CN105708796A - Sustained release preparation containing trazodone hydrochloride oral solution and preparation method of sustained release preparation - Google Patents

Sustained release preparation containing trazodone hydrochloride oral solution and preparation method of sustained release preparation Download PDF

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CN105708796A
CN105708796A CN 201610176071 CN201610176071A CN105708796A CN 105708796 A CN105708796 A CN 105708796A CN 201610176071 CN201610176071 CN 201610176071 CN 201610176071 A CN201610176071 A CN 201610176071A CN 105708796 A CN105708796 A CN 105708796A
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preparation
medicine
solution
sustained
release
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CN 201610176071
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黄伟棠
王秋成
林虹
贾文强
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深圳市泛谷药业股份有限公司
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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
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0053Mouth and digestive tract, i.e. intraoral and peroral administration
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/10Dispersions; Emulsions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005Wall or coating material
    • A61K9/5021Organic macromolecular compounds
    • A61K9/5026Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005Wall or coating material
    • A61K9/5021Organic macromolecular compounds
    • A61K9/5036Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose

Abstract

The invention discloses a sustained release preparation containing a trazodone hydrochloride oral solution and a preparation method of the sustained release preparation. The sustained release preparation is a suspended type oral solution which is slowly released within 24 hours. The suspended oral solution contains a solution and medicine resin coating micro-capsules. The medicine resin coating micro-capsules are made from a medicine resin polymer containing deprementia type medicine and ion exchange resin and a sustained release material on the outer layer of the medicine resin polymer. By means of the preparation, medicine can be slowly released into bodies, the aims of the stable blood medicine concentration and the long efficacy time duration are achieved, a patient only needs to take the preparation once every day to achieve the treatment effect, and the preparation prepared into the suspended type oral solution can be conveniently and easily swallowed by the patient.

Description

一种含盐酸曲唑酮口服溶液的缓释制剂及其制备方法 Sustained-release preparation and preparation method of oxazolone oral solution containing tramadol hydrochloride

技术领域 FIELD

[0001] 本发明涉及医药领域,尤其涉及的是一种含盐酸曲唑酮口服溶液的缓释制剂、以及制备该含盐酸曲唑酮口服溶液的方法。 [0001] The present invention relates to the field of medicine, in particular, it relates to sustained release formulations containing trazodone hydrochloride oral solution, and a method for preparing the oral tramadol hydrochloride trazodone containing solution.

背景技术 Background technique

[0002] 抑郁症是一种患病率高、严重危害人类身心健康、具有高自杀风险的精神疾病,以显著而持久的心境低落为主要特征,由生物、社会、心理等多种因素所致。 [0002] Depression is a high prevalence of serious harm to human health, with a high suicide risk of mental illness, to a significant and persistent low mood as the main feature, the biological, social, psychological and other factors caused . 由于现代社会生活节奏的加快和强烈的竞争压力,致使抑郁症发病率逐年增加并且发病年龄日趋年轻化, 已成为危害人类身心健康的常见病。 Due to intense competition and pressure to speed up the pace of modern social life, resulting in an increased incidence of depression every year and increasingly younger age of onset, it has become a common harm to human physical and mental health.

[0003] 盐酸曲唑酮是一种非典型的四环类抗抑郁药,它能阻断5-HT(5_羟色胺)的重吸收,其代谢产物又具有拮抗5-HT的作用,从而产生抗抑郁效果。 [0003] trazodone hydrochloride is an atypical tetracyclic antidepressant, it can block 5-HT (5_ serotonin) reuptake, and its metabolites have antagonistic effect of 5-HT, to produce antidepressant effect. 由于它能选择性阻断Hl受体和αΐ肾上腺受体,从而产生明显的镇静和催眠作用。 Because it can selectively block the receptor Hl and αΐ adrenoceptor, resulting in significant sedative and hypnotic effects.

[0004] 目前国内市面上销售的盐酸曲唑酮制剂,均为普通片剂(50mg或IOOmg/片,日剂量为50-200mg),平均一天需要给药2-3次,而盐酸曲唑酮缓释片目前已经进口国内仍在临床阶段,该缓释片是由AngeIini Labopharm公司研究开发并于2010年2月在美国上市,商品名为Oleptro,上市规格有150mg和300mg。 [0004] trazodone formulation currently on the market, are ordinary tablets (50mg or IOOmg / sheet, a daily dose of 50-200mg), need to be administered 2-3 times a day on average, and trazodone hydrochloride sustained Release tablets is now imported into the country is still in the clinical phase, the sustained-release tablets was developed by the research company AngeIini Labopharm and in February 2010 in the United States, the trade name Oleptro, listed specifications are 150mg and 300mg. 由于盐酸曲唑酮具有倦睡、视力模糊、出汗、肌肉疼痛、胃肠道反应等副作用,因此缓释制剂具有很大的优势,其相对平稳的释药浓度极大减轻了上述副作用的强度,且服药方便,一天服药一次。 Since trazodone hydrochloride having drowsiness, blurred vision, sweating, muscle pain, gastrointestinal reactions and other side effects, sustained release formulations and therefore has a great advantage that a relatively stable concentration of the drug release greatly reduce the strength of these side effects and convenient medication, medication once a day.

[0005] CN101252932提供了美国上市的盐酸曲唑酮缓释片(Oleptro)处方及制备工艺,采用赋形剂羟丙基二淀酸粉磷酯(商品名Contramid)和粘合剂羟丙甲纤维素等材料来控制药物的释放。 [0005] CN101252932 provided trazodone hydrochloride sustained release tablets (Oleptro) listed U.S. formulation and preparation, using two excipients hydroxypropyl starch phosphate ester acid powder (trade name Contramid) and a binder fiber hypromellose Su and other materials to control the release of the drug. 其所使用的羟丙基二淀酸粉磷酯目前国内尚无药用级别的辅料可使用。 Two hydroxypropyl starch phosphate ester acid powder are still no they use pharmaceutical grade excipients may be used. 同时按其处方工艺所制得的缓释片子体型相对较大,不利于小孩和老人吞服使用。 At the same time their prescription process prepared sustained-release film size is relatively large, is not conducive to swallow children and the elderly to use.

[0006] CN 102935074 A提供了成都康弘药业集团股份有限公司公开的一种盐酸曲唑酮渗透栗控释片的制备方法,其控释片包含药片芯、半透膜包衣和释药孔三部分组成,其制备工艺对设备的配备和性能要求较高,同时其工艺要求的精确度对产业化的实现难度较大, 同时因其为口服固体制剂同样对有吞咽困难的年老和小孩患者的吞服服用有一定的不便。 [0006] CN 102935074 A provides one kind of music preparing trazodone hydrochloride osmotic controlled release tablets and Li Kanghong Chengdu Pharmaceutical Group Co. disclosed that controlled release tablets comprising a tablet core and a semipermeable membrane coat release hole three parts, with the preparation process of the apparatus and high performance requirements, while the accuracy requirements of the process which is difficult to achieve industry, while its oral solid formulation of the same elderly have difficulty swallowing and children swallow patients taking a certain inconvenience.

[0007] 因此,现有技术存在缺陷,需要改进。 [0007] Thus, deficiencies of the prior art, needs to be improved.

发明内容 SUMMARY

[0008] 本发明所要解决的技术问题是:提供一种一日给药一次的盐酸曲唑酮液体缓释制剂,患者每日只需服用一次即可达到治疗效果,吞咽方便容易的含盐酸曲唑酮口服溶液的缓释制剂。 [0008] The present invention solves the technical problem are: to provide a once a day administration of the sustained release trazodone hydrochloride liquid formulation, administered once-daily patient to achieve a therapeutic effect, to facilitate easy swallowing containing tramadol hydrochloride oral sustained release formulation of the oxazolone solution.

[0009] 本发明的技术方案如下:一种含盐酸曲唑酮口服溶液的缓释制剂,其为在24h内实现缓慢释放的混悬型口服溶液,混悬型口服溶液包含有溶液和药物树脂包衣微囊,药物树脂包衣微囊包括含有精神抑郁类药物和离子交换树脂的药物树脂聚合物、以及药物树脂聚合物外层的缓释材料。 [0009] aspect of the present invention is as follows: a slow release oral formulation of trazodone hydrochloride-containing solution, which is a type suspension to achieve slow release oral solution within 24h, suspension-type oral solution with the resin solution and the drug coating the microcapsules, the microcapsules comprising a drug-resin coating containing a resin polymer depression pharmaceutical drugs and the ion exchange resin, and the outer layer of sustained release pharmaceutical resin polymer material.

[0010] 应用于上述技术方案,所述的缓释制剂中,精神抑郁类药物为盐酸曲唑酮,药物树脂聚合物为曲唑酮树脂聚合物。 [0010] applied to the above aspect, the sustained release formulation, depression drugs of trazodone hydrochloride, the drug trazodone resin polymer is a polymer resin.

[0011] 应用于各个上述技术方案,所述的缓释制剂中,离子交换树脂为酸性阳离子交换树脂。 [0011] is applied to each of the above aspect, the sustained release formulation, an acidic ion exchange resin is a cation exchange resin.

[0012] 应用于各个上述技术方案,所述的缓释制剂中,离子交换树脂为粒径粉碎要求通过250目筛以上,粒径为0.1-60微米的离子交换树脂;或者,优选地,离子交换树脂为粒径粉碎要求通过150目筛以上,粒径在0.1-100微米的离子交换树脂。 [0012] is applied to each of the above aspect, the sustained release formulation, the ion exchange resin is required particle size by pulverization above 250 mesh screen, particle size of 0.1 to 60 microns ion exchange resin; or, preferably, ion exchange resin is pulverized particle size requirements by more than 150 mesh sieve, particle size of 0.1 to 100 microns ion exchange resin.

[0013] 应用于各个上述技术方案,所述的缓释制剂中,药物树脂包衣微囊的粒径为0.1-150微米,并且,药物树脂包衣微囊在混悬型口服溶液的含量为20%-60%。 [0013] is applied to each of the above technical solutions, the sustained release formulation, the particle size of the drug resin coated microcapsules 0.1 to 150 micrometers, and the content of the drug in the microcapsules suspension resin coated type of oral solution 20% -60%.

[0014] 应用于各个上述技术方案,所述的缓释制剂中,所述缓释材料为包含聚丙烯酸树脂类或乙基纤维素类的缓释材料。 [0014] is applied to each of the above aspect, the sustained release formulation, the extended release material comprising a polyacrylic acid resin or ethyl cellulose type sustained release material.

[0015] 应用于各个上述技术方案,所述的缓释制剂中,混悬型口服溶液中,其采用的溶剂为去离子水,采用的助悬剂为结合有羟丙甲纤维素类或羧甲基纤维素类或海藻酸钠或卡波姆系列中的一种或几种的阿拉伯胶或黄原胶;采用的调味剂为山梨醇或果糖类;采用的离子螯合剂为乙二胺四乙酸、乙二胺四乙酸二钠,乙二胺四乙酸二钠、二乙基三胺五乙酸二钠中的一种或任意几种的混合物;采用的酸度调节剂为盐酸或柠檬酸缓冲盐或磷酸缓冲盐类;采用的防腐剂为尼泊金类。 [0015] is applied to each of the above aspect, the sustained release formulation, oral suspension type solution, the solvent which is used is deionized water, suspending agent is used in combination with a hypromellose-based or carboxylic methyl cellulose or sodium alginate type or one or more carbomers series of gum arabic or xanthan gum; flavoring agent employed is fructose, sorbitol or the like; ion chelator used is ethylene diamine tetraacetic acid, disodium edetate, disodium edetate, disodium one kind of diethylene triamine pentaacetic acid or a mixture of any above; pH adjusting agent used is hydrochloric acid or citric acid salt buffer or phosphate buffered salts; preservative employed is parabens.

[0016] 应用于各个上述技术方案,一种制备上述任一所述含盐酸曲唑酮口服溶液的缓释制剂的方法,A:采用盐酸曲唑酮和树脂离子进行离子交换步骤,得到曲唑酮树脂聚合物;B: 采用包含聚丙烯酸树脂或乙基纤维素的缓释材料对曲唑酮树脂聚合物进行包衣,得到曲唑酮树脂包衣微囊;C:采用去离子水和曲唑酮树脂包衣微囊,制得混悬型口服溶液。 Method [0016] applied to each of the above technical solutions, a process for preparing any of the foregoing sustained-release preparation trazodone hydrochloride, the oral solutions containing, A: using trazodone hydrochloride ions and an ion exchange resin step, to give letrozole ketone resin polymer; B: using sustained-release materials comprising a polyacrylic resin or ethyl cellulose of trazodone coated resin polymer, to obtain a resin-coated microcapsules trazodone; C: deionized water and curved oxazolone resin coated microcapsules, suspension-type oral solution was prepared.

[0017] 应用于各个上述技术方案,所述的方法中,步骤B中,曲唑酮树脂包衣微囊是采用加热干燥或加热抽真空或冻干干燥步骤制成。 [0017] is applied to each of the above technical solutions, in the method, in step B, trazodone resin coated microcapsules are heated using heat or vacuum drying or freeze-drying step is made.

[0018] 应用于各个上述技术方案,所述的方法中,还包括步骤D:使用棕色聚酯瓶或玻璃瓶外加遮光纸盒对混悬型口服溶液进行包装,每个最小包装的药液体积为5~500ml。 [0018] is applied to each of the above technical solution, the method further includes Step D: Use brown polyester or glass bottles, applied to the suspension-type light-shielding tray packaging oral solution, each minimum volume of liquid packaging is 5 ~ 500ml.

[0019] 采用上述方案,本发明提供的盐酸曲唑酮的体外释放度根据原研缓释片在相同介质和溶出方法条件下的体外溶出数据确定本品Ih释放不大于30%,6h累计释放在30-55%, 12h累计释放小于80%,24h累计释放应不低于80%。 [0019] With the above embodiment, in vitro release of trazodone hydrochloride of the present invention provides the release of this product Ih vitro dissolution data of the original research sustained release tablets in the same medium and the dissolution process conditions determined in accordance with not more than 30%, 6h cumulative release 30-55%, 12h cumulative release less than 80%, 24h cumulative release should not be less than 80%. 因而能够使药物缓慢释放进入体内,达到血药浓度平稳,药效持续时间长的目的,患者每日只需服用一次即可达到治疗效果,采用制成混悬型口服溶液的制剂,患者吞咽方便容易。 It is possible to slowly release the drug into the body, to achieve stable blood concentration, long duration of efficacy purposes, only patients treated once daily to achieve a therapeutic effect, use is made of a suspension-type formulation for oral solution, facilitate swallowing easy.

附图说明 BRIEF DESCRIPTION

[0020] 图1为现有规格150mg和300mg的原研缓释片,以及实施例中实验1和实验2制备的盐酸曲唑酮缓混悬型口服溶液在相同条件的释放曲线图。 [0020] FIG. 1 is a conventional specifications 150mg and 300mg of sustained-release tablets of the original research, as well as embodiments in the same experimental conditions the release profile of FIG. 1 and 2 prepared in Experimental tramadol hydrochloride trazodone buffer type suspension oral solution.

具体实施方式 detailed description

[0021] 以下结合附图和具体实施例,对本发明进行详细说明。 [0021] The following embodiments in conjunction with accompanying drawings and specific embodiments, the present invention will be described in detail.

[0022] 本实施例提供了一种含盐酸曲唑酮口服溶液的缓释制剂,本实施例针对现有上市制剂的不足,同时根据已上市缓释制剂一日用量初步确定服用剂量含盐酸曲唑酮用量为150mg和300mg/天,以确保新制剂的有效性。 [0022] The present embodiment provides a sustained release formulation for oral administration containing a solution of trazodone hydrochloride, the present embodiment the formulation listed shortcomings of the current embodiment, while the initial daily dose is determined according to the dosage containing tramadol hydrochloride marketed sustained-release formulation oxazolone in an amount of 150mg and 300mg / day, to ensure the validity of the new formulations. 再根据盐酸曲唑酮的理化性质进行大量的制剂研究,完成了一日给药一次缓释液体混悬剂的研制工作。 Then a large number of physical and chemical properties of the formulation according to the study trazodone hydrochloride, completing a sustained release liquid suspension is administered once a day development work.

[0023] 含盐酸曲唑酮的口服液体缓释制剂,用盐酸曲唑酮溶解于蒸馏水或去离子水中溶解完全,浓度在0.1~22mg/ml,其中,优选浓度约为20mg/ml,选择粉碎过200目以上的离子交换树脂,其中,优选粉碎过300目以上的离子交换树脂,离子交换树脂优选强酸性阳离子交换树脂,按盐酸曲唑酮/离子交换树脂重量比为1: 〇. 5~1:3的量投入离子交换树脂进行加热和充分搅拌进行离子交换,其中,优选的盐酸曲唑酮/离子交换树脂的重量比为1:0.9, 优选的加热保持温度在50±5°C,最后,所得盐酸曲唑酮离子交换树脂可选择在蒸发仪器上加热烘干或者采用加热抽真空或冻干的方式去除水分,最后制得盐酸曲唑酮树脂聚合物。 [0023] Oral liquid preparations containing sustained release of trazodone, trazodone hydrochloride by dissolving in distilled or deionized water and completely dissolved at a concentration of 0.1 ~ 22mg / ml, wherein preferably a concentration of about 20mg / ml, selected pulverization upwards of 200 mesh ion exchange resin, wherein preferably pulverized or more 300 mesh ion exchange resin, the ion exchange resin is preferably a strongly acidic cation exchange resin, according to trazodone / ion exchange resin weight ratio of 1: square 5 ~ 1: the quantity of ion-exchanged resin was heated and stirred sufficiently ion exchange, wherein the preferred trazodone hydrochloride / ion exchange resin weight ratio of 1: 0.9, preferably heated keeping the temperature at 50 ± 5 ° C, Finally, the resulting trazodone hydrochloride ion exchange resin selectively heating it or by heating and drying or vacuum freeze-dried to remove moisture on the evaporator apparatus, to obtain the final trazodone hydrochloride resin polymer.

[0024] 控制盐酸曲唑酮树脂聚合物的水分在0.1~6%,其中,优选控制盐酸曲唑酮树脂聚合物的水分在〇. 5-3%,盐酸曲唑酮树脂包衣微囊含量控制在20-65%之间,优选地,盐酸曲挫酮树脂包衣微囊含量控制在45 ± 10%。 [0024] moisture control trazodone hydrochloride resin polymer in 0.1 to 6%, wherein the control trazodone hydrochloride resin polymer in water is preferably square. 5-3%, the content of the microcapsule coating resin trazodone hydrochloride controlled between 20-65%, preferably tramadol hydrochloride setback ketone resin coated microcapsules content is controlled to 45 ± 10%. 盐酸曲唑酮树脂包衣微囊的粒径应不大于100um〇 Trazodone hydrochloride resin coated microcapsule particle size not greater than 100um〇

[0025] 所得盐酸曲唑酮树脂聚合物是采用含有聚丙烯酸树脂或乙基纤维素的缓释材料的95%乙醇溶液进行包衣,其中聚丙烯酸树脂可选型号包括聚丙烯酸树脂II、聚丙烯酸树脂III、聚丙烯酸树脂IV,也包括采用EUDRAGI'T®系列的材料进行包衣,包衣方式可采用喷雾干燥法或空气悬浮包衣法。 [0025] The resulting resin polymer trazodone is the use of 95% ethanol solution containing a sustained release material, or a polyacrylic resin coated ethylcellulose, polyacrylic acid resin wherein the polyacrylic acid resin available models II, polyacrylic acid resin III, IV polyacrylic acid resins, also comprising using series EUDRAGI'T® coated material, coating process embodiment using spray drying or air suspension coating method. 其中喷雾干燥法是将药物树脂直接分散于丙烯酸树脂或乙基纤维素的乙醇溶液中,乙醇溶液中可加入适量的增塑剂、抗粘剂和消泡剂,在惰性的热气流中雾化、干燥,使溶解囊材的溶剂迅速蒸发,将盐酸曲唑酮树脂聚合物包囊,得到近似球形的自由流动的干燥粉末。 Spray dry method wherein the drug is dispersed in acrylic resin directly or ethyl cellulose in ethanol, the ethanol solution may be added an appropriate amount of plasticizer, and an antifoaming agent, an inert hot gas stream in atomized in , dried, the solvent evaporates rapidly dissolve the balloon material, the trazodone hydrochloride polymer resin encapsulated, and dried to give a free flowing powder substantially spherical.

[0026] 而空气悬浮包衣法则首先利用垂直强气流将载药树脂聚合物悬浮于流化室内,将丙烯酸树脂或乙基纤维素含增塑剂的乙醇溶液喷雾附于树脂表面,其中,乙醇溶液中可加入适量的增塑剂、抗粘剂和消泡剂,热气流很快将溶剂蒸发,缓释材料囊材在药物树脂表面沉积成膜,于45±5°C温度下干燥即得盐酸曲唑酮树脂微囊。 [0026] First, the air suspension coating using the law of strong vertical airflow medicated resin polymer is suspended in the fluidizing chamber, an acrylic resin or ethyl cellulose by spraying an ethanol solution containing the plasticizer is attached to the resin surface, wherein the alcohol the solution may be added an appropriate amount of plasticizer, and an antifoaming agent, hot air will soon solvent was evaporated, the drug delivery material in the balloon material forming the resin deposited on the surface, at a temperature of 45 ± 5 ° C and dried to obtain trazodone hydrochloride resin microcapsules. 上述两种方法需控制乙醇残留限度,并最终控制乙醇残留不超过0.2%。 Both methods required control limits residual ethanol, and ultimately control the residual ethanol is not more than 0.2%. 测定盐酸曲唑酮树脂聚合物的包衣微囊含量应在18 ~65%。 Determination of trazodone hydrochloride microcapsules coated resin polymer content should be 18 to 65%.

[0027]最后制备混悬型口服溶液: [0027] Preparation of the final suspension type oral solution:

[0028]往容器一定量的去离子水中加入适量的吐温80和聚山梨醇或果糖使其溶解,再加入适量的药物树脂聚合物包衣微囊,充分浸渍,备用。 [0028] To the container a quantity of deionized water was added small amount of Tween 80 and polysorbate or fructose dissolved, then add an appropriate amount of drug resin polymer coating the microcapsules, sufficiently impregnated, the standby.

[0029] 往容器二定量的去离子水中加入金属螯合剂搅拌溶解、再加入抑菌剂搅拌或加热使其充分溶解或分散,最后再加入助悬剂使其充分溶胀,备用。 [0029] To quantify the two containers of deionized water and stirred to dissolve the metal chelating agent, bacteriostatic agent was added with stirring or heating to fully dissolve or disperse, then add a suspending agent sufficiently swollen standby.

[0030] 往容器三种定量的去离子水中加入酸度调节剂,搅拌使其充分溶解,备用。 [0030] To quantify the container three kinds of deionized water was added acidity adjusting agent, stirring to fully dissolve standby.

[0031] 将容器一中溶液缓缓加入容器二中搅拌均匀,再将容器三中溶液缓慢加入容器二中,控制药液最终pH在3.0~5.0,摇匀后测定沉降体积比,应满足要求,从而制得混悬型口服溶液。 [0031] The vessel was slowly added a solution vessel Stir II, III and then the container was slowly added to the vessel in two, the control liquid final pH 3.0 to 5.0, after shaking was measured sedimentation volume ratio, should meet the requirements , thereby preparing a suspension-type oral solution.

[0032] 体外溶出试验是筛选处方确定工艺的重要手段,而且对制剂的质量控制有着重要作用。 [0032] In vitro dissolution test screening formulation is an important means to determine the process, but also for quality control of plays an important role. 本实施例采用经脱气处理的900ml 0.15mol/l NaCl为释放介质转速50r/min,温度37 °C。 This embodiment employs degassed treated 900ml 0.15mol / l NaCl as release medium speed 50r / min, a temperature of 37 ° C. 根据中国药典2015版四部0931项第二法(桨法)操作,分别于1,2,3,6,8,12,24h取样IOml,经0.45μπι微孔滤膜滤过,弃去初滤液,取续滤液备用,及时补加同温度,同体积的相应介质,将续滤液于311nm处测定吸光度,根据标准曲线计算不同时间样品液浓度,考察24小时的累计释放量与时间的关系,其中,原研缓释片150mg和300mg、以及本实施例的实验1和实验2的释放数据如表一所示。 According to China Pharmacopoeia 2015 Edition 0931 four second method (paddle method) operation, respectively 1,2,3,6,8,12,24h sampling IOml, by 0.45μπι microporous membrane filtration, the filtrate was discarded early, filtrate taken standby, additional time at the same temperature, the same volume of the respective medium, to the filtrate at 311nm absorbance was measured at different time sample concentration calculated from the standard curve, look at the relationship with the 24-hour cumulative release time, wherein, original research and sustained release tablets 150mg 300mg, according to the present embodiment and the experimental embodiment 1 and 2 experimental release data as shown in table.

[0033] 本实施例供的盐酸曲唑酮的体外释放度根据原研缓释片在相同介质和溶出方法条件下的体外溶出数据确定本品Ih释放不大于30%,6h累计释放在30-55%,12h累计释放小于80%,24h累计释放应不低于80%。 [0033] The present embodiment vitro release of trazodone hydrochloride according to the in vitro dissolution data for the original research sustained release tablets in the same dissolution medium and determining the product of the process conditions Ih release not more than 30%, 6h The cumulative release at 30-55 %, 12h cumulative release less than 80%, 24h cumulative release should not be less than 80%. 因而能够使药物缓慢释放进入体内,达到血药浓度平稳,药效持续时间长的目的。 It is possible to slowly release the drug into the body, to achieve stable blood concentration, long duration of efficacy purposes.

[0034] 将按照本发明制成的盐酸曲唑酮缓释制剂进行了高温、高湿、光照实验,结果表明本品在高温、高湿、光照、条件下,稳定性较好。 [0034] The follow trazodone hydrochloride sustained-release preparation of the present invention is made of high temperature, humidity, light experimental results show that the product under high temperature, high humidity, lighting conditions, good stability.

[0035] 实验1: 盐酸曲唑酮2.7g AMBERLITEIRP69 3.0g 乙战纤维素0 04g [0035] Experiment 1: trazodone hydrochloride 2.7g AMBERLITEIRP69 3.0g 0 04g cellulose acetate war

[0036] PEG4000 0.8g PEG400 0.08g 95%乙醇适量 [0036] PEG4000 0.8g PEG400 0.08g 95% Ethanol q.s.

[0037] 曲唑酮树脂聚合物的制备:先将聚乙烯苯磺酸阳离子交换树脂AMBERLITE IRP69 粉碎过300目筛,盐酸曲唑酮/聚乙烯苯磺酸阳离子交换树脂AMBERLITE IRP69按0.9:1重量比的量,将盐酸曲唑酮加入适量(按主药溶解浓度20mg/ml计算加水)的去离子水,搅拌溶解,在搅拌下再加入AMBERLITE IRP69阳离子交换树脂混匀,定时取样,测定溶液中药物的浓度。 [0037] Preparation of trazodone resin polymer: first polyethylene sulfonic acid cation exchange resin AMBERLITE IRP69 sifted through a 300 mesh sieve, trazodone hydrochloride / polyvinyl sulfonic acid cation exchange resin AMBERLITE IRP69 by 0.9: 1 wt. quantity ratio of the trazodone hydrochloride was added an appropriate amount (by primary drug dissolved concentration of 20mg / ml is calculated by adding water) in deionized water, stirred and dissolved under stirring added AMBERLITE IRP69 cation exchange resin mix regular sampling, assay solution concentration of the drug. 当药物浓度不再随时间而变化时即待达到平衡,用去离子水洗去树脂表面的未结合药物,在40 °C -60 °C干燥即得载药树脂。 When the drug concentration is no longer changes with time until equilibrium is reached i.e., the surface of the resin with deionized water to unbound drug at 40 ° C -60 ° C and dried to obtain drug-loaded resin.

[0038]曲唑酮树脂聚合物的包衣:将上述干燥的载药树脂加入乙基纤维素含PEG4000和PEG400增塑剂的95%乙醇溶液(乙基纤维素浓度约:4% )中,搅拌均匀,将药物树脂混悬液栗入喷雾干燥器中包衣,得到药物树脂缓释微粒。 [0038] Trazodone coating resin polymer: The above drug-loaded resin was dried ethylcellulose containing PEG4000 and PEG400 95% ethanol solution of a plasticizer (ethylcellulose concentration of about: 4%), the stir the suspension Li drug resin coating into a spray dryer, to obtain a sustained release drug-resin particles. 进风温度控制在45±5°C。 Inlet air temperature was controlled at 45 ± 5 ° C. 制得盐酸曲唑酮树脂聚合物包衣微囊,测定其主药含量约为38.68%。 Trazodone hydrochloride obtained resin polymer coating the microcapsules, which measured about 38.68% of the main drug content. 曲唑酮树脂包衣微囊(含-y: 38.68%) 3.88g 吐温80 0.005g 阿拉伯胶12.5g 山梨醇BOg Trazodone resin coated microcapsules (containing -y: 38.68%) 3.88g Tween 80 0.005g acacia 12.5g sorbitol BOg

[0039] K15M 4g 尼泊金甲酯(Mg: 盐酸0.04ml 总计100mL. [0039] K15M 4g methyl paraben (Mg: 0.04ml hydrochloric total 100mL.

[0040] 混悬型口服溶液的制备:往容器一定量,约50%的水量的去离子水中加入适量的吐温80和聚山梨醇微热使其溶解,再加入适量的药物树脂聚合物包衣微囊,充分浸渍,备用。 [0040] Preparation of the suspension-type oral solution: the container to a certain amount, approximately 50% of the water deionized water was added the appropriate amount of Tween 80 and polysorbate micro heat to dissolve, then add an appropriate amount of drug resin polymer coating clothing microcapsules, sufficiently impregnated, the standby.

[0041] 往容器二定量。 [0041] To vessel two quantitative. 约40%的水量的去离子水中加入金属螯合剂搅拌溶解、再加入抑菌剂搅拌或加热使其充分溶解或分散,最后再加入助悬剂使其充分溶胀,备用。 About 40% of the water of deionized water and stirred to dissolve the metal chelating agent, bacteriostatic agent was added with stirring or heating to fully dissolve or disperse, then add a suspending agent sufficiently swollen standby.

[0042]往容器三种定量,约10 %的水量的去离子水中加入酸度调节剂,搅拌使其充分溶解,备用。 [0042] To quantify three kinds of containers, about 10% of water deionized water was added acidity adjusting agent, stirring to fully dissolve standby.

[0043] 将容器一中溶液缓缓加入容器二中搅拌均匀,再将容器三中溶液缓慢加入容器二中,控制药液最终pH在3.0~5.0,摇勾后测定沉降体积比,应符合要求,最后得到混悬型口服溶液。 [0043] The vessel was slowly added a solution vessel Stir II, III and then the container was slowly added to the vessel in two, the control liquid final pH 3.0 to 5.0, measured after shaking hook sedimentation volume ratio, should meet the requirements Finally, to obtain a suspension-type oral solution.

[0044] 实验2: 盐酸曲唑酮3.0g AMBERLiTE IRP69 2.7g [0044] Experiment 2: trazodone hydrochloride 3.0g AMBERLiTE IRP69 2.7g

[0045] 乙基纤维素0.04g PEG4000 0.8g PEG400 0.08g [0045] ethylcellulose 0.04g PEG4000 0.8g PEG400 0.08g

[0046] 95%乙醇适量 [0046] 95% Ethanol q.s.

[0047] 曲唑酮树脂聚合物的制备:先将聚乙烯苯磺酸阳离子交换树脂AMBERLITE IRP69 粉碎过300目筛,盐酸曲唑酮/聚乙烯苯磺酸阳离子交换树脂AMBERLITE IRP69按1:0.9重量比的量,将盐酸曲唑酮加入适量(按主药溶解浓度20mg/ml计算加水)的去离子水,搅拌溶解,在搅拌下再加入AMBERLITE IRP69阳离子交换树脂混匀,定时取样,测定溶液中药物的浓度。 Preparation of [0047] Trazodone resin polymer: first polyethylene sulfonic acid cation exchange resin AMBERLITE IRP69 sifted through a 300 mesh sieve, trazodone hydrochloride / polyvinyl sulfonic acid cation exchange resin AMBERLITE IRP69 1: 0.9 by weight quantity ratio of the trazodone hydrochloride was added an appropriate amount (by primary drug dissolved concentration of 20mg / ml is calculated by adding water) in deionized water, stirred and dissolved under stirring added AMBERLITE IRP69 cation exchange resin mix regular sampling, assay solution concentration of the drug. 当药物浓度不再随时间而变化时即待达到平衡,用去离子水洗去树脂表面的未结合药物,在40 °C -60 °C干燥即得载药树脂。 When the drug concentration is no longer changes with time until equilibrium is reached i.e., the surface of the resin with deionized water to unbound drug at 40 ° C -60 ° C and dried to obtain drug-loaded resin.

[0048]曲唑酮树脂聚合物的包衣:将上述干燥的载药树脂加入乙基纤维素含PEG4000和PEG400增塑剂的95%乙醇溶液(乙基纤维素浓度约8% )中,搅拌均匀,将药物树脂混悬液栗入喷雾干燥器中包衣,得到药物树脂缓释微粒。 [0048] Trazodone coating resin polymer: in the drying of the drug containing ethyl cellulose resin was added a plasticizer PEG4000 and PEG400 95% ethanol (about 8% ethylcellulose concentration), with stirring homogeneous, the drug suspension is Li resin coating into a spray dryer, to obtain a sustained release drug-resin particles. 进风温度控制在45±5°C。 Inlet air temperature was controlled at 45 ± 5 ° C. 制得盐酸曲唑酮树脂聚合物包衣微囊,测定其主药含量约为43.56%。 Trazodone hydrochloride obtained resin polymer coating the microcapsules, which measured about 43.56% of the main drug content. 曲唑酮树脂包衣微囊(含量43.56%) 3.45g 吐温80 0.005g 两拉伯胶12,5g 山梨醇30g Trazodone resin-coated microcapsules (content 43.56%) 3.45g Tween 80 0.005g two gum arabic sorbitol 30g 12,5g

[0049] K15M 4g 尼泊金甲酯o.lg 盐酸0 04m丨总汁100mL [0049] K15M 4g o.lg acid methyl paraben 0 04m Shu 100mL total juice

[0050] 混悬口服溶液的制备:往容器一定量,约50 %的水量的去离子水中加入适量的吐温80和聚山梨醇微热使其溶解,再加入适量的药物树脂聚合物包衣微囊,充分浸渍,备用。 [0050] Preparation of oral suspension solution: the container to a certain amount, approximately 50% of the water of an appropriate amount of deionized water was added Tween 80 Polysorbate fever and dissolved, and then adding an appropriate amount of the polymer coated drug resin microcapsules, sufficiently impregnated, the standby. [0051 ]往容器二定量,约40 %的水量,的去离子水中加入金属螯合剂搅拌溶解、再加入抑菌剂搅拌或加热使其充分溶解或分散,最后再加入助悬剂使其充分溶胀,备用。 [0051] To quantify two containers, about 40% of the water, deionized water was added and stirred to dissolve the metal chelating agent, bacteriostatic agent was added with stirring or heating to fully dissolve or disperse, then add a suspending agent sufficiently swell ,spare.

[0052]往容器三种定量,约10 %的水量的去离子水中加入酸度调节剂,搅拌使其充分溶解,备用。 [0052] To quantify three kinds of containers, about 10% of water deionized water was added acidity adjusting agent, stirring to fully dissolve standby.

[0053] 将容器一中溶液缓缓加入容器二中搅拌均匀,再将容器三中溶液缓慢加入容器二中,控制药液最终pH在3.0~5.0,摇勾后测定沉降体积比,应符合要求,,最后得到混悬型口服溶液。 [0053] The vessel was slowly added a solution vessel Stir II, III and then the container was slowly added to the vessel in two, the control liquid final pH 3.0 to 5.0, measured after shaking hook sedimentation volume ratio, should meet the requirements Finally ,, oral solution resulting suspension type.

[0054] 以下表一为现有Angelini Labopharm公司研究开发的规格有150mg和300mg盐酸曲唑酮缓释片,以及本实施例中实验1和实验2制备的盐酸曲唑酮缓混悬型口服溶液的释放数据表,其释放曲线图如图1所示: [0054] The following Table 1 gives the specifications of the conventional research and development company Angelini Labopharm 150mg and 300mg trazodone hydrochloride sustained release tablets, as well as the experimental examples and the present embodiment tramadol hydrochloride prepared in Experiment 2 was suspended type oxazolone slow oral solution 1 release of the data table, which release profile shown in Figure 1:

[0055]表一: [0055] Table I:

Figure CN105708796AD00081

[0057]以上仅为本发明的较佳实施例而已,并不用于限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明的保护范围之内。 [0057] The above embodiment is only preferred embodiments of the present invention, but not intended to limit the present invention, any modifications within the spirit and principle of the present invention, equivalent substitutions and improvements should be included in the present invention. within the scope of protection.

Claims (10)

  1. 1. 一种含盐酸曲唑酮口服溶液的缓释制剂,其特征在于, 其为在24h内实现缓慢释放的混悬型口服溶液,混悬型口服溶液包含有溶液和药物树脂包衣微囊,药物树脂包衣微囊包括含有精神抑郁类药物和离子交换树脂的药物树脂聚合物、以及药物树脂聚合物外层的缓释材料。 An extended release formulation containing trazodone hydrochloride oral solution, characterized in that it is an oral solution for the realization of suspension type in the slow release 24h, suspension-type oral solution and a solution containing microcapsules coated drug-resin , resin coated medicament comprises microcapsules containing a drug polymer resin depression drugs and the ion exchange resin, and the outer layer of sustained release pharmaceutical resin polymer material.
  2. 2. 根据权利要求1所述的缓释制剂,其特征在于:精神抑郁类药物为盐酸曲唑酮,药物树脂聚合物为曲唑酮树脂聚合物。 2. A sustained release formulation according to claim 1, wherein: depression drugs of trazodone hydrochloride, the drug trazodone resin polymer is a polymer resin.
  3. 3. 根据权利要求1所述的缓释制剂,其特征在于:离子交换树脂为酸性阳离子交换树脂。 3. The sustained release formulation according to claim 1, wherein: the ion exchange resin is an acidic cation exchange resin.
  4. 4. 根据权利要求3所述缓释制剂,其特征在于:离子交换树脂为粒径粉碎要求通过250 目筛以上,粒径为0.1-60微米的离子交换树脂;或者,优选地,离子交换树脂为粒径粉碎要求通过150目筛以上,粒径在0.1-100微米的离子交换树脂。 4. The extended release formulation according to claim 3, characterized in that: the ion exchange resin particle size by pulverization in claim 250 mesh or more, a particle size of 0.1 to 60 microns ion exchange resin; or, preferably, an ion exchange resin pulverization particle size 150 mesh sieve by the above requirements, a particle size of 0.1 to 100 microns in an ion exchange resin.
  5. 5. 根据权利要求1所述缓释制剂,其特征在于:药物树脂包衣微囊的粒径为0.1-150微米,并且,药物树脂包衣微囊在混悬型口服溶液的含量为20%-60%。 5. The extended release formulation according to claim 1, wherein: the resin-coated pharmaceutical particle diameter of 0.1 to 150 micrometers microcapsules, and the drug content in the microcapsules coated resin type suspension 20% oral solution -60%.
  6. 6. 根据权利要求1所述的缓释制剂,其特征在于:所述缓释材料为包含聚丙烯酸树脂类或乙基纤维素类的缓释材料。 6. The sustained release formulation according to claim 1, wherein: said release material comprises a polyacrylic resin or cellulose-based sustained-release materials ethyl.
  7. 7. 根据权利要求1所述缓释制剂,其特征在于:混悬型口服溶液中,其采用的溶剂为去离子水,采用的助悬剂为结合有羟丙甲纤维素类或羧甲基纤维素类或海藻酸钠或卡波姆系列中的一种或几种的阿拉伯胶或黄原胶;采用的调味剂为山梨醇或果糖类;采用的离子螯合剂为乙二胺四乙酸、乙二胺四乙酸二钠,乙二胺四乙酸二钠、二乙基三胺五乙酸二钠中的一种或任意几种的混合物;采用的酸度调节剂为盐酸或柠檬酸缓冲盐或磷酸缓冲盐类;采用的防腐剂为尼泊金类。 7. The extended release formulation according to claim 1, wherein: oral solution type suspension in which the solvent used is deionized water, suspending agent is used in combination with hydroxypropyl methylcellulose or carboxymethyl celluloses cellulosic or sodium alginate or one or more series of carbomer or xanthan gum acacia; flavoring agent employed is fructose, sorbitol or the like; ion chelator used is ethylene diamine tetraacetic acid, disodium edetate, disodium edetate, disodium one kind of diethylene triamine pentaacetic acid or a mixture of any above; pH adjusting agent used is hydrochloric acid or citric acid or phosphate buffered saline buffer salts; preservative employed is parabens.
  8. 8. -种制备上述权利要求1-7任一所述含盐酸曲唑酮口服溶液的缓释制剂的方法,其特征在于,包括步骤:A:采用盐酸曲唑酮和树脂离子进行离子交换步骤,得到曲唑酮树脂聚合物;B:采用包含聚丙烯酸树脂或乙基纤维素的缓释材料对曲唑酮树脂聚合物进行包衣, 得到曲唑酮树脂包衣微囊;C:采用去离子水和曲唑酮树脂包衣微囊,制得混悬型口服溶液。 8. --containing sustained release formulations trazodone hydrochloride oral solution is prepared according to any one of the preceding claims 1-7 species claims, characterized in that, comprising the steps of: A: trazodone hydrochloride using ion ion exchange resin and the step of to give a polymer resin trazodone; B: using sustained-release materials comprising a polyacrylic resin or ethyl cellulose of trazodone coated resin polymer, to obtain a resin-coated microcapsules trazodone; C: to use DI water and trazodone resin coated microcapsules, suspension-type oral solution was prepared.
  9. 9. 根据权利要求8所述的方法,其特征在于:步骤B中,曲唑酮树脂包衣微囊是采用加热干燥或加热抽真空或冻干干燥步骤制成。 9. The method according to claim 8, wherein: step B, trazodone resin coated microcapsules are heated using heat or vacuum drying or freeze-drying step is made.
  10. 10. 根据权利要求8所述的方法,其特征在于:还包括步骤D:使用棕色聚酯瓶或玻璃瓶外加遮光纸盒对混悬型口服溶液进行包装,每个最小包装的药液体积为5~500ml。 10. The method according to claim 8, characterized in further comprising: Step D: brown polyester or glass bottles, using the light shielding applied to the suspension tray-type packaging oral solution, a minimum liquid volume of each package is 5 ~ 500ml.
CN 201610176071 2016-03-24 2016-03-24 Sustained release preparation containing trazodone hydrochloride oral solution and preparation method of sustained release preparation CN105708796A (en)

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Citations (4)

* Cited by examiner, † Cited by third party
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CN1634006A (en) * 2004-11-11 2005-07-06 沈阳药科大学 Venlafaxine hydrochloride liquid slow-release preparation and its preparation method
CN1820752A (en) * 2005-12-02 2006-08-23 深圳市制药厂 Oral liquor slow releasing preparation containing codeine and chlorophenamine and its preparing method
CN101252932A (en) * 2005-09-09 2008-08-27 莱博法姆公司;莱博法姆欧洲有限公司;莱博法姆(巴巴多斯)有限公司 Trazodone composition for once a day administration
CN103622942A (en) * 2013-11-04 2014-03-12 江苏大学 Levodopa/carbidopa compound sustained-release suspension and preparation method thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1634006A (en) * 2004-11-11 2005-07-06 沈阳药科大学 Venlafaxine hydrochloride liquid slow-release preparation and its preparation method
CN101252932A (en) * 2005-09-09 2008-08-27 莱博法姆公司;莱博法姆欧洲有限公司;莱博法姆(巴巴多斯)有限公司 Trazodone composition for once a day administration
CN1820752A (en) * 2005-12-02 2006-08-23 深圳市制药厂 Oral liquor slow releasing preparation containing codeine and chlorophenamine and its preparing method
CN103622942A (en) * 2013-11-04 2014-03-12 江苏大学 Levodopa/carbidopa compound sustained-release suspension and preparation method thereof

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