CN1333679A - 可分散的磷脂稳定的微粒 - Google Patents

可分散的磷脂稳定的微粒 Download PDF

Info

Publication number
CN1333679A
CN1333679A CN99815645A CN99815645A CN1333679A CN 1333679 A CN1333679 A CN 1333679A CN 99815645 A CN99815645 A CN 99815645A CN 99815645 A CN99815645 A CN 99815645A CN 1333679 A CN1333679 A CN 1333679A
Authority
CN
China
Prior art keywords
dosage form
water
insoluble
agent
dispersing solid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN99815645A
Other languages
English (en)
Other versions
CN1287769C (zh
Inventor
I·帕里克
A·K·米斯拉
R·敦加
M·G·瓦雄
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
RTP Pharma Corp
Original Assignee
RTP Pharma Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by RTP Pharma Corp filed Critical RTP Pharma Corp
Publication of CN1333679A publication Critical patent/CN1333679A/zh
Application granted granted Critical
Publication of CN1287769C publication Critical patent/CN1287769C/zh
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin

Abstract

一种包含以纳米或微米粒状固体存在的水不溶性化合物的快速分散固体干燥治疗剂型,所述粒状固体依靠至少存在一种磷脂进行表面稳定,所述粒状固体分散遍布于一种填充基质中。当所述剂型导入到含水环境中时,所述填充基质在不到2分钟内基本上完全溶解,由此释放出不聚集和/或不附聚状态的水不溶性粒状固体物。所述基质包括水不溶性物质或用于治疗的水不溶性或难溶于水的化合物、磷脂和任选还包括至少一种非离子、阴离子、阳离子或两亲型表面活性剂连同一种基质或填充剂,需要时还包括释放剂。所述水不溶性颗粒的容重平均粒径为5微米或以下。

Description

可分散的磷脂稳定的微粒
发明领域
本发明涉及包含约0.05-10微米尺寸的水不溶性或难溶性药物颗粒的组合物，所述药物颗粒具有吸附在其表面的表面改性剂或各种试剂(其至少一种是磷脂)的组合。所述组合物包括基质形成剂(matrix-forming agent)，其以足以可冷冻干燥和随后在与含水环境接触时释放出表面涂覆的药物颗粒的量存在。小的表面涂覆颗粒有时称为微晶(在美国专利5,091,187和5,091,188号)、微粒(WO98/07414)、毫微粒(美国专利5,145,684和5,302,401和美国专利5,145,684号)。
本发明还提供制备这种表面和基质形成剂上吸附了表面改性剂或各种试剂(其至少一种是磷脂)的组合的水不溶性或难溶性药物颗粒的干燥组合物的方法。所述基质形成剂以足以可冷冻干燥(诸如低压冻干法)和随后在与含水环境接触时释放出表面涂覆的药物颗粒的量存在。所述方法包括将所述磷脂涂覆的颗粒与基质形成剂接触一定时间并在足以让磷脂涂覆的药物颗粒冷冻干燥的条件下进行。
发明背景
水不溶性化合物的不良的生物利用度长期以来一直是制药和诊断业的一个问题。虽然认为具有大于1％(w/v)的水溶解性的化合物就不会出现溶出度相关的生物利用度和吸收的问题，但是，许多新化学品展现出比该值低得多的水溶解性(参见Pharmaceutical DosageForms-Tablets，第一卷，13页，H.Lieberman编，Marcel Dekker，Inc，1980)。由于不良的水溶性，许多高度有用的化合物不能得到有效开发或以其它不符合需要的方式配制。许多这种化合物在水介质中不稳定，一些需要在油中溶解。使得其剂型经常以时令人不愉快的摄入形式或甚至是使用起来痛苦的非经肠方式给药。这可导致不良的病人顺应性以及潜在的由于不必要的医治处理带来的总治疗费用的上升。所以需要开发这些水不溶性化合物的可以最简单的可能形式给药的剂型：快速分散的固体剂型。
制备快速分散的固体剂型药物已有许多方法。解决该问题的传统方法包括使用混合技术和/或制粒技术将生物活性成分分散于药学上可接受的赋形剂中。可使用具体为本领域人们所熟悉的功能赋形剂来辅助释放出药物，例如美国专利5,178,878中所述的泡腾崩解剂。
正如美国专利4,371,516、4,758,598、5,272,137中的所述，冷冻干燥技术先前一直作为一种改善固体剂型的崩解从而释放药物的方法使用。另外，喷雾干燥技术一直以如同美国专利5,776,491的类似目的使用，所述专利描述了聚合物组分、加溶组分和填充剂(bulkingagent)作为在喷雾干燥中的基质形成组分的用途。这种颗粒基质在导入到含水环境时快速崩解释放出药物。虽然这些方法产生快速释放药物的剂型，但是它们具有许多缺点，水不溶性或难溶于水的药物尤其如此。在这种情况下，水不溶性化合物的悬浮液可能在完成冷冻干燥或喷雾干燥处理前沉降而导致颗粒聚集和潜在不均匀的干燥剂型。另外，当用作基质形成剂时以葡聚糖为代表的多糖大分子与重新溶解的(reconstituted)冷冻干燥的脂质体的悬浮液的聚集倾向有关(Miyajima，1997)。所以，糖类基质形成剂的适当选择和使用难以确定，我们相信这与所考虑的水不溶性颗粒的表面物理化学性质有关。
另外，水不溶性化合物的悬浮液由于奥氏催熟法而产生不想要的颗粒尺寸生长。为了缩短这个过程，这些悬浮在水环境中的微粒化材料的稳定可使用本领域技术人员熟知的各种药学上可接受的赋形剂的组合物来获得。这种方法可参见例如共同授权的美国专利5,631,023和5,302,401号和EP0193208。
例如美国专利5,631,023公开了使用最大为0.05％(重量)的黄原胶作为悬浮和絮凝剂与明胶(分散水不溶性药物颗粒)制备快速溶解片剂(10秒钟)的方法。甘露糖醇被用作优选的抗冻剂。将所述悬浮液在模中冷冻干燥而形成固体剂型。
在美国专利5,302,401中，描述了在低压冻干时降低粒径生长的方法。其公开了含有具有吸附在表面的表面改性剂的颗粒与抗冻剂的组合物，抗冻剂存在的量足以形成毫微粒-抗冻剂组合物。一种优选的表面改性剂是聚乙烯基吡咯烷酮，优选的抗冻剂是碳水化合物如蔗糖。还公开了制备具有吸附在表面的表面改性剂以及相伴的抗冻剂的颗粒的方法。该专利具体以5％Danazol与1.5％PVP和蔗糖(2％)或甘露糖醇(2％)作为抗冻剂。这样虽然各种抗冻剂均适用并且足以在低压冻干时起到保护活性剂的作用，但是得到的固体产物常常难以在水介质中重新分散。
EP0193208描述了低压冻干试剂涂覆的胶乳颗粒而可在没有聚集的情况下重新溶解(reconstitution)的方法，并且讨论了混入两性离子缓冲剂诸如氨基酸、稳定剂诸如PVP或牛血清清蛋白(bovinealbumin)和抗冻剂诸如Dextran T10或其它多糖的需要。本发明简述
本发明涉及通过具体选择为恢复初级颗粒所需的赋形剂和方法改善微化颗粒的分散性。该方法的本质是产生水不溶性或难溶于水的化合物的微粒和亚微粒的稳定水悬浮液的能力。在本发明的实施中所需的这些颗粒可按照美国专利5,091,187和5,091,188以及WO98/07414公开的方法制备，这些专利的公开通过引用并入本文。简要地说，水不溶性或难溶于水的化合物在表面改性剂或各种试剂(其至少一种为吸附在所述颗粒表面的磷脂)的组合物的存在下分散在水介质中。当前述悬浮液使用本领域人们熟悉的各种方法处理施加应力时发生颗粒破碎，所述方法包括但不限于声裂法、碾磨、均化、微流化、和反溶剂和溶剂沉淀。这样制备的颗粒称为微粒，在此将其定义为具有从纳米到微米的标称直径的不规则、非球形或球形的固体颗粒，在其上面吸附了至少一种表面改性剂并且其中一种为磷脂。
根据本发明，这样制备的微粒悬浮液与表面改性剂和域基质形成剂进一步混合，所述试剂的量足以容许进行冷冻干燥和随后在与水环境接触时释放出表面涂覆的药物颗粒。这些组分的选择用于最大程度地降低微粒在干燥时集聚的倾向。由于这种聚集体具有非常高的表面积而使接触的程度达到使颗粒相互作用形成不可逆晶格，因而这种聚集体极难重新分散。
为了最大程度增加表面积、生物利用度和溶出度，在药剂开发中通常需要具有小粒径的药物。在上述方法中适合的介质形成剂的导入用于在冷冻干燥处理时和在通过抑制任何颗粒附聚或颗粒生长的倾向得到的冷冻干燥产物中稳定磷脂涂覆的药物颗粒。
本发明的描述
本发明提供用于水不溶性化合物的快速崩解固体剂型，其释放出用一种或多种表面改性剂(包括但不限于磷脂)稳定的初级粒子。一些优选的水不溶性药物的例子包括防真菌剂、免疫抑制剂和免疫活性剂、抗病毒剂、抗瘤剂、镇痛剂和消炎剂、抗生素、抗癫痫药、麻醉剂、安眠药、镇静剂、抗紧张剂、神经弛缓药、抗抑郁剂、抗焦虑剂、抗惊厥剂、拮抗剂、神经元阻断剂、抗胆碱能药和拟胆碱药、抗毒蕈碱剂和毒蕈碱剂、肾上腺素能阻断剂和抗心律不齐药(antarrhythmics)、抗高血压药、激素和营养素。这些药物的详细说明可参见1990年Mack Publishing Co.，PA 18版的Remington’sPharmaceutical Sciences。在水悬浮液中所述水不溶性成分的浓度可为0.1-60％(重量)，优选为5-30％(重量)。
首先将水不溶性化合物在一种或多种表面稳定剂的存在下制备成水悬浮液，其中至少一种表面稳定剂是磷脂。所述磷脂可以是天然磷脂或合成磷脂，包括但不限于磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰丝氨酸、磷脂酰肌醇、磷脂酰甘油、磷脂酸、溶血磷脂、卵磷脂或大豆磷脂或其组合。所述磷脂可以成盐、脱盐、氢化或部分氢化或可以是天然、半合成或合成的。在水悬浮液中磷脂成分的浓度可在0.1-90％(重量)、优选0.5-50％(重量)和更优选1-20％(重量)范围内。
一些适用的第二和附加表面改性剂的例子包括：(a)天然表面活性剂诸如酪蛋白、明胶、天然磷脂、西黄蓍胶、蜡、微囊树脂(entericresins)、石蜡、阿拉伯胶、明胶和胆固醇，(b)非离子表面活性剂诸如聚氧乙烯脂肪醇醚、脱水山梨醇脂肪酸酯、聚氧乙烯脂肪酸酯、脱水山梨醇酯、甘油单硬脂酰酯、聚乙二醇、鲸蜡醇、十六醇十八醇混合物、十八醇、聚羟体、polaxamines、甲基纤维素、羟基纤维素、羟丙基纤维素、羟丙基甲基纤维素、非结晶纤维素和合成磷脂；(c)阴离子表面活性剂诸如月桂酸钾、硬脂酸三乙醇胺、月桂基硫酸钠、烷基聚氧乙烯硫酸盐、藻酸钠、二辛基磺基琥珀酸钠、负电荷磷脂(磷脂酰甘油、磷脂酰肌醇、磷脂酰丝氨酸、磷脂酸和它们的盐)、和负电荷甘油酯、羧甲基纤维素钠和羧甲基纤维素钙；(d)阳离子表面活性剂诸如季铵化合物、苯扎氯铵(benzalkonium chloride)、十六基三甲基溴化铵和月桂基二甲基苄基氯化铵；(e)胶态粘土诸如膨润土和V字胶。这些表面活性剂的详细说明可参见1990年Mack PublishingCo.，PA 18版的Remington’s Pharmaceutical Sciences和1986年Lachman等人的Theory and Practice of Industrial Pharmacy。在水悬浮液中附加表面活性剂的浓度为0.1-90％(重量)、优选0.5-50％(重量)并更优选1-20％(重量)。这些表面活性剂根据表面活性剂的性质、浓度和数目可在配料初加入或在冷冻干燥前的后处理加入或结合两种情况加入。
得到的粗分散体基本上易于使用包括剪切、挤压、搅拌和/或空化的传统的混合方法将表面活性剂分散于整个水介质中。对本发明公开来说，所述粗分散体被称为预混合物。
然后将所述预混合物进行促使颗粒粉碎的处理，所述处理包括但不限于声裂法、碾磨、均化、微流化和反溶剂和溶剂沉淀。磨碎时间可不同并且取决于药物的物理化学性质、表面活性剂的物理化学性质和所选的磨碎方法。例如，可使用以使用设备如APV Gaulin E15，Avestin C50或MFIC微流化器M110EH为代表的高压均化方法。在该方法中，在没有显著牺牲药物和/或表面活性剂稳定性的压力和温度下，预混合物中的颗粒尺寸得到了降低。适合的处理压力为约2000-30,000psi，优选约5,000-20,000psi，更优选约10,000-18,000psi，适合的操作温度为约2-65℃，更优选10-45℃。处理的流体循环通过均化室，在这种方式下以确保整个流体掺和物分散均化而得到微米或亚微米颗粒的均匀悬浮液。使用基于激光衍射的仪器MalvernMastersizer Microplus测得所得到的悬浮治疗剂的平均容重粒径为0.05-10微米，优选为0.2-5微米。
然后将得到的通过一种或多种表面改性剂稳定的微粒的均匀悬浮液与基质形成填充剂和/或释放剂(干燥或水溶液形式)混合并然后干燥。所述填充剂或基质形成剂提供了药物颗粒包埋或保留在其中的物质。释放剂有助于与水介质接触时基质的崩解。选择填充剂/释放剂以便形成载体基质，其干燥后形成可快速分散的片剂，在水介质中重新溶解时释放出原级颗粒。基质形成剂/释放剂的例子包括(a)糖类和多糖诸如甘露糖醇、海藻糖、乳糖、蔗糖、山梨糖醇、麦芽糖；(b)润湿剂诸如甘油、丙二醇、聚乙二醇；(c)天然或合成聚合物诸如明胶、葡聚糖、淀粉、聚乙烯吡咯烷酮、聚羟体、丙烯酸酯；(d)无机添加剂诸如胶态硅石、三代磷酸钙和；(e)纤维素基聚合物诸如微晶纤维素、羟甲基纤维素、羟丙基纤维素、甲基纤维素。基质形成剂可在产生治疗剂的微化颗粒(配制)前加入或在冷冻干燥前的微粒均匀悬浮液形成前加入。在水悬浮液中基质形成剂的浓度可在0.1-90％(重量)、优选0.5-50％(重量)并更优选在1-20％(重量)之间变化。
所制备的水悬浮液可使用本领域人们熟悉的几种方法干燥。喷雾干燥、喷涂和冷冻干燥是其中最常用的方法。表1中引用的例子均使用冷冻干燥作为干燥方法，但并无意只限于使用冷冻干燥法。优选的冷冻干燥法涉及减压下从水悬浮液介质升华掉冷冻水的低压冻干法。这种悬浮液的低压冻干可在适合的容器诸如玻璃瓶、敞口盘、单位剂型模(unit dosage form molds)中进行或者原位喷雾在载体上。低压冻干处理的一个例子是将所制备的含基质形成剂的微粒悬浮液分布于不锈钢托盘上，而所述托盘置于在压力分级的密封室中温度保持在5℃的预平衡架上。然后将制备的悬浮液以5到50℃/分钟的速率降温直到所有悬浮液介质完全固化。由于不同界面(架-托盘-液体)之间的能耗，这种方法只使用中等温度梯度。一般情况下，通常在-50℃下冷冻1厘米的稀水悬浮液的时间为40-90分钟。低压冻干室外的冷冻也可如下进行：(a)在冷却的板上冷冻，例如在盘上冷冻或者在冷却转鼓上以小颗粒的形式冷冻，(b)滴加于液氮或一些其它的冷却液体中，(c)与液体CO2或液氮共喷雾，或(d)用循环冷空气冷冻。
对于进行连续冷冻干燥需要单独冷却。通过将溶液滴加到液氮中产生小颗粒的设备的商品如Cryopelprocess(Buchmuller andWeyermanns，1990)。如果产物需要在无菌条件下处理(如在制备可注射的干燥制剂的情况)，在冻干室内直接冷冻是有益的。
将这样获得的固化制备的悬浮液在这种温度下保持2小时的时间以确保全部结晶完全。在室内的压力降低到约5mm Hg、并优选约0.1mm Hg的压力。冷冻水的升华通过将低压冻干器的架温度提高到约-30到-10℃并将材料在该温度下保持约20小时直到完成初步干燥阶段来达到。干燥时间取决于许多因素，其中一些因素相当恒定并且大致为如冰的升华热、冷冻悬浮液的导热性和传质系数。其它因素如室内的温度和压力则可有大的差异。可进一步提高架的温度将来进行按照样品的组成所必需的第二步干燥。
当室的条件回到周围条件时，从低压冷冻循环收获材料。所收获的干燥材料可通过粗磨操作来便于处理或进一步与其它赋形剂的共混，而这种处理或共混是得到所需固体剂型所必需的。所述赋形剂可包括用于压制的制片助剂、硬明胶包囊的助流剂和用于干粉吸入剂的分散剂。
用于本发明的基质形成剂必须在与含水环境接触时能溶解或分散并释出磷脂涂覆的治疗剂颗粒。一旦重新溶解生，产物变成具有与预干燥悬浮液相同分散程度的悬浮体，优选聚集的初级颗粒不多于20％(重量)并更优选不多于10％(重量)，理想下少于1％(重量)(通过本领域人们熟悉的粒度分析和显微方法来揭示)。令人惊异的是，按照本发明制备的冷冻干燥悬浮液可在延长的时间下存贮(甚至在高温和高湿下)，而在重新溶解时不会有这种再分散性性能的损失并因此基本没有颗粒聚集。按照此中的实施例6-10的组成制备的冷冻干燥悬浮液可在室温下存贮至少60天，表明可与药剂适用期一致的时间内长期存贮。
将按照本发明制备的固体剂型材料定义为拥有快速分散的性能。这种性能等同于源于本发明的冷冻干燥饼在置于含水介质中(相当于药剂给药于体内系统的情况)完成崩解所需的时间。崩解时间可通过体外试验如观察在37℃水中的崩解时间来测量。将药剂材料浸没于水中，没有强加的搅拌，记录所观察到的材料基本分散所需的时间。在本文中定义的“快速”是指崩解时间少于2分钟，优选少于30秒钟并最优选少于10秒钟。
活性成分的溶出速度或释放速率也可受到药剂性能和微粒组成的影响，从而使药剂成为快释(5-60秒钟)、中释(15分钟崩解大约75％)或缓释。
在某些情况下，目视显微观察或扫描电子显微照片可能显示有颗粒聚集体的存在，但是这些颗粒是小粒径颗粒并且包括初始预冷冻干燥悬浮液颗粒的聚集体。这些聚集体易于被低水平能量如短时间的声裂法或物理搅拌分散并因此显示了本发明的关键特征，即防止粒径的增长和不可逆聚集和/或附聚。
实施例
通过表1所归纳的实施例举例说明了本发明的快速分散的固体药剂。在该表中所示的组成均以干燥产物的重量百分数计。应理解可在均化步骤或干燥步骤前将填充剂加入悬浮体中。
表1.组成(％(重量))和固体剂型实施例的属性
制剂编号 磷脂     附加表面活性剂 活性成分 填充剂 性质
E80  P100H  Myrj52  PVP17  NaDeox  吐温80  CyA  ITR  FEN 类型  量 类型   量 崩解时间(sec) 低压冻干前粒径(微米) 低压冻干后粒径(微米)
 1 -  -  -  -  -  -  33  -  -  LAC  67  - -   5  10.6  13.3
 2 -  -  -  -  -  -  62.5  -  -  PVP17  37.5  - -   5  10.2  17.4
 3 -  -  4.6  -  1.1  -  23  -  -  MAN  5.5  LAC 46  60  0.66  48.9
 4 23.1  -  -  -  -  -  -  -  76.9  -  -  - -  ＞2min  0.91  85.50
 5 -  5.6  -  -  -  5.6  -  -  27.8  MAN  61.0  - -  10  0.97  6.73
 6 9.1  -  -  -  -  -  -  -  33.3  SUC  45.5  SOR 15 1   5  0 97  0.98
 7 11.1  -  -  -  -  -  -  27.8  -  TRE  33.3  LAC 27.8   5  1.15  1.15
 8 15.4  -  -  -  -  -  -  38.4  -  TRE  46 2  - -   5  1.15  1.12
 9 -  8.4  4.2  -  1.0  -  21.1  -  -  MAN  23.2  LAC 42.1  15  0.92  1.33
 10 -  11.9  6.0  17.9  1.5  -  29.9  -  -  MAN  32.8  - -   5  0.91  1.08
符号和注释：
CyA＝环孢菌素；E80＝脂质体E80；FEN＝非诺贝特；ITR＝伊曲康唑；MAN＝甘露糖醇；NaDeox＝脱氧胆酸钠；P100H＝Phospholipon 100H；PVP17＝聚乙烯吡咯烷酮；SOR＝山梨糖醇；SUC＝蔗糖；TRE＝海藻糖
上表所示的制剂1和2说明从这些组成合物获得可重新溶解的颗粒，表明颗粒的较大尺寸(约10微米)很少带来聚集方面的问题。这些较大的颗粒易于通过传统的颗粒破碎技术获得。但是，为了明显影响生物利用度，需要尺寸上小一数量级的颗粒。这些颗粒使用美国专利5,091,187号和5,091,188号所描述的生产微晶的方法、WO98/07414号所描述的生产微粒的方法和美国专利5,145,684、5,302,401和5,145,684号所描述的生产毫微晶体的方法来获得。为了恢复初始的悬浮体颗粒，源于这些组合物的颗粒需要具体选择赋形剂和操作条件。实施例3到5说明当如美国专利5,302,401中所述的那样使用常规的冷冻干燥抗冻剂诸如乳糖或PVP17时某些微粒组合物并不适当地重新溶解。对于这些实施例来说，形成了包括黏附的初级颗粒的大聚集体。
实施例6到10说明初始悬浮体颗粒在干燥粉末重新溶解时容易快速地恢复而无需额外搅拌。这些实施例需要小心选择也可用作抗冻剂以及润湿剂的填充剂，诸如制剂8中的海藻糖和制剂10中的甘露糖醇。
或者，当单种基质形成填充剂并不适合时(如在蔗糖的情况下)，所述组合物可包括选自药学上可接受的试剂诸如蔗糖、海藻糖、甘露糖醇、山梨糖醇或乳糖的填充剂的混合物。实施例制剂6、7和9中说明了这种类型的组合物。在图6和7各自显示了非诺贝特制剂6在低压冻干/重新溶解步骤前后的容重粒径分布轮廓。该实施例证明在低压冻干和重新溶解后粒径分布没有变化的理想方案。
无意提出任何具体理论解释，可猜测填充剂混合物的组分可同时用于抑制由于包括抗冻、润湿剂作用、可分散性和其它的一种或多种机制而在低压冻干/重新溶解时的粒径增加。
当试图在干燥剂型(其包括作为表面稳定剂之一的磷脂)的重新溶解后恢复未聚集的颗粒悬浮体时，这些标准是非常重要的考虑因素。
除了上面提及的实施例组合物外，本发明的制剂可另外包括适量的pH缓中盐和pH调节剂诸如氢氧化钠和/或药学可接受的酸。磷脂化学领域技术人员熟知在低于4和高于10的pH下磷脂分子出现普遍的水解。所以，在均化前通常调节悬浮体的pH到该范围内。如果需要，可在于燥步骤前调节pH。
虽然已结合目前认为最实用和优选的实施方案描述了本发明和实施例，但是应该理解本发明并不限于所公开的实施方案，相反，本发明将覆盖在下面权利要求书的宗旨和范围内的各种修改和等同方案。

Claims (10)

1、一种包含以纳米或微米粒状固体存在的水不溶性化合物的快速分散固体治疗剂型，所述粒状固体用一种或多种表面改性剂进行表面稳定，所述表面改性剂的至少一种可为磷脂，分散遍布于填充基质(bulking matrix)中的粒状固体任选还包括干燥时构成治疗剂型的释放剂，其中当所述剂型导入到含水环境中时所述填充/释放基质在不到2分钟内基本上完全崩解，由此释放出不聚集和/或不附聚状态的水不溶性粒状固体。
2、权利要求1的快速分散固体剂型，其中所述水不溶性粒状固体组分主要由包括用于治疗的水不溶性或难溶于水的化合物的颗粒的水不溶性物质的组合物、磷脂和任选还有至少一种非离子、阴离子、阳离子或两亲型表面活性剂组成，其中所述水不溶性颗粒的容重平均粒径为5微米或以下。
3、权利要求1的快速分散固体剂型，其中所述填充/释放基质组分选自糖类、多糖、润湿剂、天然或合成聚合物、无机添加剂或纤维素基聚合物。
4、权利要求3的快速分散固体剂型，其中所述polyof、糖类或多糖为甘露糖醇、海藻糖、乳糖、蔗糖、山梨糖醇、dentrose、mulodextrose或麦芽糖。
5、权利要求3的快速分散固体剂型，其中所述润湿剂是甘油、丙二醇或聚乙二醇。
6、权利要求3的快速分散固体剂型，其中所述天然或合成聚合物是明胶、葡聚糖、淀粉、聚乙烯吡咯烷酮、聚羟体或丙烯酸酯。
7、权利要求3的快速分散固体剂型，其中所述无机添加剂为胶态硅石或三代磷酸钙。
8、权利要求3的快速分散固体剂型，其中所述纤维素基聚合物为微晶纤维素、羟甲基纤维素、羟丙基纤维素或甲基纤维素。
9、权利要求1的快速分散固体剂型，其中在含水介质中的崩解时间少于2分钟并优选少于60秒，更优选少于30秒，最优选少于10秒。
10、权利要求1的快速分散固体剂型，还含有泡腾剂、粘合剂、调味品、在所述剂型外表面的聚合物涂层、着色剂(color)或其组合。
CNB998156450A 1998-11-20 1999-11-19 可分散的磷脂稳定的微粒 Expired - Fee Related CN1287769C (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US10920298P 1998-11-20 1998-11-20
US60/109,202 1998-11-20

Publications (2)

Publication Number Publication Date
CN1333679A true CN1333679A (zh) 2002-01-30
CN1287769C CN1287769C (zh) 2006-12-06

Family

ID=22326353

Family Applications (1)

Application Number Title Priority Date Filing Date
CNB998156450A Expired - Fee Related CN1287769C (zh) 1998-11-20 1999-11-19 可分散的磷脂稳定的微粒

Country Status (24)

Country Link
US (3) US7939105B2 (zh)
EP (1) EP1133281A1 (zh)
JP (2) JP4809533B2 (zh)
KR (1) KR20010073232A (zh)
CN (1) CN1287769C (zh)
AU (1) AU767154B2 (zh)
BG (1) BG65254B1 (zh)
BR (1) BR9915738A (zh)
CA (1) CA2349203C (zh)
CZ (1) CZ20011739A3 (zh)
EE (1) EE05190B1 (zh)
HK (1) HK1042856B (zh)
HU (1) HUP0105089A3 (zh)
ID (1) ID29270A (zh)
IL (2) IL143197A0 (zh)
IS (1) IS5945A (zh)
NO (1) NO331819B1 (zh)
NZ (1) NZ511792A (zh)
PL (1) PL201578B1 (zh)
RU (1) RU2233654C2 (zh)
SK (1) SK288117B6 (zh)
UA (1) UA80652C2 (zh)
WO (1) WO2000030616A1 (zh)
ZA (1) ZA200104069B (zh)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004045619A1 (fr) * 2002-11-21 2004-06-03 Wuhan Liyuanheng Pharmaceutical Technology Ltd. Injection de poudre nanometrique de lecithine congelee et sechee d'un acide ursolique et son procede de preparation
CN102413829A (zh) * 2009-05-05 2012-04-11 埃科比奥法姆有限公司 含有磷脂纳米颗粒形式阿比朵尔的药物组合物
CN104096204A (zh) * 2014-07-23 2014-10-15 重庆大学 小儿肺咳泡腾片及其制备方法
CN104906044A (zh) * 2015-05-22 2015-09-16 广州中科蓝华生物科技有限公司 一种癸氧喹酯纳米制剂及其制备方法与应用
CN105295063A (zh) * 2015-10-15 2016-02-03 安徽山河药用辅料股份有限公司 一种表面改性微晶纤维素及其制备方法
CN110755392A (zh) * 2019-11-18 2020-02-07 扬子江药业集团广州海瑞药业有限公司 一种利伐沙班片药物组合物及制备方法

Families Citing this family (54)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6465016B2 (en) * 1996-08-22 2002-10-15 Research Triangle Pharmaceuticals Cyclosporiine particles
KR100694667B1 (ko) * 1999-12-08 2007-03-14 동아제약주식회사 생체내이용률 향상과 개인간 및 개인내 흡수 편차를감소시킨 이트라코나졸 함유 항진균성 제제
NZ522239A (en) * 2000-04-20 2004-03-26 Skyepharma Canada Inc Improved water-insoluble drug particle process
ES2372746T3 (es) * 2000-09-20 2012-01-26 Jagotec Ag Micropartículas de fibrato estabilizadas.
CA2423335C (en) * 2000-09-20 2011-03-01 Rtp Pharma Inc. Spray drying process and compositions of fenofibrate
US8586094B2 (en) * 2000-09-20 2013-11-19 Jagotec Ag Coated tablets
US8067032B2 (en) 2000-12-22 2011-11-29 Baxter International Inc. Method for preparing submicron particles of antineoplastic agents
US9700866B2 (en) 2000-12-22 2017-07-11 Baxter International Inc. Surfactant systems for delivery of organic compounds
US6663897B2 (en) 2001-02-06 2003-12-16 Dsm Ip Assets B.V. Oral itraconazole formulations and methods of making the same
JP2004523552A (ja) * 2001-02-22 2004-08-05 スカイファーマ・カナダ・インコーポレーテッド 低減した摂食−絶食効果を伴うフィブラート−スタチンの組合わせ
DE60100389T2 (de) 2001-07-11 2004-05-19 Apr Applied Pharma Research S.A. Fettlösliche Substanzen enthaltende Granulate und Verfahren zu ihrer Herstellung
GB0119480D0 (en) 2001-08-09 2001-10-03 Jagotec Ag Novel compositions
US20060003012A9 (en) 2001-09-26 2006-01-05 Sean Brynjelsen Preparation of submicron solid particle suspensions by sonication of multiphase systems
IL160570A0 (en) 2001-09-26 2004-07-25 Baxter Int Preparation of submicron sized nanoparticles via dispersion and solvent or liquid phase removal
DE10244504A1 (de) * 2002-09-25 2004-04-08 Capsulution Nanoscience Ag Schnellfreisetzende Darreichungsform mit schwerlöslichem Wirkstoff
AU2002356294A1 (en) 2002-12-13 2004-07-09 Jagotec Ag A topical nanoparticulate spironolactone formulation
ITRM20040539A1 (it) * 2004-11-02 2005-02-02 Mavi Sud S R L Preparati a base di chitina o suoi derivati per uso cosmetico o medico.
BRPI0608173A2 (pt) * 2005-02-24 2010-11-09 Elan Pharma Int Ltd composição, uso da mesma, e, método de produzir uma composição de docetaxel nanoparticulada ou análogo do mesmo
WO2007079147A2 (en) 2005-12-28 2007-07-12 Advanced Bionutrition Corporation A delivery vehicle for probiotic bacteria comprising a dry matrix of polysaccharides, saccharides and polyols in a glass form and methods of making same
US20080050450A1 (en) * 2006-06-26 2008-02-28 Mutual Pharmaceutical Company, Inc. Active Agent Formulations, Methods of Making, and Methods of Use
CA2673120C (en) 2006-12-18 2012-08-07 Advanced Bionutrition Corporation A dry food product containing live probiotic
WO2008135828A2 (en) 2007-05-03 2008-11-13 Pfizer Products Inc. Nanoparticles comprising a drug, ethylcellulose, and a bile salt
US8703204B2 (en) 2007-05-03 2014-04-22 Bend Research, Inc. Nanoparticles comprising a cholesteryl ester transfer protein inhibitor and anon-ionizable polymer
EP2162120B1 (en) 2007-06-04 2016-05-04 Bend Research, Inc Nanoparticles comprising a non-ionizable cellulosic polymer and an amphiphilic non-ionizable block copolymer
WO2008149230A2 (en) 2007-06-04 2008-12-11 Pfizer Products Inc. Nanoparticles comprising drug, a non-ionizable cellulosic polymer and tocopheryl polyethylene glycol succinate
EP2240162A4 (en) 2007-12-06 2013-10-09 Bend Res Inc NANOTE PARTICLES WITH A NON-IONIZABLE POLYMER AND AN AMIN-FUNCTIONALIZED METHACRYLATE COPOLYMER
EP2231169B1 (en) 2007-12-06 2016-05-04 Bend Research, Inc. Pharmaceutical compositions comprising nanoparticles and a resuspending material
DE102008047910A1 (de) 2008-09-19 2010-03-25 Molkerei Meggle Wasserburg Gmbh & Co. Kg Tablettierhilfsstoff auf Laktose- und Cellulosebasis
US20100159010A1 (en) * 2008-12-24 2010-06-24 Mutual Pharmaceutical Company, Inc. Active Agent Formulations, Methods of Making, and Methods of Use
EP2381929B1 (en) * 2008-12-29 2015-07-08 Samyang Biopharmaceuticals Corporation Pharmaceutical composition of lyophilized formulation and preparation method of the same
WO2010111565A2 (en) 2009-03-27 2010-09-30 Advanced Bionutrition Corporation Microparticulated vaccines for the oral or nasal vaccination and boostering of animals including fish
EP2435554B1 (en) 2009-05-26 2017-07-26 Advanced Bionutrition Corporation Stable dry powder composition comprising biologically active microorganisms and/or bioactive materials and methods of making
GB0913255D0 (en) * 2009-07-30 2009-09-02 Sisaf Ltd Topical composition
KR100980749B1 (ko) 2009-12-17 2010-09-07 삼일제약주식회사 페노피브레이트-함유 과립 및 이를 포함하는 약학 조성물
US9504750B2 (en) 2010-01-28 2016-11-29 Advanced Bionutrition Corporation Stabilizing composition for biological materials
WO2011094469A2 (en) * 2010-01-28 2011-08-04 Advanced Bionutrition Corporation Dry glassy composition comprising a bioactive material
EP2409683A1 (en) * 2010-07-06 2012-01-25 KRKA, D.D., Novo Mesto Stable aqueous formulations comprising poorly water soluble active ingredients
NZ607226A (en) 2010-08-13 2015-03-27 Advanced Bionutrition Corp Dry storage stabilizing composition for biological materials
PL221351B1 (pl) * 2012-03-14 2016-03-31 Politechnika Warszawska Sposób otrzymywania nanocząstek polisacharydowych
ES2952419T3 (es) 2012-05-11 2023-10-31 Activus Pharma Co Ltd Nanopolvo de compuesto orgánico, método de producción del mismo, y suspensión
CA2878624C (en) * 2012-08-17 2021-03-02 Smartek International Llc Preparation of desiccated liposomes for use in compressible delivery systems
US20140199439A1 (en) * 2013-01-14 2014-07-17 Sunny Delight Beverages Company Coated calcium particulates for use in beverage products
US10525057B2 (en) 2013-09-24 2020-01-07 Otsuka Pharmaceutical Co., Ltd. Method of providing aripiprazole to patients having impaired CYP2D6 or CYP3A4 enzyme function
GB201402556D0 (en) 2014-02-13 2014-04-02 Crystec Ltd Improvements relating to inhalable particles
EP3169359A4 (en) * 2014-07-18 2018-04-18 Msd Wellcome Trust Hilleman Laboratories Pvt. Ltd. An improved thermostable spray dried rotavirus vaccine formulation and process thereof
CA2967662A1 (en) 2014-11-21 2016-05-26 Biohaven Pharmaceutical Holding Company Ltd. Sublingual formulation of riluzole
EP3328215B1 (en) 2015-07-29 2021-07-07 Advanced BioNutrition Corp. Stable dry probiotic compositions for special dietary uses
SG11201809669RA (en) 2016-05-20 2018-11-29 Biohaven Pharm Holding Co Ltd Use of glutamate modulating agents with immunotherapies to treat cancer
KR20190108104A (ko) 2016-12-31 2019-09-23 바이오엑셀 테라퓨틱스 인코포레이티드 불안의 치료를 위한 설하 덱스메데토미딘의 용도
IL274532B1 (en) 2017-11-12 2024-01-01 Biohaven Pharm Holding Co Ltd Using the prodrug riluzole to treat ataxias
CN114983981A (zh) 2018-06-27 2022-09-02 比奥克斯塞尔医疗股份有限公司 含右美托咪定的膜制剂及其制造方法
BR112022000992A2 (pt) 2019-07-19 2022-06-14 Arx Llc Regimes de tratamento de dexmedetomidina não sedantes
WO2021235425A1 (ja) * 2020-05-20 2021-11-25 株式会社リコー 脂質ナノ粒子を含有する粒子及びその製造方法
CN114886856A (zh) * 2022-06-09 2022-08-12 山西辅仁恒峰药业有限公司 一种奥司他韦纳米干混悬剂的制备方法及应用

Family Cites Families (293)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US396255A (en) * 1889-01-15 Atmospheric gas-burner
DE440337C (de) 1925-09-22 1927-01-31 Zellstoff Und Papierfabrikatio Herstellung von schwefliger Saeure fuer die Sulfitlaugengewinnung
US2803582A (en) 1956-07-16 1957-08-20 Leonid S Cherney Local anesthetic composition
NL120093C (zh) 1958-07-24
US3137631A (en) 1959-12-01 1964-06-16 Faberge Inc Encapsulation in natural products
US3216897A (en) 1961-11-02 1965-11-09 Air Reduction Injectable anesthetic
US3185625A (en) * 1961-11-08 1965-05-25 Brown Ethan Allan Injectionable substances
DE1792410B2 (de) 1967-09-01 1980-03-13 Apoteksvarucentralen Vitrum Apotekareaktiebolaget, Stockholm Arzneimittelzubereitung zur intravenösen Injektion
US3981984A (en) 1968-04-01 1976-09-21 Colorcon Incorporated Color film coating of tablets and the like
US3594476A (en) 1969-05-12 1971-07-20 Massachusetts Inst Technology Submicron aqueous aerosols containing lecithin
US3937668A (en) 1970-07-15 1976-02-10 Ilse Zolle Method for incorporating substances into protein microspheres
NL7012832A (zh) 1970-08-29 1972-03-02
US3715432A (en) 1971-01-22 1973-02-06 Massachusetts Inst Technology Submicron aqueous aerosols containing lecithin
US3794476A (en) 1972-12-26 1974-02-26 Ppg Industries Inc Method for thermally tempering glass sheet by liquid quenching
GB1413186A (en) 1973-06-27 1975-11-12 Toyo Jozo Kk Process for encapsulation of medicaments
GB1472793A (en) 1974-03-28 1977-05-04 Ici Ltd Pharmaceutical compositions
US4798846A (en) * 1974-03-28 1989-01-17 Imperial Chemical Industries Plc Pharmaceutical compositions
US3965255A (en) 1974-05-01 1976-06-22 E. E. Eljim Ecology Ltd. Controlled drug releasing preparations
JPS5612114B2 (zh) 1974-06-07 1981-03-18
GB1502774A (en) 1974-06-25 1978-03-01 Nat Res Dev Immunological preparations
CH588887A5 (zh) 1974-07-19 1977-06-15 Battelle Memorial Institute
US4073943A (en) 1974-09-11 1978-02-14 Apoteksvarucentralen Vitrum Ab Method of enhancing the administration of pharmalogically active agents
US4107288A (en) 1974-09-18 1978-08-15 Pharmaceutical Society Of Victoria Injectable compositions, nanoparticles useful therein, and process of manufacturing same
JPS5186117A (en) 1975-01-27 1976-07-28 Tanabe Seiyaku Co Johoseibiryushiseizainoseiho
US4006025A (en) * 1975-06-06 1977-02-01 Polaroid Corporation Process for dispersing sensitizing dyes
JPS5231981A (en) 1975-08-18 1977-03-10 Takeda Chem Ind Ltd Microcapsule preparation method
CA1077842A (en) 1975-10-09 1980-05-20 Minnesota Mining And Manufacturing Company Albumin medicament carrier system
DE2557615C2 (de) 1975-12-20 1985-08-14 Bayer Ag, 5090 Leverkusen Neue Niclosamid-Suspensionsformulierungen
GB1523965A (en) 1976-03-19 1978-09-06 Ici Ltd Pharmaceutical compositions containing steroids
GB1578776A (en) 1976-06-10 1980-11-12 Univ Illinois Hemoglobin liposome and method of making the same
US4078052A (en) 1976-06-30 1978-03-07 The United States Of America As Represented By The Secretary Of Health, Education And Welfare Large unilamellar vesicles (LUV) and method of preparing same
GB1548022A (en) 1976-10-06 1979-07-04 Wyeth John & Brother Ltd Pharmaceutial dosage forms
US4086257A (en) 1976-10-12 1978-04-25 Sears Barry D Phosphatidyl quaternary ammonium compounds
US4320121A (en) 1976-10-12 1982-03-16 Sears Barry D Method of emulsifying cholesterol, cholesterol esters and triglyceride compounds
US4351831A (en) 1977-11-02 1982-09-28 Massachusetts Institute Of Technology Process and composition for treating disorders by administering isoxsurpine and choline
US4356167A (en) 1978-01-27 1982-10-26 Sandoz, Inc. Liposome drug delivery systems
US4235871A (en) 1978-02-24 1980-11-25 Papahadjopoulos Demetrios P Method of encapsulating biologically active materials in lipid vesicles
US4529561A (en) 1978-03-24 1985-07-16 The Regents Of The University Of California Method for producing liposomes in selected size range
US4186183A (en) 1978-03-29 1980-01-29 The United States Of America As Represented By The Secretary Of The Army Liposome carriers in chemotherapy of leishmaniasis
US4298594A (en) 1978-04-14 1981-11-03 Arthur D. Little, Inc. Xenobiotic delivery vehicles, method of forming them and method of using them
GB2026340B (en) 1978-07-03 1982-12-22 Ash P Stabilising microvesicles
US4329332A (en) 1978-07-19 1982-05-11 Patrick Couvreur Biodegradable submicroscopic particles containing a biologically active substance and compositions containing them
US4219548A (en) 1978-09-01 1980-08-26 The Procter & Gamble Company Topical anti-inflammatory composition
US4369182A (en) 1978-09-27 1983-01-18 A. Nattermann & Cie Gmbh Inflammation-preventing pharmaceutical composition of oral administration
DE2856333C2 (de) 1978-12-27 1983-09-22 A. Nattermann & Cie GmbH, 5000 Köln Oral einnehmbare Arzneimittel mit entzündungshemmender Wirkung
IT1111367B (it) 1978-11-17 1986-01-13 Serono Ist Farm Processo per la preparazione estemporanea di liposomi e liposomi cosi' ottenuti
GR73668B (zh) 1978-11-21 1984-03-28 Hoffmann La Roche
US4328222A (en) 1978-11-21 1982-05-04 Hoffmann-La Roche Inc. Pharmaceutical compositions for parenteral or local administration
US4241046A (en) 1978-11-30 1980-12-23 Papahadjopoulos Demetrios P Method of encapsulating biologically active materials in lipid vesicles
US4421747A (en) 1978-12-27 1983-12-20 A. Nattermann & Cie. Gmbh Inflammation-preventing pharmaceutical composition of oral administration
US4378354A (en) 1978-12-27 1983-03-29 A. Nattermann & Cie. Gmbh Inflammation-preventing pharmaceutical composition of oral administration
US4316884A (en) 1979-01-25 1982-02-23 Adria Laboratories, Inc. Sustained release pharmaceutical formulation
DE2914788A1 (de) 1979-04-11 1980-10-16 Nattermann A & Cie Parenteral applizierbare, stabile arzneimittelloesungen mit entzuendungshemmender wirkung
US4345588A (en) 1979-04-23 1982-08-24 Northwestern University Method of delivering a therapeutic agent to a target capillary bed
JPS6030652B2 (ja) 1979-05-07 1985-07-17 株式会社ミドリ十字 静脈注射用脂肪乳剤
US4294916A (en) 1979-05-22 1981-10-13 Ciba-Geigy Ag Photographic silver halide material containing a dye filter or a dye anti-halation layer
US4231938A (en) 1979-06-15 1980-11-04 Merck & Co., Inc. Hypocholesteremic fermentation products and process of preparation
JPS562353A (en) 1979-06-20 1981-01-12 Ricoh Co Ltd Novel disazo compound and its preparation
CA1173360A (en) 1979-06-22 1984-08-28 Jurg Schrank Pharmaceutical preparations
US4309404A (en) * 1979-08-09 1982-01-05 American Home Products Corporation Sustained release pharmaceutical compositions
US4543370A (en) 1979-11-29 1985-09-24 Colorcon, Inc. Dry edible film coating composition, method and coating form
DE3003886A1 (de) * 1980-02-02 1981-08-13 Olympia Werke Ag, 2940 Wilhelmshaven Farbbandkassette fuer eine schreib- o.ae. bueromaschine
AR220263A1 (es) 1980-02-19 1980-10-15 Bago Lab Sa Procedimiento para obtener una preparacion inyectable de sulfonamida potenciada de baja irritabilidad
US4302459A (en) 1980-03-19 1981-11-24 The United States Of America As Represented By The Secretary Of The Army Liposome carriers in leishmaniasis chemotherapy with 8-aminoquinoline derivatives
JPS56152739A (en) 1980-04-25 1981-11-26 Tanabe Seiyaku Co Ltd Production of microcapsule
US4475919A (en) 1980-04-28 1984-10-09 Colorcon, Inc. Colored medicinal tablet, natural color pigment and method for using the pigment in coloring food, drug and cosmetic products
JPS609726B2 (ja) 1980-05-15 1985-03-12 株式会社 ミドリ十字 ステロイド製剤
JPS6222729Y2 (zh) 1980-06-04 1987-06-10
DK149080C (da) 1980-06-06 1986-07-28 Sankyo Co Fremgangsmaade til fremstilling af derivater af ml-236b-carboxylsyre
US4331654A (en) 1980-06-13 1982-05-25 Eli Lilly And Company Magnetically-localizable, biodegradable lipid microspheres
DE3024416C2 (de) 1980-06-28 1982-04-15 Gödecke AG, 1000 Berlin Verfahren zur Herstellung von Arzneimitteln mit retardierter Wirkstoff-Freisetzung
US4450171A (en) * 1980-08-05 1984-05-22 Merck & Co., Inc. Antihypercholesterolemic compounds
US4683256A (en) 1980-11-06 1987-07-28 Colorcon, Inc. Dry edible film coating composition, method and coating form
DE3169595D1 (en) 1980-11-10 1985-05-02 Gersonde Klaus Method of preparing lipid vesicles by ultrasonic treatment, the use of this method and apparatus for its application
US4394372A (en) 1980-12-22 1983-07-19 The Procter & Gamble Company Process for making lipid membrane structures
US4432975A (en) * 1981-04-13 1984-02-21 Icn Pharmaceuticals, Inc. Process for introducing vitamin B-12 into the bloodstream
US4397846A (en) 1981-05-15 1983-08-09 Murray Weiner Storage-stable lipid vesicles and method of preparation
IE53696B1 (en) 1981-12-02 1989-01-18 Wyeth John & Brother Ltd Solid shaped articles
US4448784A (en) * 1982-04-12 1984-05-15 Hoechst-Roussel Pharmaceuticals, Inc. 1-(Aminoalkylphenyl and aminoalkylbenzyl)-indoles and indolines and analgesic method of use thereof
US4485054A (en) 1982-10-04 1984-11-27 Lipoderm Pharmaceuticals Limited Method of encapsulating biologically active materials in multilamellar lipid vesicles (MLV)
US4739073A (en) * 1983-11-04 1988-04-19 Sandoz Pharmaceuticals Corp. Intermediates in the synthesis of indole analogs of mevalonolactone and derivatives thereof
WO1984002131A1 (en) 1982-11-22 1984-06-07 Sandoz Ag Analogs of mevalolactone and derivatives thereof, processes for their production, pharmaceutical compositions containing them and their use as pharmaceuticals
US5030453A (en) 1983-03-24 1991-07-09 The Liposome Company, Inc. Stable plurilamellar vesicles
US4515736A (en) 1983-05-12 1985-05-07 The Regents Of The University Of California Method for encapsulating materials into liposomes
US4725442A (en) 1983-06-17 1988-02-16 Haynes Duncan H Microdroplets of water-insoluble drugs and injectable formulations containing same
US4622219A (en) 1983-06-17 1986-11-11 Haynes Duncan H Method of inducing local anesthesia using microdroplets of a general anesthetic
JPS601122A (ja) 1983-06-20 1985-01-07 Green Cross Corp:The ビフエニリルプロピオン酸誘導体脂肪乳剤
JPS606619A (ja) 1983-06-27 1985-01-14 Kyowa Chem Ind Co Ltd 鉄分欠乏症処置剤及びその製法
US4704295A (en) 1983-09-19 1987-11-03 Colorcon, Inc. Enteric film-coating compositions
US4492720A (en) 1983-11-15 1985-01-08 Benjamin Mosier Method of preparing microspheres for intravascular delivery
US4532089A (en) 1984-01-14 1985-07-30 Northwestern University Method of preparing giant size liposomes
JPS60174726A (ja) 1984-02-21 1985-09-09 Nippon Shinyaku Co Ltd 注射用医薬組成物
US4610868A (en) 1984-03-20 1986-09-09 The Liposome Company, Inc. Lipid matrix carriers for use in drug delivery systems
JPS60208910A (ja) 1984-03-31 1985-10-21 Green Cross Corp:The 水難溶性薬物・リン脂質複合体の製造方法
US4963367A (en) 1984-04-27 1990-10-16 Medaphore, Inc. Drug delivery compositions and methods
DE3421468A1 (de) 1984-06-08 1985-12-19 Dr. Rentschler Arzneimittel Gmbh & Co, 7958 Laupheim Lipidnanopellets als traegersystem fuer arzneimittel zur peroralen anwendung
US4643894A (en) * 1984-07-24 1987-02-17 Colorcon, Inc. Maltodextrin coating
US4828841A (en) * 1984-07-24 1989-05-09 Colorcon, Inc. Maltodextrin coating
JPS6176414A (ja) 1984-09-21 1986-04-18 Shionogi & Co Ltd リポソーム製剤の製法
US4761288A (en) 1984-09-24 1988-08-02 Mezei Associates Limited Multiphase liposomal drug delivery system
JPS61174940A (ja) 1985-01-29 1986-08-06 Oogawara Kakoki Kk ワックス類コーテイング単核状マイクロカプセルおよびその製造方法
US4727077A (en) * 1985-02-20 1988-02-23 Ishihara Sangyo Kaisha Ltd. Benzoyl urea compounds, process for their production, and antitumorous compositions containing them
US4693912A (en) 1985-02-28 1987-09-15 Technicon Instruments Corporation Lyophilization of reagent-coated particles
JPH0688911B2 (ja) 1985-06-06 1994-11-09 国立予防衛生研究所長 インフルエンザワクチン及びその製造方法
JPS6222729A (ja) * 1985-07-23 1987-01-30 Kao Corp 易崩壊性錠剤
US4766046A (en) 1985-09-27 1988-08-23 Liposome Technology, Inc. Stabilized liposome/amphotericin composition and method
JPH0617309B2 (ja) 1985-11-29 1994-03-09 株式会社ビタミン研究所 アドリアマイシン包埋リポソ−ム製剤
US4803070A (en) 1986-04-15 1989-02-07 Ribi Immunochem Research Inc. Immunological emulsion adjuvants for polysaccharide vaccines
US4806352A (en) 1986-04-15 1989-02-21 Ribi Immunochem Research Inc. Immunological lipid emulsion adjuvant
US4806350A (en) 1986-04-18 1989-02-21 Norden Laboratories, Inc. Vaccine formulation
US4802924A (en) * 1986-06-19 1989-02-07 Colorcon, Inc. Coatings based on polydextrose for aqueous film coating of pharmaceutical food and confectionary products
US4940727A (en) 1986-06-23 1990-07-10 Merck & Co., Inc. Novel HMG-CoA reductase inhibitors
US5116870A (en) * 1986-06-23 1992-05-26 Merck & Co., Inc. HMG-CoA reductase inhibitors
DE3623376A1 (de) 1986-07-11 1988-01-21 Behringwerke Ag Pharmazeutische formulierung und verfahren zu deren herstellung
FR2602423B1 (fr) * 1986-08-08 1989-05-05 Ethypharm Sa Procede de preparation d'un medicament a base de fenofibrate, medicament obtenu par ce procede
US4776991A (en) 1986-08-29 1988-10-11 The United States Of America As Represented By The Secretary Of The Navy Scaled-up production of liposome-encapsulated hemoglobin
CA1338736C (fr) 1986-12-05 1996-11-26 Roger Baurain Microcristaux comportant une substance active presentant une affinite pour les phospholipides, et au moins un phospholipide, procede de preparation
US5320906A (en) 1986-12-15 1994-06-14 Vestar, Inc. Delivery vehicles with amphiphile-associated active ingredient
DK175531B1 (da) 1986-12-15 2004-11-22 Nexstar Pharmaceuticals Inc Leveringsvehikel med amphiphil-associeret aktiv bestanddel
US5179079A (en) 1986-12-16 1993-01-12 Novo Nordisk A/S Nasal formulation and intranasal administration therewith
US4837028A (en) * 1986-12-24 1989-06-06 Liposome Technology, Inc. Liposomes with enhanced circulation time
US4839111A (en) 1987-02-02 1989-06-13 The University Of Tennessee Research Corporation Preparation of solid core liposomes
US5154930A (en) * 1987-03-05 1992-10-13 The Liposome Company, Inc. Pharmacological agent-lipid solution preparation
US5091378A (en) * 1987-05-22 1992-02-25 E. R. Squibb & Sons, Inc. Phosphorus-containing HMG-CoA reductase inhibitors, new intermediates and method
US4904646A (en) * 1987-05-22 1990-02-27 E. R. Squibb & Sons, Inc. Phosphorus-containing HMG-COA reductase inhibitors
US5017716A (en) * 1987-05-22 1991-05-21 E.R. Squibb & Sons, Inc. Phosphorous-containing HMG-CoA reductase inhibitors, new intermediates and method
FR2617047B1 (fr) 1987-06-23 1991-05-10 Sanofi Sa Composition de gelatine resistant au tannage, capsules a base de cette composition et leur application pharmaceutique, notamment au fenofibrate
CA1336714C (en) 1987-08-20 1995-08-15 Yoshihiro Fujikawa Quinoline type mevalonolactone inhibitors of cholesterol biosynthesis
US4997837A (en) * 1987-09-08 1991-03-05 Warner-Lambert Company 6-(((substituted)pyridin-3-yl)alkyl)-and alkenyl)-tetrahydro-4-hydroxypyran-2-one inhibitors of cholesterol biosynthesis
US4906624A (en) * 1987-09-08 1990-03-06 Warner-Lambert Company 6-(((Substituted)pyridin-3-yl)alkyl)-and alkenyl)-tetrahydro-4-hydroxypyran-2-one inhibitors of cholesterol biosynthesis
US4929620A (en) * 1987-12-10 1990-05-29 Warner-Lambert Company 5-pyrimidinyl-3,5-dihydroxy-6-heptenoic acid compounds useful as inhibitors of cholesterol biosynthesis
US5001128A (en) * 1987-12-21 1991-03-19 Rhone-Poulenc Rorer Pharmaceuticals Inc. HMG-COA reductase inhibitors
US4900754A (en) * 1987-12-21 1990-02-13 Rorer Pharmaceutical Corp. HMG-COA reductase inhibitors
US5001144A (en) * 1987-12-21 1991-03-19 Rhone-Poulenc Rorer Pharmaceuticals Inc. Substituted cyclohexene derivatives as HMG-CoA reductase inhibitors
US4994494A (en) * 1987-12-21 1991-02-19 Rhone-Poulenc Rorer Pharmaceuticals Inc. HMG-COA reductase inhibitors
US4939143A (en) 1987-12-21 1990-07-03 Rorer Pharmaceutical Corporation Substituted cyclohexene derivatives as HMG-CoA reductase inhibitors
US5360593A (en) 1987-12-29 1994-11-01 Alcon Laboratories, Inc. Heat sterilization of labile antibiotics
DE68900991D1 (de) 1988-01-29 1992-04-23 Sankyo Co Cyclosporin-zusammensetzungen.
US4946864A (en) 1988-02-01 1990-08-07 Merck & Co., Inc. Novel HMG-CoA reductase inhibitors
FR2627696B1 (fr) 1988-02-26 1991-09-13 Fournier Innovation Synergie Nouvelle forme galenique du fenofibrate
US5021453A (en) 1988-03-02 1991-06-04 Merck & Co., Inc. 3-keto HMG-CoA reductase inhibitors
DE68914495T2 (de) 1988-03-02 1994-10-27 Merck & Co Inc Antihypercholesterolemisches Mittel.
US4920109A (en) * 1988-04-18 1990-04-24 Merck & Co., Inc. Antifungal compositions and method of controlling mycotic infections
US5006362A (en) 1988-05-09 1991-04-09 Berwind Pharmaceutical Services, Inc. Branding pharmaceutical dosage forms, food and confectionery products with aqueous ingestible inks
US5744477A (en) * 1988-05-10 1998-04-28 The Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Method for treatment of obesity using prolactin modulators and diet
US5166171A (en) 1988-05-13 1992-11-24 Hoechst Aktiengesellschaft 6-phenoxymethyl-4-hydroxytetrahydropyran-2-ones and 6-thiphenoxymethyl-4-hydroxytetrahydropyran-2-ones and the corresponding dihydroxycarboxylic acid derivatives, salts and esters, and in treating hypercholesterolemia
US5217707A (en) 1988-06-16 1993-06-08 Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt. Pharmaceutical composition and process for the preparation thereof
US4897402A (en) * 1988-06-29 1990-01-30 Merck & Co., Inc. 5-oxa, 5-thia, 5-aza HmG-CoA reductase inhibitors
US4963538A (en) 1988-06-29 1990-10-16 Merck & Co., Inc. 5-oxygenated HMG-CoA reductase inhibitors
IT1226726B (it) 1988-07-29 1991-02-05 Zambon Spa Composti attivi come inibitori della biosintesi del colesterolo.
US5196440A (en) * 1988-07-29 1993-03-23 Zambon Group S.P.A. Compounds active as inhibitors of the cholesterol biosynthesis
US5342625A (en) * 1988-09-16 1994-08-30 Sandoz Ltd. Pharmaceutical compositions comprising cyclosporins
DE3832570A1 (de) * 1988-09-24 1990-03-29 Hoechst Ag 7-substituierte derivate der 3,5-dihydroxyhept-6-insaeure, verfahren zur ihrer herstellung, ihre verwendung als arzneimittel, sowie zwischenprodukte
GB8822857D0 (en) 1988-09-29 1988-11-02 Patralan Ltd Pharmaceutical formulations
US4906657A (en) * 1988-12-21 1990-03-06 Warner-Lambert Company Bicyclo heptane and bicyclo octane substituted inhibitors of cholesterol synthesis
US4957940A (en) 1988-12-21 1990-09-18 Warner-Lambert Company Bicyclo heptane and bicyclo octane substituted inhibitors of cholesterol synthesis
US4950675A (en) 1988-12-21 1990-08-21 Warner-Lambert Company Pyridine di-mevalono-lactones as inhibitors of cholesterol biosynthesis
DE3903056A1 (de) 1989-02-02 1990-08-09 Braun Melsungen Ag Fettemulsion zur intraperitonealen applikation, ihre herstellung und anwendung
DE3903057A1 (de) 1989-02-02 1990-08-09 Braun Melsungen Ag Fettemulsion zur endotrachealen applikation, ihre herstellung und anwendung
US4923861A (en) * 1989-02-07 1990-05-08 Warner-Lambert Company 6-(2-(2-(Substituted amino)-3-quinolinyl) ethenyl and ethyl) tetrahydro-4-hydroxypyran-2-one inhibitors of cholesterol biosynthesis
US5130306A (en) 1989-03-13 1992-07-14 Merck & Co., Inc. 5-Oxygenated HMG-COA reductase inhibitors
US5132312A (en) 1989-03-27 1992-07-21 Rhone-Poulenc Rorer Pharmaceuticals Inc. Substituted cyclohexene derivatives as HMG-CoA reductase inhibitors
AU614465B2 (en) 1989-04-05 1991-08-29 Yissum Research Development Company Of The Hebrew University Of Jerusalem Medicinal emulsions
US5102911A (en) * 1989-06-09 1992-04-07 Merck & Co, Inc. 4-Substituted HMG-CoA reductase inhibitors
US4970231A (en) 1989-06-09 1990-11-13 Merck & Co., Inc. 4-substituted HMG-CoA reductase inhibitors
FI94339C (fi) 1989-07-21 1995-08-25 Warner Lambert Co Menetelmä farmaseuttisesti käyttökelpoisen /R-(R*,R*)/-2-(4-fluorifenyyli)- , -dihydroksi-5-(1-metyylietyyli)-3-fenyyli-4-/(fenyyliamino)karbonyyli/-1H-pyrroli-1-heptaanihapon ja sen farmaseuttisesti hyväksyttävien suolojen valmistamiseksi
US4992429A (en) * 1989-08-24 1991-02-12 Rhone-Poulenc Rorer Pharmaceuticals Inc. Novel HMG-COA reductase inhibitors
US5098931A (en) * 1989-08-31 1992-03-24 Merck & Co., Inc. 7-substituted HMG-CoA reductase inhibitors
FR2651680B1 (fr) 1989-09-14 1991-12-27 Medgenix Group Sa Nouveau procede de preparation de microparticules lipidiques.
US5178878A (en) 1989-10-02 1993-01-12 Cima Labs, Inc. Effervescent dosage form with microparticles
US4946860A (en) 1989-11-03 1990-08-07 Rorer Pharmaceutical Corporation Benzothiopyranyl derivatives as HMG-CoA reductase inhibitors
JP2785981B2 (ja) * 1989-11-20 1998-08-13 株式会社資生堂 乳化組成物
IT1237793B (it) * 1989-12-21 1993-06-17 Zambon Spa Composti attivi come inibitori dell'enzima hmg-coa reduttasi
US5389377A (en) 1989-12-22 1995-02-14 Molecular Bioquest, Inc. Solid care therapeutic compositions and methods for making same
US5025000A (en) 1990-03-02 1991-06-18 E. R. Squibb & Sons, Inc. Phosphorus-containing HMG-CoA reductase inhibitor compounds
IT1241088B (it) * 1990-03-27 1993-12-29 Chiesi Farma Spa Procedimento per la preparazione di complessi piroxicam/ciclodestrina,prodotti ottenuti e loro composizioni farmaceutiche
JP3165438B2 (ja) 1990-04-04 2001-05-14 バーウィンド・ファーマス―ティカル・サーヴィスィーズ・インコーポレーテッド 水性のマルトデキストリン及びセルロースポリマーフィルムコーティング
US5246707A (en) 1990-04-26 1993-09-21 Haynes Duncan H Sustained release delivery of water-soluble bio-molecules and drugs using phospholipid-coated microcrystals, microdroplets and high-concentration liposomes
US5091187A (en) 1990-04-26 1992-02-25 Haynes Duncan H Phospholipid-coated microcrystals: injectable formulations of water-insoluble drugs
US5091188A (en) 1990-04-26 1992-02-25 Haynes Duncan H Phospholipid-coated microcrystals: injectable formulations of water-insoluble drugs
CA2039763A1 (en) 1990-04-30 1991-10-31 Henry Y. Pan Combination of pravastatin and a fibric acid derivative, and method for treating dyslipidemia using such combination
US5298497A (en) * 1990-05-15 1994-03-29 E. R. Squibb & Sons, Inc. Method for preventing onset of hypertension employing a cholesterol lowering drug
US5622985A (en) * 1990-06-11 1997-04-22 Bristol-Myers Squibb Company Method for preventing a second heart attack employing an HMG CoA reductase inhibitor
CA2048395A1 (en) 1990-08-23 1992-02-24 Henry Y. Pan Method for preventing onset of or treating type iii hyperlipoproteinemia employing pravastatin
US5112857A (en) * 1990-09-04 1992-05-12 Merck & Co., Inc. Hmg-coa reductase inhibitor metabolites
HU205550B (en) 1990-11-27 1992-05-28 Egyt Gyogyszervegyeszeti Gyar Process for producing pyroxycam solution of increased stability, free from effects damaging tussues
HU211580A9 (hu) 1990-11-27 1995-12-28 Egyt Gyogyszervegyeszeti Gyar Megnövelt stabilitású, szövetkárosító hatás nélküli piroxikam-oldatok Az átmeneti oltalom az 1., 2., 5. és 6. igénypontokra vonatkozik.
US5552160A (en) 1991-01-25 1996-09-03 Nanosystems L.L.C. Surface modified NSAID nanoparticles
US5145684A (en) 1991-01-25 1992-09-08 Sterling Drug Inc. Surface modified drug nanoparticles
US5399363A (en) 1991-01-25 1995-03-21 Eastman Kodak Company Surface modified anticancer nanoparticles
US5182298A (en) * 1991-03-18 1993-01-26 Merck & Co., Inc. Cholesterol lowering agents
MX9201782A (es) 1991-04-19 1992-10-01 Sandoz Ag Particulas de sustancias biologicamente activas, sustancialmente insolubles en agua, proceso para su produccion y composicion farmaceutica que las contiene.
US5256689A (en) 1991-05-10 1993-10-26 Merck & Co., Inc. Cholesterol lowering compounds
US5135935A (en) 1991-05-17 1992-08-04 Merck & Co., Inc. Squalene synthetase inhibitors
US5250435A (en) 1991-06-04 1993-10-05 Merck & Co., Inc. Mutant strains of Aspergillus terreus for producing 7-[1,2,6,7,8,8a(R)-hexa-hydro-2(S),6(R)-dimethyl-8(S)-hydroxy-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid (triol acid),I)
US5202327A (en) * 1991-07-10 1993-04-13 E. R. Squibb & Sons, Inc. Phosphorus-containing hmg-coa reductase inhibitors
DE4131562A1 (de) 1991-09-18 1993-03-25 Medac Klinische Spezialpraep Arzneistofftraeger aus festen lipidteilchen-feste lipidnanosphaeren (sln)
DE4140192C2 (de) 1991-12-05 1996-02-29 Alfatec Pharma Gmbh Sol-gesteuerte Thermokolloidmatrix auf Gelatinebasis für perorale Retardformen
HU9203780D0 (en) 1991-12-12 1993-03-29 Sandoz Ag Stabilized pharmaceutical products of hmg-coa reductase inhibitor and method for producing them
JP3059559B2 (ja) 1991-12-17 2000-07-04 日本バイエルアグロケム株式会社 殺虫性グアニジン誘導体
US5260332A (en) 1992-02-07 1993-11-09 Merci & Co., Inc. Cholesterol lowering compounds
US5262435A (en) 1992-02-10 1993-11-16 Merck & Co., Inc. Cholesterol lowering compounds
US5272137A (en) 1992-02-14 1993-12-21 Mcneil-Pfc, Inc. Aqueous pharmaceutical suspension for pharmaceutical actives
US5286895A (en) * 1992-02-19 1994-02-15 Merck & Co., Inc. Cholesterol lowering compounds
US5302604A (en) * 1992-03-09 1994-04-12 Merck & Co., Inc. Cholesterol lowering compounds produced by directed biosynthesis
EP0570829B1 (de) 1992-05-18 2001-04-25 CicloMulsion AG Cyclosporin(e) enthaltende pharmazeutische Zubereitung zur intravenösen Applikation sowie Verfahren zu ihrer Herstellung
US5369125A (en) 1992-07-17 1994-11-29 Merck & Co., Inc. Cholesterol-lowering agents
US5283256A (en) * 1992-07-22 1994-02-01 Merck & Co., Inc. Cholesterol-lowering agents
US5317031A (en) 1992-10-19 1994-05-31 Merck & Co., Inc. Cholesterol lowering compounds
US5346702A (en) 1992-12-04 1994-09-13 Sterling Winthrop Inc. Use of non-ionic cloud point modifiers to minimize nanoparticle aggregation during sterilization
US5298262A (en) 1992-12-04 1994-03-29 Sterling Winthrop Inc. Use of ionic cloud point modifiers to prevent particle aggregation during sterilization
US5302401A (en) 1992-12-09 1994-04-12 Sterling Winthrop Inc. Method to reduce particle size growth during lyophilization
US5340564A (en) 1992-12-10 1994-08-23 Sterling Winthrop Inc. Formulations comprising olin 10-G to prevent particle aggregation and increase stability
US5336507A (en) 1992-12-11 1994-08-09 Sterling Winthrop Inc. Use of charged phospholipids to reduce nanoparticle aggregation
US5352459A (en) 1992-12-16 1994-10-04 Sterling Winthrop Inc. Use of purified surface modifiers to prevent particle aggregation during sterilization
US5326552A (en) 1992-12-17 1994-07-05 Sterling Winthrop Inc. Formulations for nanoparticulate x-ray blood pool contrast agents using high molecular weight nonionic surfactants
CA2091152C (en) 1993-03-05 2005-05-03 Kirsten Westesen Solid lipid particles, particles of bioactive agents and methods for the manfuacture and use thereof
US5785976A (en) 1993-03-05 1998-07-28 Pharmacia & Upjohn Ab Solid lipid particles, particles of bioactive agents and methods for the manufacture and use thereof
US5576016A (en) 1993-05-18 1996-11-19 Pharmos Corporation Solid fat nanoemulsions as drug delivery vehicles
CH686761A5 (de) 1993-05-27 1996-06-28 Sandoz Ag Galenische Formulierungen.
US5639474A (en) 1993-07-01 1997-06-17 Hanmi Pharm. Ind., Ltd. Cyclosporin soft capsule composition
WO1995001782A2 (en) * 1993-07-09 1995-01-19 R.P. Scherer Corporation Method for making freeze dried drug dosage forms
DE4323636A1 (de) 1993-07-15 1995-01-19 Hoechst Ag Arzneistoffzubereitungen aus umhüllten, schwerstwasserlöslichen Arzneistoffen für Inhalationsarzneiformen und Verfahren zu ihrer Herstellung
US5565215A (en) 1993-07-23 1996-10-15 Massachusettes Institute Of Technology Biodegradable injectable particles for imaging
DE4329446A1 (de) 1993-09-01 1995-03-02 Basf Ag Verfahren zur Herstellung von feinteiligen Farb- oder Wirkstoffzubereitungen
JPH09504293A (ja) * 1993-10-28 1997-04-28 ザ、プロクター、エンド、ギャンブル、カンパニー マグネシウムアルミニウムシリケート及び複数の活性成分を含有した速溶解性剤形
US5567592A (en) * 1994-02-02 1996-10-22 Regents Of The University Of California Screening method for the identification of bioenhancers through the inhibition of P-glycoprotein transport in the gut of a mammal
US5635210A (en) 1994-02-03 1997-06-03 The Board Of Regents Of The University Of Oklahoma Method of making a rapidly dissolving tablet
AU682580B2 (en) * 1994-02-25 1997-10-09 Takeda Chemical Industries Ltd. Injectable emulsions containing antifungal triazole derivatives
US5364633A (en) 1994-03-14 1994-11-15 Dow Corning Corporation Silicone vesicles and entrapment
GB9405304D0 (en) 1994-03-16 1994-04-27 Scherer Ltd R P Delivery systems for hydrophobic drugs
IL113139A0 (en) 1994-03-28 1995-06-29 Nycomed Imaging As Diagnostic compositions comprising imaging agents encapsulated in liposomes
GB9409778D0 (en) * 1994-05-16 1994-07-06 Dumex Ltd As Compositions
FR2722984B1 (fr) 1994-07-26 1996-10-18 Effik Lab Procede de preparation de formes pharmaceutiques seches et les compositions pharmaceutiques ainsi realisees
GB9421836D0 (en) * 1994-10-28 1994-12-14 Scherer Corp R P Process for preparing solid pharmaceutical dosage forms of hydrophobic substances
US5858398A (en) 1994-11-03 1999-01-12 Isomed Inc. Microparticular pharmaceutical compositions
US5603951A (en) 1994-11-09 1997-02-18 Hanmi Pharm. Ind. Co., Ltd. Cyclosporin-containing soft capsule compositions
DE4440337A1 (de) 1994-11-11 1996-05-15 Dds Drug Delivery Services Ges Pharmazeutische Nanosuspensionen zur Arzneistoffapplikation als Systeme mit erhöhter Sättigungslöslichkeit und Lösungsgeschwindigkeit
US5660854A (en) 1994-11-28 1997-08-26 Haynes; Duncan H Drug releasing surgical implant or dressing material
KR0167613B1 (ko) 1994-12-28 1999-01-15 한스 루돌프 하우스, 니콜 케르커 사이클로스포린-함유 연질캅셀제 조성물
US5545628A (en) 1995-01-10 1996-08-13 Galephar P.R. Inc. Pharmaceutical composition containing fenofibrate
US5569448A (en) 1995-01-24 1996-10-29 Nano Systems L.L.C. Sulfated nonionic block copolymer surfactants as stabilizer coatings for nanoparticle compositions
FR2730231B1 (fr) 1995-02-02 1997-04-04 Fournier Sca Lab Association de fenofibrate et de vitamine e, utilisation en therapeutique
US5560931A (en) 1995-02-14 1996-10-01 Nawosystems L.L.C. Formulations of compounds as nanoparticulate dispersions in digestible oils or fatty acids
US5571536A (en) 1995-02-06 1996-11-05 Nano Systems L.L.C. Formulations of compounds as nanoparticulate dispersions in digestible oils or fatty acids
US5510118A (en) 1995-02-14 1996-04-23 Nanosystems Llc Process for preparing therapeutic compositions containing nanoparticles
SI9500173B (sl) * 1995-05-19 2002-02-28 Lek, Trofazna farmacevtska oblika s konstantnim in kontroliranim sproščanjem amorfne učinkovine za enkrat dnevno aplikacijo
US5716928A (en) * 1995-06-07 1998-02-10 Avmax, Inc. Use of essential oils to increase bioavailability of oral pharmaceutical compounds
FR2737121B1 (fr) 1995-07-27 1997-10-03 Cl Pharma Nouvelles formulations galeniques du fenofibrate et leurs applications
US5827822A (en) 1996-03-25 1998-10-27 Sangstat Medical Corporation Cyclosporin a formulations as nanoparticles
US5834025A (en) 1995-09-29 1998-11-10 Nanosystems L.L.C. Reduction of intravenously administered nanoparticulate-formulation-induced adverse physiological reactions
CZ288631B6 (cs) 1996-01-18 2001-08-15 Galena, A. S. Léčivé přípravky s obsahem cyklosporinu
US5686133A (en) 1996-01-31 1997-11-11 Port Systems, L.L.C. Water soluble pharmaceutical coating and method for producing coated pharmaceuticals
DE19608750A1 (de) 1996-03-06 1997-09-11 Durachemie Gmbh & Co Kg Verfahren zur Herstellung von Fenofibrat-Präparaten
EP0914822A4 (en) 1996-03-14 2002-08-07 Bayer Ag PREPARATION OF ECADOTRIL WITH FAST MICRODISPERSION AND RELEASE
US5637625A (en) 1996-03-19 1997-06-10 Research Triangle Pharmaceuticals Ltd. Propofol microdroplet formulations
US5660858A (en) 1996-04-03 1997-08-26 Research Triangle Pharmaceuticals Cyclosporin emulsions
ATE260646T1 (de) * 1996-04-16 2004-03-15 Novartis Consumer Health Sa Schnell zerfallende orale dosierungsform
DE69728206T2 (de) 1996-05-14 2005-03-10 Dsm Ip Assets B.V. Herstellungsverfahren für Carotenoid-Zusammensetzungen
US7255877B2 (en) * 1996-08-22 2007-08-14 Jagotec Ag Fenofibrate microparticles
US6465016B2 (en) * 1996-08-22 2002-10-15 Research Triangle Pharmaceuticals Cyclosporiine particles
DE69734988T2 (de) * 1996-08-22 2006-09-21 Jagotec Ag Zubereitungen enthaltend mikropartikel von wasserunlöslichen stoffen und verfahren zu deren herstellung
US5891469A (en) * 1997-04-02 1999-04-06 Pharmos Corporation Solid Coprecipitates for enhanced bioavailability of lipophilic substances
US5807580A (en) * 1996-10-30 1998-09-15 Mcneil-Ppc, Inc. Film coated tablet compositions having enhanced disintegration characteristics
US5919776A (en) * 1996-12-20 1999-07-06 Merck & Co., Inc. Substituted aminoquinolines as modulators of chemokine receptor activity
FR2758459B1 (fr) * 1997-01-17 1999-05-07 Pharma Pass Composition pharmaceutique de fenofibrate presentant une biodisponibilite elevee et son procede de preparation
US6045829A (en) 1997-02-13 2000-04-04 Elan Pharma International Limited Nanocrystalline formulations of human immunodeficiency virus (HIV) protease inhibitors using cellulosic surface stabilizers
US5976577A (en) * 1997-07-11 1999-11-02 Rp Scherer Corporation Process for preparing fast dispersing solid oral dosage form
US6180660B1 (en) * 1997-08-26 2001-01-30 Merck & Co., Inc. Cholesterol-lowering therapy
CA2214895C (en) 1997-09-19 1999-04-20 Bernard Charles Sherman Improved pharmaceutical composition comprising fenofibrate
US6027747A (en) * 1997-11-11 2000-02-22 Terracol; Didier Process for the production of dry pharmaceutical forms and the thus obtained pharmaceutical compositions
US5891845A (en) * 1997-11-21 1999-04-06 Fuisz Technologies Ltd. Drug delivery systems utilizing liquid crystal structures
US6063762A (en) 1997-12-05 2000-05-16 Chong Kun Dang Corp. Cyclosporin-containing microemulsion preconcentrate composition
CN100379407C (zh) * 1997-12-19 2008-04-09 史密丝克莱恩比彻姆公司 生产咀嚼分散片的方法
US6086376A (en) 1998-01-30 2000-07-11 Rtp Pharma Inc. Dry aerosol suspension of phospholipid-stabilized drug microparticles in a hydrofluoroalkane propellant
FR2776191B1 (fr) * 1998-03-23 2002-05-31 Theramex Composition hormonale topique a effet systemique
EP1067914B1 (en) 1998-03-30 2006-02-22 Jagotec Ag Composition and method of preparing microparticles of water-insoluble substances
US6337092B1 (en) 1998-03-30 2002-01-08 Rtp Pharma Inc. Composition and method of preparing microparticles of water-insoluble substances
CA2333648C (en) * 1998-05-29 2008-10-21 Rtp Pharma Inc. Thermoprotected microparticle compositions and process for terminal steam sterilization thereof
US8293277B2 (en) * 1998-10-01 2012-10-23 Alkermes Pharma Ireland Limited Controlled-release nanoparticulate compositions
US6375986B1 (en) * 2000-09-21 2002-04-23 Elan Pharma International Ltd. Solid dose nanoparticulate compositions comprising a synergistic combination of a polymeric surface stabilizer and dioctyl sodium sulfosuccinate
US6180138B1 (en) * 1999-01-29 2001-01-30 Abbott Laboratories Process for preparing solid formulations of lipid-regulating agents with enhanced dissolution and absorption
US6248363B1 (en) * 1999-11-23 2001-06-19 Lipocine, Inc. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
US6270806B1 (en) 1999-03-03 2001-08-07 Elan Pharma International Limited Use of peg-derivatized lipids as surface stabilizers for nanoparticulate compositions
US6267989B1 (en) 1999-03-08 2001-07-31 Klan Pharma International Ltd. Methods for preventing crystal growth and particle aggregation in nanoparticulate compositions
US6057289A (en) 1999-04-30 2000-05-02 Pharmasolutions, Inc. Pharmaceutical composition comprising cyclosporin in association with a carrier in a self-emulsifying drug delivery system
US6982281B1 (en) 2000-11-17 2006-01-03 Lipocine Inc Pharmaceutical compositions and dosage forms for administration of hydrophobic drugs
NZ522239A (en) * 2000-04-20 2004-03-26 Skyepharma Canada Inc Improved water-insoluble drug particle process
ATE389455T1 (de) * 2000-05-10 2008-04-15 Jagotec Ag Zerkleinerung mittels mahlkörper
US6368628B1 (en) * 2000-05-26 2002-04-09 Pharma Pass Llc Sustained release pharmaceutical composition free of food effect
CA2423335C (en) * 2000-09-20 2011-03-01 Rtp Pharma Inc. Spray drying process and compositions of fenofibrate
FR2819720B1 (fr) 2001-01-22 2004-03-12 Fournier Lab Sa Nouveaux comprimes de fenofibrate
JP2004523552A (ja) * 2001-02-22 2004-08-05 スカイファーマ・カナダ・インコーポレーテッド 低減した摂食−絶食効果を伴うフィブラート−スタチンの組合わせ

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004045619A1 (fr) * 2002-11-21 2004-06-03 Wuhan Liyuanheng Pharmaceutical Technology Ltd. Injection de poudre nanometrique de lecithine congelee et sechee d'un acide ursolique et son procede de preparation
CN102413829A (zh) * 2009-05-05 2012-04-11 埃科比奥法姆有限公司 含有磷脂纳米颗粒形式阿比朵尔的药物组合物
CN104096204A (zh) * 2014-07-23 2014-10-15 重庆大学 小儿肺咳泡腾片及其制备方法
CN104096204B (zh) * 2014-07-23 2017-10-13 重庆大学 小儿肺咳泡腾片及其制备方法
CN104906044A (zh) * 2015-05-22 2015-09-16 广州中科蓝华生物科技有限公司 一种癸氧喹酯纳米制剂及其制备方法与应用
CN105295063A (zh) * 2015-10-15 2016-02-03 安徽山河药用辅料股份有限公司 一种表面改性微晶纤维素及其制备方法
CN105295063B (zh) * 2015-10-15 2019-01-11 安徽山河药用辅料股份有限公司 一种表面改性微晶纤维素及其制备方法
CN110755392A (zh) * 2019-11-18 2020-02-07 扬子江药业集团广州海瑞药业有限公司 一种利伐沙班片药物组合物及制备方法
CN110755392B (zh) * 2019-11-18 2020-09-01 扬子江药业集团广州海瑞药业有限公司 一种利伐沙班片药物组合物及制备方法

Also Published As

Publication number Publication date
HK1042856B (zh) 2007-07-27
JP2002530321A (ja) 2002-09-17
KR20010073232A (ko) 2001-07-31
BG65254B1 (bg) 2007-10-31
EP1133281A1 (en) 2001-09-19
HK1042856A1 (en) 2002-08-30
CN1287769C (zh) 2006-12-06
NO20012467D0 (no) 2001-05-18
US7939105B2 (en) 2011-05-10
JP2011137031A (ja) 2011-07-14
EE05190B1 (et) 2009-08-17
UA80652C2 (uk) 2007-10-10
PL348868A1 (en) 2002-06-17
SK6852001A3 (en) 2001-12-03
EE200100269A (et) 2002-08-15
WO2000030616A1 (en) 2000-06-02
US7939106B2 (en) 2011-05-10
ID29270A (id) 2001-08-16
IS5945A (is) 2001-05-18
HUP0105089A3 (en) 2002-09-30
JP4809533B2 (ja) 2011-11-09
IL143197A (en) 2009-09-01
HUP0105089A2 (hu) 2002-05-29
CA2349203A1 (en) 2000-06-02
AU1737500A (en) 2000-06-13
BG105573A (en) 2002-01-31
US20030206949A1 (en) 2003-11-06
RU2233654C2 (ru) 2004-08-10
BR9915738A (pt) 2001-10-02
US20020106403A1 (en) 2002-08-08
IL143197A0 (en) 2002-04-21
CA2349203C (en) 2013-05-21
SK288117B6 (sk) 2013-09-03
PL201578B1 (pl) 2009-04-30
NO20012467L (no) 2001-07-18
NO331819B1 (no) 2012-04-10
ZA200104069B (en) 2003-01-07
AU767154B2 (en) 2003-10-30
US20110244032A1 (en) 2011-10-06
NZ511792A (en) 2003-08-29
CZ20011739A3 (cs) 2001-10-17

Similar Documents

Publication Publication Date Title
CN1287769C (zh) 可分散的磷脂稳定的微粒
AU761205B2 (en) Composition and method of preparing microparticles of water-insoluble substances
CA2212803C (en) Redispersible nanoparticulate film matrices with protective overcoats
US20080038333A1 (en) Formulations For Poorly Soluble Drugs
SK58497A3 (en) Pharmaceutical nanosuspensions for medicament administration as systems with increased saturation solubility and speed of dissolution
JPH06227967A (ja) ナノ粒子を含む組成物及びその製造方法
KR20200046018A (ko) 멜록시캄을 함유하는 주사용 약학 조성물 및 그 제조 방법
JPH06343854A (ja) ナノカプセルの貯蔵安定度改良法
EP0834314A1 (en) Granules containing pranlukast, process for producing the granules, and method of lowering cohesiveness of pranlukast
CN1295472A (zh) 卡维地洛－盖仑制剂
US20040001888A1 (en) Solid dosage forms for rapid dissolution of poorly soluble drugs
WO2017209216A1 (ja) 難溶性薬物の微粒子を含有する医薬組成物の製造方法
MXPA01004991A (en) Dispersible phospholipid stabilized microparticles
Chua et al. Evaluating spray gelation and spray freeze drying as the granulation method to prepare oral tablets of amorphous drug nanoplex

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
REG Reference to a national code

Ref country code: HK

Ref legal event code: GR

Ref document number: 1042856

Country of ref document: HK

CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20061206

Termination date: 20151119

CF01 Termination of patent right due to non-payment of annual fee