] Preparation:

[0196] 将处方量的聚乙烯吡咯烷酮K30配置成聚乙烯吡咯烷酮K30乙醇溶液,再加入处方量的滑石粉制软材,后过20目筛制湿颗粒,置于60°C下干燥2h,将干燥后的颗粒过40目(粒径380μπι)筛,得制粒后的辅料颗粒。 [0196] The formulation amounts of polyvinylpyrrolidone K30 configured polyvinylpyrrolidone K30 alcohol solution was added talc soft material made of the prescribed dose after 20 mesh Sieve wet granules, drying is placed 60 ° C for 2h, the the dried granules through 40 mesh (particle diameter 380μπι) screen to give particles after granulation excipients. 将处方量的环丝氨酸过100目筛,再与制粒后的辅料混匀,按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。 The prescribed amount of a cycloserine through 100 mesh sieve, and then mixed with the granulated materials according to specifications of each capsule containing 250mg of cycloserine filled gelatin No. 1 empty capsules.

[0197] 上述方法制备的胶囊,其干燥失重为0.814%,在水中崩解时间为4分钟,在pH 1.2、 ?!14.0、?!16.8以及水中的15分钟的溶出度均大于90%。 Capsules prepared in [0197] the above-described method, the loss on drying was 0.814%, the disintegration time of 4 min in water at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 90%.

[0198] 稳定性数据见表3。 [0198] The stability data are shown in Table 3.

[0199] 实施例20 [0199] Example 20

[0200] 环丝氨酸占总量64.1%,环丝氨酸含量99.713%,湿法制粒的辅料60目,溶剂为水,粘合剂占总量1. 〇%,粘合剂为羟丙甲纤维素E5。 [0200] cycloserine total 64.1%, 99.713% Cycloserine content, 60 mesh wet granulation excipient, solvent is water, the binder comprises 1 billion total% binder hypromellose E5 .

[0201] 处方: [0201] Prescription:

[0202] [0202]

Figure CN105476976BD00151

[0203]制备方法: [0203] Preparation:

[0204] 将处方量的滑石粉与羟丙甲纤维素E5混匀,加入适量的水制软材,后过40目筛制湿颗粒,置于60°C下干燥2h,将干燥后的颗粒过60目筛整粒,得制粒后的辅料颗粒。 [0204] The formulation amounts of talc and hypromellose E5 mixing, water was added q.s. made of soft material, made after the 40 mesh sieve wet granules, drying is placed 60 ° C for 2h, the dried granules through a 60 mesh sieve, the auxiliary particles obtained after granulation. 将处方量的环丝氨酸过100目筛,再与制粒后的辅料混匀,按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。 The prescribed amount of a cycloserine through 100 mesh sieve, and then mixed with the granulated materials according to specifications of each capsule containing 250mg of cycloserine filled gelatin No. 1 empty capsules.

[0205] 上述方法制备的胶囊,其干燥失重为0.558 %,在水中崩解时间为4分钟,在pH 1.2、 ?!14.0、?!16.8以及水中的15分钟的溶出度均大于90%。 Capsules prepared in [0205] the above-described method, the loss on drying was 0.558%, the disintegration time of 4 min in water at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 90%.

[0206] 稳定性数据见表3。 [0206] The stability data are shown in Table 3.

[0207] 实施例21 [0207] Example 21

[0208] 环丝氨酸占总量64.1%,环丝氨酸含量99.713%,湿法制粒的辅料60目,溶剂为水,粘合剂占总量1. 〇%,粘合剂为羟丙纤维素MF。 [0208] cycloserine, 64.1% of the total, the content of 99.713% Cycloserine, 60 mesh wet granulation excipient, solvent is water, the binder comprises 1 billion total%, the binder is hydroxypropylcellulose MF.

[0209] 处方: [0209] Prescription:

[0210] [0210]

Figure CN105476976BD00152

[0211] 制备方法: [0211] Preparation:

[0212] 将处方量的滑石粉与羟丙纤维素MF混匀,加入适量的水制软材,后过40目筛制湿颗粒,置于60°C下干燥2h,将干燥后的颗粒过60目筛整粒,得制粒后的辅料颗粒。 [0212] The prescribed amount of talc mixed with MF hydroxypropylcellulose, water was added q.s. made of soft material, made after the 40 mesh sieve wet granules, drying is placed 60 ° C for 2h, the dried granules 60 mesh sieve, to obtain the granulated excipient particles. 将处方量的环丝氨酸过100目筛,再与制粒后的辅料混匀,按每粒胶囊含环丝氨酸250mg的规格填充I 号明胶空心胶囊。 The prescribed amount of a cycloserine through 100 mesh sieve, and then mixed with the granulated materials according to specifications of each capsule containing 250mg of cycloserine I, filled hollow gelatin capsules.

[0213] 上述方法制备的胶囊,其干燥失重为0.679 %,在水中崩解时间为4分钟,在pH 1.2、?!14.0、?!16.8以及水中的15分钟的溶出度均大于90%。 Capsules prepared in [0213] the above-described method, the loss on drying was 0.679%, the disintegration time of 4 min in water at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 90%.

[0214] 稳定性数据见表3。 [0214] The stability data are shown in Table 3.

[0215] 表3 [0215] TABLE 3

[0216] [0216]

Figure CN105476976BD00161

[0217] 实施例22 [0217] Example 22

[0218] 环丝氨酸占总量64.1 %,环丝氨酸含量99.713%,干法制粒的辅料60目,可压性辅料用量占总量10%,可压性辅料为无水乳糖。 [0218] 64.1% of the total cycloserine, cycloserine content of 99.713%, dry granulation auxiliaries 60 mesh, compressible excipients with 10% of the total amount, compressible excipient is lactose anhydrous.

[0219] 处方: [0219] Prescription:

[0220] [0220]

Figure CN105476976BD00171

[0221] 制备方法: [0221] Preparation:

[0222] 将处方量的滑石粉和无水乳糖混匀后干法制粒,制60目的辅料颗粒。 [0222] The formulation amounts of talc and anhydrous lactose after mixing dry granulation excipient particles made of 60 mesh. 将处方量的环丝氨酸过100目筛,再与制粒后的辅料混匀,按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。 The prescribed amount of a cycloserine through 100 mesh sieve, and then mixed with the granulated materials according to specifications of each capsule containing 250mg of cycloserine filled gelatin No. 1 empty capsules.

[0223] 上述方法制备的胶囊,其干燥失重为1.215%,在水中崩解时间为5分钟,在pH 1.2、 ?!14.0、?!16.8以及水中的15分钟的溶出度均大于90%。 Capsules prepared in [0223] the above-described method, the loss on drying was 1.215%, the disintegration time of 5 min in water, at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 90%.

[0224] 稳定性数据见表4。 [0224] The stability data shown in Table 4.

[0225] 实施例23 [0225] Example 23

[0226] 环丝氨酸占总量64.1 %,环丝氨酸含量99.713 %,干法制粒的辅料60目,可压性辅料用量占总量16%,可压性辅料为无水乳糖。 [0226] 64.1% of the total cycloserine, cycloserine content of 99.713%, dry granulation auxiliaries 60 mesh, compressible excipients with 16% of the total amount, compressible excipient is lactose anhydrous.

[0227] 处方: [0227] Prescription:

[0228] [0228]

Figure CN105476976BD00172

[0229]制备方法: [0229] Preparation:

[0230] 将处方量的滑石粉和无水乳糖混匀后干法制粒,制60目的辅料颗粒。 [0230] The formulation amounts of talc and anhydrous lactose after mixing dry granulation excipient particles made of 60 mesh. 将处方量的环丝氨酸过100目筛,再与制粒后的辅料混匀,按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。 The prescribed amount of a cycloserine through 100 mesh sieve, and then mixed with the granulated materials according to specifications of each capsule containing 250mg of cycloserine filled gelatin No. 1 empty capsules.

[0231] 上述方法制备的胶囊,其干燥失重为1.153%,在水中崩解时间为5分钟,在pH 1.2、 ?!14.0、?!16.8以及水中的15分钟的溶出度均大于90%。 Capsules prepared in [0231] the above-described method, the loss on drying was 1.153%, the disintegration time of 5 min in water, at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 90%.

[0232] 稳定性数据见表4。 [0232] The stability data shown in Table 4.

[0233] 实施例24 [0233] Example 24

[0234] 环丝氨酸占总量64.1 %,环丝氨酸含量99.713 %,干法制粒的辅料60目,可压性辅料用量占总量10%,可压性辅料为淀粉。 [0234] 64.1% of the total cycloserine, cycloserine content of 99.713%, dry granulation auxiliaries 60 mesh, compressible excipients with 10% of the total amount, compressible excipients is starch.

[0235] 处方: [0235] Prescription:

[0236] [0236]

Figure CN105476976BD00181

[0237]制备方法: [0237] Preparation:

[0238] 将处方量的滑石粉和淀粉混匀后干法制粒,制60目的辅料颗粒。 [0238] The formulation amounts of talc and starch after mixing dry granulation excipient particles made of 60 mesh. 将处方量的环丝氨酸过100目筛,再与制粒后的辅料混匀,按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。 The prescribed amount of a cycloserine through 100 mesh sieve, and then mixed with the granulated materials according to specifications of each capsule containing 250mg of cycloserine filled gelatin No. 1 empty capsules.

[0239] 上述方法制备的胶囊,其干燥失重为1.589 %,在水中崩解时间为5分钟,在pH 1.2、?!14.0、?!16.8以及水中的15分钟的溶出度均大于90%。 Capsules prepared in [0239] the above-described method, the loss on drying was 1.589%, the disintegration time of 5 min in water, at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 90%.

[0240] 稳定性数据见表4。 [0240] The stability data shown in Table 4.

[0241] 表4 [0241] TABLE 4

[0242] [0242]

Figure CN105476976BD00182

[0243] 实施例25 [0243] Example 25

[0244] 环丝氨酸占总量64.1 %,环丝氨酸含量99.713 %,环丝氨酸与辅料一起干法制粒60目,可压性辅料用量占总量0 %。 [0244] cycloserine, 64.1% of the total, the content of 99.713% Cycloserine, cycloserine, together with granulation excipients dry 60 mesh, compressible excipients with 0% of the total amount.

[0245] 处方: [0245] Prescription:

[0246] [0246]

Figure CN105476976BD00183

[0247]制备方法: [0247] Preparation:

[0248] 将处方量的环丝氨酸过100目筛,再与滑石粉混匀后干法制粒,制60目的颗粒,再将制粒后的颗粒按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。 [0248] A prescribed amount of a cycloserine through a 100 mesh sieve, and then mixed with the talc dry granulation, prepared 60-mesh granules, and then the particles were granulated by each capsule containing 250mg of cycloserine specification No. 1 filled hollow gelatin capsules.

[0249] 上述方法制备的胶囊,其干燥失重为0.637 %,在水中崩解时间为14分钟,在pH 1.2、 ?!14.0、?!16.8以及水中的15分钟的溶出度均小于70%。 Capsules prepared in [0249] the above-described method, the loss on drying was 0.637%, the disintegration time of 14 minutes in water, at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is less than 70%.

[0250] 稳定性数据见表5。 [0250] The stability data are shown in Table 5.

[0251] 实施例26 [0251] Example 26

[0252] 环丝氨酸占总量64.1 %,环丝氨酸含量99.713 %,环丝氨酸与辅料一起干法制粒60目,可压性辅料用量占总量10%,可压性辅料为无水乳糖。 [0252] 64.1% of the total cycloserine, cycloserine content of 99.713%, with dry excipients with the granulation cycloserine 60 mesh, compressibility accounted for 10% of the total materials used, compressible excipient is lactose anhydrous.

[0253] 处方: [0253] Prescription:

[0254] [0254]

Figure CN105476976BD00191

[0255]制备方法: [0255] Preparation:

[0256] 将处方量的环丝氨酸过100目筛,再与滑石粉以及无水乳糖混匀后干法制粒,制60 目的颗粒,再将制粒后的颗粒按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。 [0256] A prescribed amount of a cycloserine than 100 mesh, then after granulation, talc, lactose anhydrous and dry mixed to prepare 60 mesh particles, the particles were then granulated by each capsule containing 250mg of cycloserine specification No. 1 gelatin filled hollow capsules.

[0257] 上述方法制备的胶囊,其干燥失重为0.985%,在水中崩解时间为9分钟,在pH 1.2、 ?!14.0、?!16.8以及水中的15分钟的溶出度均大于85%。 Capsules prepared in [0257] the above-described method, the loss on drying was 0.985%, disintegration time in water of 9 minutes, at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 85%.

[0258] 稳定性数据见表5。 [0258] The stability data are shown in Table 5.

[0259] 实施例27 [0259] Example 27

[0260] 环丝氨酸占总量64.1 %,环丝氨酸含量99.713 %,环丝氨酸与辅料一起干法制粒60目,可压性辅料用量占总量10%,可压性辅料为淀粉。 [0260] 64.1% of the total cycloserine, cycloserine content of 99.713%, with dry excipients with the granulation cycloserine 60 mesh, compressibility accounted for 10% of the total materials used, compressible excipients is starch.

[0261] 处方: [0261] Prescription:

[0262] [0262]

Figure CN105476976BD00192

[0263]制备方法: [0263] Preparation:

[0264] 将处方量的环丝氨酸过100目筛,再与滑石粉以及淀粉混匀后干法制粒,制60目的颗粒,再将制粒后的颗粒按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。 [0264] A prescribed amount of a cycloserine through a 100 mesh sieve, and then mixed with the starch, talc and dry granulation, prepared 60-mesh granules, and then the particles were granulated by each capsule containing 250mg of cycloserine filled specifications No. 1 gelatin capsule casings.

[0265]上述方法制备的胶囊,其干燥失重为1.122%,在水中崩解时间为12分钟,在pH 1.2、 ?!14.0、?!16.8以及水中的15分钟的溶出度均小于85%。 Capsules prepared in [0265] the above-described method, the loss on drying was 1.122%, the disintegration time of 12 minutes in water, at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is less than 85%.

[0266] 稳定性数据见表5。 [0266] The stability data are shown in Table 5.

[0267] 表5 [0267] TABLE 5

[0268] [0268]

Figure CN105476976BD00201

[0269] 实施例28 [0269] Example 28

[0270] 环丝氨酸占总量64.1 %,环丝氨酸含量99.713 %,环丝氨酸与辅料一起湿法制粒60目,溶剂为乙醇,粘合剂用量占总量0 %。 [0270] cycloserine, 64.1% of the total, the content of 99.713% Cycloserine, cycloserine wet granulated together with excipients mesh 60, the solvent is ethanol, with the total amount of 0% adhesive.

[0271] 处方: [0271] Prescription:

[0272] [0272]

Figure CN105476976BD00202

[0273]制备方法: [0273] Preparation:

[0274] 将处方量的环丝氨酸过100目筛,再与滑石粉混匀后加入适量的乙醇制软材,过40 目筛制湿颗粒,置于60°C下干燥2h,将干燥后的颗粒过60目筛整粒,再将制粒后的颗粒按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。 [0274] A prescribed amount of a cycloserine through a 100 mesh sieve, and then mixed with talc after adding an appropriate amount of ethanol produced soft material, through the 40 mesh wet granules prepared, placed in drying 60 ° C for 2h, after drying particles passed through a 60 mesh sieve, the particles were then granulated by each capsule containing 250mg of cycloserine specification No. 1 gelatin filled hollow capsules.

[0275] 上述方法制备的胶囊,其干燥失重为0.667 %,在水中崩解时间为4分钟,在pH 1.2、 ?!14.0、?!16.8以及水中的15分钟的溶出度均大于90%。 Capsules prepared in [0275] the above-described method, the loss on drying was 0.667%, the disintegration time of 4 min in water at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 90%.

[0276] 稳定性数据见表6。 [0276] The stability data are shown in Table 6.

[0277] 实施例29 [0277] Example 29

[0278] 环丝氨酸占总量64.1 %,环丝氨酸含量99.713 %,环丝氨酸与辅料一起湿法制粒60目,溶剂为乙醇,粘合剂用量占总量1.0 %,粘合剂为聚乙烯吡咯烷酮K30。 [0278] accounted for 64.1% of the total amount of cycloserine, cycloserine content of 99.713%, cycloserine wet granulated together with excipients mesh 60, the solvent is ethanol, 1.0% of the total amount binder, the binder is polyvinylpyrrolidone K30 .

[0279] 处方: [0279] Prescription:

[0280] [0280]

Figure CN105476976BD00211

[0281] 制备方法: [0281] Preparation:

[0282] 将处方量的聚乙烯吡咯烷酮K30配置成聚乙烯吡咯烷酮K30的乙醇溶液,将处方量的环丝氨酸过100目筛,再与滑石粉混匀,再加入配置好的聚乙烯吡咯烷酮K30乙醇溶液,搅匀制软材,再过40目筛制湿颗粒,置于60°C下干燥2h,再将干燥的颗粒过60目筛整粒,再将制粒后的颗粒按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。 [0282] The formulation amounts of polyvinylpyrrolidone K30 configured ethanol solution of polyvinylpyrrolidone K30, the prescribed amount of cycloserine through 100 mesh sieve, and then mixed with talc, configured added an ethanol solution of polyvinylpyrrolidone K30 , made of soft material mix, another 40 mesh sieve wet granules, drying is placed 60 ° C for 2h, and then dried granules through a 60 mesh sieve, the particles were then granulated by each capsule containing ring serine 250mg specification No. 1 gelatin filled hollow capsules.

[0283] 上述方法制备的胶囊,其干燥失重为0.784 %,在水中崩解时间为4分钟,在pH 1.2、?!14.0、?!16.8以及水中的15分钟的溶出度均大于90%。 Capsules prepared in [0283] the above-described method, the loss on drying was 0.784%, the disintegration time of 4 min in water at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 90%.

[0284] 稳定性数据见表6。 [0284] The stability data are shown in Table 6.

[0285] 表6 [0285] TABLE 6

[0286] [0286]

Figure CN105476976BD00212

[0287] 实施例30 (优选实施例) [0287] Example 30 (preferred embodiment)

[0288] 环丝氨酸占总量64.1 %,环丝氨酸含量99.713 %,环丝氨酸与辅料一起流化床制粒60〜80目,溶剂为乙醇,粘合剂用量占总量1.0 %,粘合剂为聚乙烯吡咯烷酮K30。 [0288] cycloserine, 64.1% of the total, the content of 99.713% Cycloserine, fluidized bed granulation with excipients cycloserine 60~80 mesh together, and the solvent is ethanol, 1.0% of the total amount with an adhesive, binder polyvinylpyrrolidone K30.

[0289] 处方: [0289] Prescription:

[0290] [0290]

Figure CN105476976BD00213

[0291] [0291]

Figure CN105476976BD00221

[0292]制备方法: [0292] Preparation:

[0293] 将处方量的聚乙烯吡咯烷酮K30配置成聚乙烯吡咯烷酮K30的乙醇溶液,将处方量的环丝氨酸过100目筛,再与滑石粉混匀,置于流化床中喷加聚乙烯吡咯烷酮K30乙醇溶液制湿颗粒,并在流化状态下进行干燥,过60目到80目筛整粒,再将制粒后的颗粒按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。 [0293] The formulation amounts of polyvinylpyrrolidone K30 configured ethanol solution of polyvinylpyrrolidone K30, the prescribed amount of cycloserine through 100 mesh sieve, and then mixed with talc, was placed in a fluidized bed spray-adding polyvinylpyrrolidone K30 manufactured by wet granulation ethanol solution and dried in a fluidized state through a 60 mesh to 80 mesh sieve, the particles were then granulated by each capsule containing 250mg of cycloserine specification No. 1 gelatin filled hollow capsules.

[0294] 上述方法制备的胶囊,其干燥失重为0.532 %,在水中崩解时间为4分钟,在pH 1.2、 ?!14.0、?!16.8以及水中的15分钟的溶出度均大于90%。 Capsules prepared in [0294] the above-described method, the loss on drying was 0.532%, the disintegration time of 4 min in water at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 90%.

[0295] 稳定性数据见表7。 [0295] The stability data are shown in Table 7.

[0296] 实施例31 [0296] Example 31

[0297] 环丝氨酸占总量64.1 %,环丝氨酸含量99.713 %,环丝氨酸与辅料一起流化床制粒60〜80目,溶剂为乙醇,粘合剂用量占总量6.0 %,粘合剂为聚乙烯吡咯烷酮K30。 [0297] cycloserine, 64.1% of the total, the content of 99.713% Cycloserine, fluidized bed granulation with excipients cycloserine 60~80 mesh together, and the solvent is ethanol, 6.0% of the total amount with an adhesive, binder polyvinylpyrrolidone K30.

[0298] 处方: [0298] Prescription:

[0299] [0299]

Figure CN105476976BD00222

[0300] 制备方法: [0300] Preparation:

[0301] 将处方量的聚乙烯吡咯烷酮K30配置成聚乙烯吡咯烷酮K30的乙醇溶液,将处方量的环丝氨酸过100目筛,再与滑石粉混匀,置于流化床中喷加聚乙烯吡咯烷酮K30乙醇溶液制湿颗粒,并在流化状态下进行干燥,过60目到80目筛整粒,再将制粒后的颗粒按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。 [0301] The formulation amounts of polyvinylpyrrolidone K30 configured ethanol solution of polyvinylpyrrolidone K30, the prescribed amount of cycloserine through 100 mesh sieve, and then mixed with talc, was placed in a fluidized bed spray-adding polyvinylpyrrolidone K30 manufactured by wet granulation ethanol solution and dried in a fluidized state through a 60 mesh to 80 mesh sieve, the particles were then granulated by each capsule containing 250mg of cycloserine specification No. 1 gelatin filled hollow capsules.

[0302] 上述方法制备的胶囊,其干燥失重为0.661%,在水中崩解时间为4分钟,在pH 1.2、 ?!14.0、?!16.8以及水中的15分钟的溶出度均大于90%。 Capsules prepared in [0302] the above-described method, the loss on drying was 0.661%, the disintegration time of 4 min in water at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 90%.

[0303] 稳定性数据见表7。 [0303] The stability data are shown in Table 7.

[0304] 实施例32 [0304] Example 32

[0305] 环丝氨酸占总量64.1 %,环丝氨酸含量99.713 %,环丝氨酸与辅料一起流化床制粒60〜80目,溶剂为水,粘合剂用量占总量1.0%,粘合剂为聚乙烯吡咯烷酮K30。 [0305] cycloserine, 64.1% of the total, the content of 99.713% Cycloserine, fluidized bed granulation with excipients cycloserine 60~80 mesh together, the solvent is water, the total amount of 1.0% with an adhesive, binder polyvinylpyrrolidone K30.

[0306] 处方: [0306] Prescription:

[0307] [0307]

Figure CN105476976BD00231

[0308] 制备方法: [0308] Preparation:

[0309] 将处方量的聚乙烯吡咯烷酮K30配置成聚乙烯吡咯烷酮K30的水溶液,将处方量的环丝氨酸过100目筛,再与滑石粉混匀,置于流化床中喷加聚乙烯吡咯烷酮K30水溶液制湿颗粒,并在流化状态下进行干燥,过60目到80目筛整粒,再将制粒后的颗粒按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。 [0309] A prescribed amount of an aqueous solution of polyvinylpyrrolidone K30 polyvinylpyrrolidone K30 arranged in the prescribed amount of cycloserine through 100 mesh sieve, and then mixed with talc, was placed in a fluidized bed spray-adding polyvinylpyrrolidone K30 prepared aqueous wet granulation, fluidized state and dried through a 60 mesh to 80 mesh sieve, the particles were then granulated by each capsule containing 250mg of cycloserine specification No. 1 gelatin filled hollow capsules.

[0310] 上述方法制备的胶囊,其干燥失重为0.620 %,在水中崩解时间为4分钟,在pH 1.2、 ?!14.0、?!16.8以及水中的15分钟的溶出度均大于90%。 Capsules prepared in [0310] the above-described method, the loss on drying was 0.620%, the disintegration time of 4 min in water at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 90%.

[0311] 稳定性数据见表7。 [0311] The stability data are shown in Table 7.

[0312] 实施例33 [0312] Example 33

[0313] 环丝氨酸占总量64.1 %,环丝氨酸含量99.713 %,环丝氨酸与辅料一起流化床制粒60〜80目,溶剂为乙醇,粘合剂用量占总量3.0%,粘合剂为聚乙烯吡咯烷酮K30,明胶空心胶囊的干燥失重为13.6%。 [0313] cycloserine, 64.1% of the total, the content of 99.713% Cycloserine, fluidized bed granulation with excipients cycloserine 60~80 mesh together, and the solvent is ethanol, 3.0% of the total amount with an adhesive, binder polyvinylpyrrolidone K30, loss on drying hollow gelatin capsules was 13.6%.

[0314] 处方: [0314] Prescription:

[0315] [0315]

Figure CN105476976BD00232

[0316]制备方法: [0316] Preparation:

[0317] 将处方量的聚乙烯吡咯烷酮K30配置成聚乙烯吡咯烷酮K30的乙醇溶液,将处方量的环丝氨酸过100目筛,再与滑石粉混匀,置于流化床中喷加聚乙烯吡咯烷酮K30乙醇溶液制湿颗粒,并在流化状态下进行干燥,过60目到80目筛整粒,再将制粒后的颗粒按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。 [0317] The formulation amounts of polyvinylpyrrolidone K30 configured ethanol solution of polyvinylpyrrolidone K30, the prescribed amount of cycloserine through 100 mesh sieve, and then mixed with talc, was placed in a fluidized bed spray-adding polyvinylpyrrolidone K30 manufactured by wet granulation ethanol solution and dried in a fluidized state through a 60 mesh to 80 mesh sieve, the particles were then granulated by each capsule containing 250mg of cycloserine specification No. 1 gelatin filled hollow capsules.

[0318] 上述方法制备的胶囊,其干燥失重为0.568 %,在水中崩解时间为4分钟,在pH 1.2、 ?!14.0、?!16.8以及水中的15分钟的溶出度均大于90%。 Capsules prepared in [0318] the above-described method, the loss on drying was 0.568%, the disintegration time of 4 min in water at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 90%.

[0319] 稳定性数据见表7。 [0319] The stability data are shown in Table 7.

[0320] 实施例34 [0320] Example 34

[0321] 环丝氨酸占总量64.1%,环丝氨酸含量99.713%,环丝氨酸与辅料一起流化床制粒60〜80目,溶剂为乙醇,粘合剂用量占总量3.0%,粘合剂为聚乙烯吡咯烷酮K30,明胶空心胶囊的干燥失重为16.8%。 [0321] cycloserine, 64.1% of the total, the content of 99.713% Cycloserine, fluidized bed granulation with excipients cycloserine 60~80 mesh together, and the solvent is ethanol, 3.0% of the total amount with an adhesive, binder polyvinylpyrrolidone K30, loss on drying hollow gelatin capsules was 16.8%.

[0322] 处方: [0322] Prescription:

[0323] [0323]

Figure CN105476976BD00241

[0324]制备方法: [0324] Preparation:

[0325] 将处方量的聚乙烯吡咯烷酮K30配置成聚乙烯吡咯烷酮K30的乙醇溶液,将处方量的环丝氨酸过100目筛,再与滑石粉混匀,置于流化床中喷加聚乙烯吡咯烷酮K30乙醇溶液制湿颗粒,并在流化状态下进行干燥,过60目到80目筛整粒,再将制粒后的颗粒按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。 [0325] The formulation amounts of polyvinylpyrrolidone K30 configured ethanol solution of polyvinylpyrrolidone K30, the prescribed amount of cycloserine through 100 mesh sieve, and then mixed with talc, was placed in a fluidized bed spray-adding polyvinylpyrrolidone K30 manufactured by wet granulation ethanol solution and dried in a fluidized state through a 60 mesh to 80 mesh sieve, the particles were then granulated by each capsule containing 250mg of cycloserine specification No. 1 gelatin filled hollow capsules.

[0326] 上述方法制备的胶囊,其干燥失重为0.699 %,在水中崩解时间为4分钟,在pH 1.2、 ?!14.0、?!16.8以及水中的15分钟的溶出度均大于90%。 Capsules prepared in [0326] the above-described method, the loss on drying was 0.699%, the disintegration time of 4 min in water at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 90%.

[0327] 稳定性数据见表7。 [0327] The stability data are shown in Table 7.

[0328] 实施例35 (优选实施例) 35 (Preferred Embodiment) [0328] Embodiment

[0329] 环丝氨酸占总量64.1 %,环丝氨酸含量99.713 %,环丝氨酸与辅料一起流化床制粒60〜80目,溶剂为乙醇,粘合剂用量占总量3.0%,粘合剂为聚乙烯吡咯烷酮K30,羟丙甲纤维素空心胶囊的干燥失重为2.2%。 [0329] cycloserine, 64.1% of the total, the content of 99.713% Cycloserine, fluidized bed granulation with excipients cycloserine 60~80 mesh together, and the solvent is ethanol, 3.0% of the total amount with an adhesive, binder polyvinylpyrrolidone K30, hypromellose loss on drying of 2.2% hollow capsules.

[0330] 处方: [0330] Prescription:

[0331] [0331]

Figure CN105476976BD00242

[0332]制备方法: [0332] Preparation:

[0333] 将处方量的聚乙烯吡咯烷酮K30配置成聚乙烯吡咯烷酮K30的乙醇溶液,将处方量的环丝氨酸过100目筛,再与滑石粉混匀,置于流化床中喷加聚乙烯吡咯烷酮K30乙醇溶液制湿颗粒,并在流化状态下进行干燥,过60目到80目筛整粒,再将制粒后的颗粒按每粒胶囊含环丝氨酸250mg的规格填充1号羟丙甲纤维素空心胶囊。 [0333] The formulation amounts of polyvinylpyrrolidone K30 configured ethanol solution of polyvinylpyrrolidone K30, the prescribed amount of cycloserine through 100 mesh sieve, and then mixed with talc, was placed in a fluidized bed spray-adding polyvinylpyrrolidone K30 manufactured by wet granulation ethanol solution and dried in a fluidized state, the particles through a 60 mesh to 80 mesh sieve, and then granulating by each capsule containing 250mg of cycloserine specification No. 1 hypromellose filled fibers Su hollow capsules.

[0334] 上述方法制备的胶囊,其干燥失重为0.762%,在水中崩解时间为8分钟,在pH 1.2、 ?!14.0、?!16.8以及水中的15分钟的溶出度均大于85%。 Capsules prepared in [0334] the above-described method, the loss on drying was 0.762%, disintegration time in water was 8 minutes, at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 85%.

[0335] 稳定性数据见表7。 [0335] The stability data are shown in Table 7.

[0336] 表7 [0336] TABLE 7

[0337] [0337]

Figure CN105476976BD00251

[0338] 实施例36 [0338] Example 36

[0339] 环丝氨酸占总量64.1 %,环丝氨酸含量99.713 %,环丝氨酸与辅料一起流化床制粒60〜80目,溶剂为乙醇,粘合剂用量占总量1.0 %,粘合剂为聚乙烯吡咯烷酮K30。 [0339] cycloserine, 64.1% of the total, the content of 99.713% Cycloserine, fluidized bed granulation with excipients cycloserine 60~80 mesh together, and the solvent is ethanol, 1.0% of the total amount with an adhesive, binder polyvinylpyrrolidone K30.

[0340] 处方: [0340] Prescription:

[0341] [0341]

Figure CN105476976BD00252

[0342]制备方法: [0342] Preparation:

[0343] 将处方量的聚乙烯吡咯烷酮K30配置成聚乙烯吡咯烷酮K30的乙醇溶液,将处方量的环丝氨酸过100目筛,再与滑石粉混匀,置于流化床中喷加聚乙烯吡咯烷酮K30乙醇溶液制湿颗粒,并在流化状态下进行干燥,过60目到80目筛整粒,再将制粒后的颗粒按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。 [0343] The formulation amounts of polyvinylpyrrolidone K30 configured ethanol solution of polyvinylpyrrolidone K30, the prescribed amount of cycloserine through 100 mesh sieve, and then mixed with talc, was placed in a fluidized bed spray-adding polyvinylpyrrolidone K30 manufactured by wet granulation ethanol solution and dried in a fluidized state through a 60 mesh to 80 mesh sieve, the particles were then granulated by each capsule containing 250mg of cycloserine specification No. 1 gelatin filled hollow capsules.

[0344] 上述方法制备的胶囊,其干燥失重为0.676 %,在水中崩解时间为4分钟,在pH 1.2、?!14.0、?!16.8以及水中的15分钟的溶出度均大于90%。 Capsules prepared in [0344] the above-described method, the loss on drying was 0.676%, the disintegration time of 4 min in water at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 90%.

[0345] 稳定性数据见表8。 [0345] The stability data are shown in Table 8.

[0346] 实施例37 [0346] Example 37

[0347] 环丝氨酸占总量64.1 %,环丝氨酸含量99.668%,环丝氨酸与辅料一起流化床制粒60〜80目,溶剂为乙醇,粘合剂用量占总量I. O %,粘合剂为聚乙烯吡咯烷酮K30。 [0347] accounted for 64.1% of the total amount of cycloserine, cycloserine content of 99.668%, with a fluidized bed granulation excipients cycloserine 60~80 mesh and the solvent is alcohol, the total amount of the binder used in an amount I. O%, the adhesive agent is polyvinylpyrrolidone K30.

[0348] 处方: [0348] Prescription:

[0349] [0349]

Figure CN105476976BD00261

[0350]制备方法: [0350] Preparation:

[0351] 将处方量的聚乙烯吡咯烷酮K30配置成聚乙烯吡咯烷酮K30的乙醇溶液,将处方量的环丝氨酸过100目筛,再与滑石粉混匀,置于流化床中喷加聚乙烯吡咯烷酮K30乙醇溶液制湿颗粒,并在流化状态下进行干燥,过60目到80目筛整粒,再将制粒后的颗粒按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。 [0351] The formulation amounts of polyvinylpyrrolidone K30 configured ethanol solution of polyvinylpyrrolidone K30, the prescribed amount of cycloserine through 100 mesh sieve, and then mixed with talc, was placed in a fluidized bed spray-adding polyvinylpyrrolidone K30 manufactured by wet granulation ethanol solution and dried in a fluidized state through a 60 mesh to 80 mesh sieve, the particles were then granulated by each capsule containing 250mg of cycloserine specification No. 1 gelatin filled hollow capsules.

[0352] 上述方法制备的胶囊,其干燥失重为0.804%,在水中崩解时间为4分钟,在pH 1.2、 ?!14.0、?!16.8以及水中的15分钟的溶出度均大于90%。 Capsules prepared in [0352] the above-described method, the loss on drying was 0.804%, the disintegration time of 4 min in water at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 90%.

[0353] 稳定性数据见表8。 [0353] The stability data are shown in Table 8.

[0354] 实施例38 [0354] Example 38

[0355] 环丝氨酸占总量64.1 %,环丝氨酸含量99.619%,环丝氨酸与辅料一起流化床制粒60〜80目,溶剂为乙醇,粘合剂用量占总量1.0 %,粘合剂为聚乙烯吡咯烷酮K30。 [0355] cycloserine, 64.1% of the total, the content of 99.619% Cycloserine, fluidized bed granulation with excipients cycloserine 60~80 mesh together, and the solvent is ethanol, 1.0% of the total amount with an adhesive, binder polyvinylpyrrolidone K30.

[0356] 处方: [0356] Prescription:

[0357] [0357]

Figure CN105476976BD00262

[0¾9] 制备方法: [0¾9] Preparation:

[0360] 将处方量的聚乙烯吡咯烷酮K30配置成聚乙烯吡咯烷酮K30的乙醇溶液,将处方量的环丝氨酸过100目筛,再与滑石粉混匀,置于流化床中喷加聚乙烯吡咯烷酮K30乙醇溶液制湿颗粒,并在流化状态下进行干燥,过60目到80目筛整粒,再将制粒后的颗粒按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。 [0360] The formulation amounts of polyvinylpyrrolidone K30 configured ethanol solution of polyvinylpyrrolidone K30, the prescribed amount of cycloserine through 100 mesh sieve, and then mixed with talc, was placed in a fluidized bed spray-adding polyvinylpyrrolidone K30 manufactured by wet granulation ethanol solution and dried in a fluidized state through a 60 mesh to 80 mesh sieve, the particles were then granulated by each capsule containing 250mg of cycloserine specification No. 1 gelatin filled hollow capsules.

[0361] 上述方法制备的胶囊,其干燥失重为0.758 %,在水中崩解时间为4分钟,在pH 1.2、 ?!14.0、?!16.8以及水中的15分钟的溶出度均大于90%。 Capsules prepared in [0361] the above-described method, the loss on drying was 0.758%, the disintegration time of 4 min in water at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 90%.

[0362] 稳定性数据见表8。 [0362] The stability data are shown in Table 8.

[0363] 实施例39 [0363] Example 39

[0364] 环丝氨酸占总量64.1 %,环丝氨酸含量99.474 %,环丝氨酸与辅料一起流化床制粒60〜80目,溶剂为乙醇,粘合剂用量占总量1.0 %,粘合剂为聚乙烯吡咯烷酮K30。 [0364] cycloserine, 64.1% of the total, the content of 99.474% Cycloserine, fluidized bed granulation with excipients cycloserine 60~80 mesh together, and the solvent is ethanol, 1.0% of the total amount with an adhesive, binder polyvinylpyrrolidone K30.

[0365] 处方: [0365] Prescription:

[0366] [0366]

Figure CN105476976BD00271

[0367]制备方法: [0367] Preparation:

[0368] 将处方量的聚乙烯吡咯烷酮K30配置成聚乙烯吡咯烷酮K30的乙醇溶液,将处方量的环丝氨酸过100目筛,再与滑石粉混匀,置于流化床中喷加聚乙烯吡咯烷酮K30乙醇溶液制湿颗粒,并在流化状态下进行干燥,过60目到80目筛整粒,再将制粒后的颗粒按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。 [0368] The formulation amounts of polyvinylpyrrolidone K30 configured ethanol solution of polyvinylpyrrolidone K30, the prescribed amount of cycloserine through 100 mesh sieve, and then mixed with talc, was placed in a fluidized bed spray-adding polyvinylpyrrolidone K30 manufactured by wet granulation ethanol solution and dried in a fluidized state through a 60 mesh to 80 mesh sieve, the particles were then granulated by each capsule containing 250mg of cycloserine specification No. 1 gelatin filled hollow capsules.

[0369] 上述方法制备的胶囊,其干燥失重为0.692 %,在水中崩解时间为4分钟,在pH 1.2、?!14.0、?!16.8以及水中的15分钟的溶出度均大于90%。 Capsules prepared in [0369] the above-described method, the loss on drying was 0.692%, the disintegration time of 4 min in water at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 90%.

[0370] 稳定性数据见表8。 [0370] The stability data are shown in Table 8.

[0371] 表8 [0371] TABLE 8

[0372] [0372]

Figure CN105476976BD00272

[0374] 实施例40 [0374] Example 40

[0375] 环丝氨酸占总量64.1 %,环丝氨酸含量99.713 %,环丝氨酸与辅料一起流化床制粒60〜80目,溶剂为乙醇,粘合剂用量占总量1.0 %,粘合剂为聚乙烯吡咯烷酮K30。 [0375] cycloserine, 64.1% of the total, the content of 99.713% Cycloserine, fluidized bed granulation with excipients cycloserine 60~80 mesh together, and the solvent is ethanol, 1.0% of the total amount with an adhesive, binder polyvinylpyrrolidone K30.

[0376] 处方: [0376] Prescription:

[0377] [0377]

Figure CN105476976BD00281

[0378]制备方法: [0378] Preparation:

[0379] 将处方量的聚乙烯吡咯烷酮K30配置成聚乙烯吡咯烷酮K30的乙醇溶液,将处方量的环丝氨酸过100目筛,再与滑石粉混匀,置于流化床中喷加聚乙烯吡咯烷酮K30乙醇溶液制湿颗粒,并在流化状态下进行干燥,过60目到80目筛整粒,再将制粒后的颗粒按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。 [0379] The formulation amounts of polyvinylpyrrolidone K30 configured ethanol solution of polyvinylpyrrolidone K30, the prescribed amount of cycloserine through 100 mesh sieve, and then mixed with talc, was placed in a fluidized bed spray-adding polyvinylpyrrolidone K30 manufactured by wet granulation ethanol solution and dried in a fluidized state through a 60 mesh to 80 mesh sieve, the particles were then granulated by each capsule containing 250mg of cycloserine specification No. 1 gelatin filled hollow capsules.

[0380] 上述方法制备的胶囊,其干燥失重为0.637 %,在水中崩解时间为4分钟,在pH 1.2、 ?!14.0、?!16.8以及水中的15分钟的溶出度均大于90%。 Capsules prepared in [0380] the above-described method, the loss on drying was 0.637%, the disintegration time of 4 min in water at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 90%.

[0381] 稳定性数据见表9。 [0381] The stability data are shown in Table 9.

[0382] 实施例41 [0382] Example 41

[0383] 环丝氨酸占总量64.1 %,环丝氨酸含量99.713 %,环丝氨酸与辅料一起流化床制粒60〜80目,溶剂为乙醇,粘合剂用量占总量1.0 %,粘合剂为聚乙烯吡咯烷酮K30。 [0383] cycloserine, 64.1% of the total, the content of 99.713% Cycloserine, fluidized bed granulation with excipients cycloserine 60~80 mesh together, and the solvent is ethanol, 1.0% of the total amount with an adhesive, binder polyvinylpyrrolidone K30.

[0384] 处方: [0384] Prescription:

[0385] [0385]

Figure CN105476976BD00282

[0387]制备方法: [0387] Preparation:

[0388] 将处方量的聚乙烯吡咯烷酮K30配置成聚乙烯吡咯烷酮K30的乙醇溶液,将处方量的环丝氨酸过100目筛,再与滑石粉混匀,置于流化床中喷加聚乙烯吡咯烷酮K30乙醇溶液制湿颗粒,并在流化状态下进行干燥,过60目到80目筛整粒,再将制粒后的颗粒按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。 [0388] The formulation amounts of polyvinylpyrrolidone K30 configured ethanol solution of polyvinylpyrrolidone K30, the prescribed amount of cycloserine through 100 mesh sieve, and then mixed with talc, was placed in a fluidized bed spray-adding polyvinylpyrrolidone K30 manufactured by wet granulation ethanol solution and dried in a fluidized state through a 60 mesh to 80 mesh sieve, the particles were then granulated by each capsule containing 250mg of cycloserine specification No. 1 gelatin filled hollow capsules.

[0389] 上述方法制备的胶囊,其干燥失重为0.741%,在水中崩解时间为4分钟,在pH 1.2、 ?!14.0、?!16.8以及水中的15分钟的溶出度均大于90%。 Capsules prepared in [0389] the above-described method, the loss on drying was 0.741%, the disintegration time of 4 min in water at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 90%.

[0390] 稳定性数据见表9。 [0390] The stability data are shown in Table 9.

[0391] 实施例42 [0391] Example 42

[0392] 环丝氨酸占总量64.1 %,环丝氨酸含量99.713 %,环丝氨酸与辅料一起流化床制粒60〜80目,溶剂为乙醇,粘合剂用量占总量1.0 %,粘合剂为聚乙烯吡咯烷酮K30。 [0392] cycloserine, 64.1% of the total, the content of 99.713% Cycloserine, fluidized bed granulation with excipients cycloserine 60~80 mesh together, and the solvent is ethanol, 1.0% of the total amount with an adhesive, binder polyvinylpyrrolidone K30.

[0393] 处方: [0393] Prescription:

[0394] [0394]

Figure CN105476976BD00291

[0395]制备方法: [0395] Preparation:

[0396] 将处方量的聚乙烯吡咯烷酮K30配置成聚乙烯吡咯烷酮K30的乙醇溶液,将处方量的环丝氨酸过100目筛,再与滑石粉混匀,置于流化床中喷加聚乙烯吡咯烷酮K30乙醇溶液制湿颗粒,并在流化状态下进行干燥,过60目到80目筛整粒,再将制粒后的颗粒按每粒胶囊含环丝氨酸250mg的规格填充1号明胶空心胶囊。 [0396] The formulation amounts of polyvinylpyrrolidone K30 configured ethanol solution of polyvinylpyrrolidone K30, the prescribed amount of cycloserine through 100 mesh sieve, and then mixed with talc, was placed in a fluidized bed spray-adding polyvinylpyrrolidone K30 manufactured by wet granulation ethanol solution and dried in a fluidized state through a 60 mesh to 80 mesh sieve, the particles were then granulated by each capsule containing 250mg of cycloserine specification No. 1 gelatin filled hollow capsules.

[0397] 上述方法制备的胶囊,其干燥失重为0.608%,在水中崩解时间为4分钟,在pH 1.2、?!14.0、?!16.8以及水中的15分钟的溶出度均大于90%。 Capsules prepared in [0397] the above-described method, the loss on drying was 0.608% in water disintegration time of 4 min, at pH 1.2,?! 14.0,?! 16.8, and 15 minutes of dissolution in water is greater than 90%.

[0398] 稳定性数据见表9。 [0398] The stability data are shown in Table 9.

[0399] 表9 [0399] Table 9

[0400] [0400]

Figure CN105476976BD00292

[0402] 本发明实施例制备得到的药物组合物可应用于制备治疗结核杆菌引起的肺结核的药物中。 [0402] The pharmaceutical compositions of the present invention obtained in Preparation Example embodiments may be applied to drugs for treating tuberculosis caused by Mycobacterium tuberculosis in. 还可以应用于制备治疗精神病、抑郁症、阿尔茨海默病或慢性疼痛的药物中应用。 It may also be applied for treating psychosis, depression, Alzheimer's disease or chronic pain pharmaceutical applications.

[0403] 以上所述实施例的各技术特征可以进行任意的组合,为使描述简洁,未对上述实施例中的各个技术特征所有可能的组合都进行描述,然而,只要这些技术特征的组合不存在矛盾,都应当认为是本说明书记载的范围。 [0403] The above technical features of embodiments can be arbitrarily combined for brevity of description, not for technical features of each of the above embodiments are all possible combinations will be described, however, as long as the combination of these features is not contradiction, they are to be considered in the scope described in this specification.

[0404] 以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对发明专利范围的限制。 [0404] Expression of the above-described embodiments are only several embodiments of the present invention, and detailed description thereof is more specific, but can not therefore be understood to limit the scope of the invention. 应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。 It should be noted that those of ordinary skill in the art, without departing from the spirit of the present invention, can make various changes and modifications, which fall within the protection scope of the present invention. 因此,本发明专利的保护范围应以所附权利要求为准。 Therefore, the protection scope of the present invention should be subject to the appended claims.

Claims (9)

1. 一种药物组合物,其特征在于,该药物组合物包括环丝氨酸和辅料,所述的药物组合物的D9O粒径为75〜380μπι,所述辅料的用量占药物组合物总质量的9〜45%; 所述辅料包括滑石粉,以及粘合剂和/或可压性辅料。 1. A pharmaceutical composition, characterized in that the pharmaceutical composition comprising a cycloserine and excipients, the pharmaceutical composition of D9O particle diameter of 75~380μπι, the total mass of the materials used in an amount of a pharmaceutical composition 9 ~ 45%; the materials include talc, a binding and / or compressible materials.
2. 根据权利要求1所述的药物组合物,其特征在于,所述滑石粉的用量占药物组合物总量的9〜45%,所述粘合剂的用量占药物组合物总质量的0〜6%,所述可压性辅料的用量占药物组合物总质量的0〜16 %。 2. The pharmaceutical composition according to claim 1, characterized in that, with 9~45% of the total amount of the pharmaceutical composition of talc, the total mass of the adhesive with an amount of a pharmaceutical composition 0 ~ 6%, 0~16% by mass of the total amount of the pharmaceutical composition compressible excipients.
3. 根据权利要求1或2所述的药物组合物,其特征在于,所述辅料包括滑石粉和粘合剂, 所述滑石粉的用量占药物组合物总质量的23〜38%,所述粘合剂的用量占药物组合物总质量的0.05〜2%。 The pharmaceutical composition according to claim 1 or claim 2, wherein said adjuvant comprises 23~38% of the total mass of the talc and binder, an amount of the talc with a pharmaceutical composition, the 0.05~2 mass% of the total amount of the pharmaceutical composition with a binder.
4. 根据权利要求1或2所述的药物组合物,其特征在于,所述辅料包括滑石粉和可压性辅料,所述滑石粉的用量占药物组合物总质量的23〜38%,所述可压性辅料的用量占药物组合物总质量的8〜14%。 4. The pharmaceutical composition of claim 1 or claim 2, wherein said excipients comprising a talc, 23~38% of the total mass of the excipients and compressibility, the talcum is used in an amount of the pharmaceutical composition, the 8~14% of the total mass of said compressible excipients used in an amount of a pharmaceutical composition.
5. 根据权利要求1或2所述的药物组合物,其特征在于,所述粘合剂选自聚乙烯吡咯烷酮、羟丙甲纤维素、羟丙纤维素、乙基纤维素、甲基纤维素、羧甲基纤维素钠、羟乙纤维素、糊精中一种或几种;所述可压性辅料选自乳糖、淀粉、磷酸氢钙、微晶纤维素、甘露醇、糊精中一种或几种。 5. The pharmaceutical composition of claim 1 or claim 2, wherein said binder is selected from polyvinyl pyrrolidone, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, ethyl cellulose, methyl cellulose , sodium carboxymethyl cellulose, hydroxyethyl cellulose acetate, one or more dextrin; the compressible excipient selected from lactose, starch, dicalcium phosphate, microcrystalline cellulose, mannitol, dextrin a one or several.
6. 根据权利要求1或2所述的药物组合物,其特征在于,该药物组合物的剂型为胶囊剂, 所述胶囊剂的空心胶囊为明胶空心胶囊或羟丙甲纤维素空心胶囊,所述空心胶囊的干燥失重〈15.0%〇 6. A pharmaceutical composition according to claim 1 or claim 2, wherein the pharmaceutical dosage composition is a capsule, the capsule hollow capsules are gelatin capsules or hollow hypromellose hollow capsules, the Loss on drying of said hollow capsule <billion 15.0%
7. 权利要求1〜6任一项所述的药物组合物的制备方法,其特征在于,包括如下步骤: 将D9q粒径为75〜380μπι的环丝氨酸与辅料按所述质量百分比混合均匀,即得所述药物组合物; 或,将环丝氨酸与辅料按所述质量百分比混合,然后进行湿法制粒、干法制粒或流化床制粒,干燥,过筛整粒,即得所述药物组合物; 或,将辅料进行湿法制粒、干法制粒或流化床制粒,干燥,过筛整粒,得D9q粒径为75〜 380μπι的辅料颗粒,再与D9q粒径为75〜380μπι的环丝氨酸按所述质量百分比进行混合,即得所述药物组合物。 The method of preparing a pharmaceutical composition according to any one of claim 1~6, wherein, comprising the steps of: a particle size of 75~380μπι D9q cycloserine with excipients uniformly mixed by the mass percentage, i.e., to give the pharmaceutical composition; or the cycloserine and mixed materials according to the mass percentage, and then wet granulation, dry granulation or fluidized bed granulation, dried and sieved and sieved, to obtain the pharmaceutical composition thereof; or the auxiliary wet granulation, dry granulation or fluidized bed granulation, dried and sieved and sieved to give a particle size of D9q 75~ 380μπι excipient particles, and then with a particle size of 75~380μπι of D9q cycloserine were mixed in the mass percentage to obtain the pharmaceutical composition.
8. 根据权利要求7所述的制备方法,其特征在于,所述药物组合物的干燥失重介于0.2 〜2%之间,D90粒径介于120〜380μπι。 8. The production method according to claim 7, wherein a loss on drying of the pharmaceutical composition is between 0.2 ~2%, D90 particle size is between 120~380μπι.
9. 权利要求1〜6任一项所述的药物组合物在制备治疗结核杆菌引起的肺结核,精神病,抑郁症,阿尔茨海默病或慢性疼痛的药物中的应用。 The pharmaceutical composition of any one of claims 1~6 application in the treatment of tuberculosis caused by Mycobacterium tuberculosis preparation, psychosis, depression, Alzheimer's disease or chronic pain 9. The medicament as claimed in claim.
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