CN1087932C - 用于吸入法的原脂质体粉末 - Google Patents
用于吸入法的原脂质体粉末 Download PDFInfo
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- CN1087932C CN1087932C CN95196978A CN95196978A CN1087932C CN 1087932 C CN1087932 C CN 1087932C CN 95196978 A CN95196978 A CN 95196978A CN 95196978 A CN95196978 A CN 95196978A CN 1087932 C CN1087932 C CN 1087932C
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Abstract
一种原脂质体粉末，该粉末包含一种结合了具有低于37℃的相转变温度的脂质或脂质混合物的单相生物活性组分分散颗粒。
Description
发明领域
本发明涉及尤其用于吸入法的原脂质体(proliposome)粉末、一种生产该原脂质体粉末的方法、含有该原脂质体粉末的组合物和它们的使用方法。
技术背景
脂质体是膜状泡囊，其由一系列交错着亲水层的同心脂质双层构成，它们可从多种天然和合成脂质例如天然和合成磷酸甘油脂类、鞘脂类和二半乳糖甘油脂类制成。脂质体的主要用途之一是作为不同种类的药物活性组分的载体，从而改进药物输送并且使一些治疗副作用降到最低。通过包封脂质体的亲水层(当活性组分是水溶性的时)，或当活性组分是亲脂性的时，通过包封脂质双层可以将药物活性组分掺入到脂质体中。
药物脂质体制剂的一个主要问题是长期稳定性。由于凝聚作用、包封的活性组分在外相中损失、活性组分或脂质材料的化学降解等而使含水脂质体分散体的稳定性受到限制。
如果使用一种固体组合物，则可在很大程度上解决这些问题，这样的固体组合物包含一种脂质体粉末，即一种干脂质体分散体或原脂质体粉末。
干燥脂质体分散体的方法具有破坏脂质体膜的危险。为了使这种危险降到最低，在保护糖的存在下干燥脂质体是必要的，如在例如WO86/01103中所描述的。
美国专利号4,906,476公开了通过吸入法用于类固醇输送的脂质体制剂。公开了应用适宜的设备输送作为粉末气溶胶的干脂质体的可能性。还公开了应用含有悬浮干脂质体粉末的推进剂溶剂，通过从独立的雾化器中喷雾和应用推进剂从而把干燥的颗粒喷雾进入肺部的输送方式。
这样的脂质体不以原脂质体粉末的形式存在，而是当粉末在脂质体的相转变温度以上的温度水合时形成原脂质体粉末。因此，与干脂质体相比，原脂质体粉末的优势是消除了脂质体由于脱水作用而遭破坏的危险性。
原脂质体粉末在前面已作了描述。
例如，美国专利4,311,712公开了通过将一种形成脂质体的两亲的脂质和一种脂质溶解的或脂质结合的生物活性化合物溶解于一种有机溶剂中，并冻干溶液而得到冻干的有效脂质体混合物，有机溶剂在冻干过程中是固体。有效脂质体混合物可以贮存和按要求制成含水的脂质体制剂。生物活性化合物可以是任何具有生物性能的化合物。
WO90/00389公开了一种含有两亲的脂质和一种环孢霉素或其衍生物的冻干的有效脂质体混合物，其应用于环孢霉素进入细胞的可能脂质体输送。冻干混合物在水介质中重新形成从而获得脂质体，其基本上包封了所有存在于冻干混合物中的环孢霉素。
WO92/11842公开了一种原脂质体粉末，当其在水或盐溶液中复制时，其形成一种含有一种多烯药物例如制霉菌素的脂质体悬浮体。
以上所有关于原脂质体组合物的专利和申请均涉及在施用前需要水合的组合物。
EP309464描述了可被吸入的原脂质体粉末组合物。该粉末组合物包括固体颗粒，其中生物活性组分是一种在脂质中的颗粒分散体。
发明目的
当期望通过吸入法输送时，我们已发现提供仅具有单相的原脂质体粉末是有利的。因此，本发明的一个目的是提供这样一种原脂质体粉末。
发明内容
本发明的以上目的可以通过采用本发明的原脂质体粉末实现，所说的粉末包含一种单相的生物活性组分分散颗粒和一种具有低于37℃的相转变温度(Tc)的脂质或脂质混合物。
粉末尤其适用于吸入法施药。
另外，还可将单相粉末描述为包含生物活性组分和相转变温度低于37℃的脂质或脂质混合物的均相分子混合物。
从术语“单相”和“均相分子混合物”可知，在本发明的粉末中没有活性组分或脂质的分离结晶相。
单相粉末能直接被吸入，并且例如在上或下呼吸系统中就地形成脂质体，其中生物活性成分全部被掺入。
通常，任何已知的适合于通过众所周知的方法制备脂质体的两亲脂质或脂质混合物可用于本发明中。脂质或脂质混合物必须具有低于体温(37℃)的相转变温度，从而使产物原脂质体粉末能够在生理条件下水合(即为了能在呼吸系统中形成脂质体)。应用成熟的方法，例如DSC法-参见例如J.Suurkuusk等，生物化学，第15卷，no.7，p.1393(1976)，可容易地测定不同脂质混合物的相转变温度。一般地，任何具有低于37℃相转变温度的天然或合成脂质或脂质混合物可用于本发明中。
作为潜在有用的脂质的实例可以提及下述的天然和合成脂质，例如天然和合成的磷酸甘油脂类、鞘脂类和二半乳糖甘油脂类。在天然甘油脂质中，包括下述的鞘脂类(SL)，如鞘磷脂(SM)、神经酰胺和脑苷脂类；半乳糖甘油脂类如二半乳糖二酰基甘油(DGalDG)；磷酸甘油脂类如蛋黄磷脂酰胆碱(e-PC)和大豆磷脂酰胆碱(s-PC)；和卵磷脂如蛋黄卵磷脂(e-lecithin)和大豆卵磷脂(s-lecithin)。在合成脂质中，包括下述的二肉豆蔻酰基磷脂酰胆碱(DMPC)、二棕榈酰基磷脂酰胆碱(DPPC)、二硬脂酰基磷脂酰胆碱(DSPC)、二月桂酰基磷脂酰胆碱(DLPC)、1-肉豆蔻酰基-2-棕榈酰基磷脂酰胆碱(DPPC)、1-棕榈酰基-2-肉豆蔻酰基磷脂酰胆碱(PMPC)和二油酰基磷脂胆酰碱(DOPC)。在脂质混合物中，可以提及：SM/PC、SM/胆固醇、ePC/胆固醇、sPC/胆固醇、PC/PS/胆固醇、DMPC/DPPC、DMPC/DPPC/CH、DMPC/CH、DPPC/DOPC、DPPC/DOPC/CH、DLPC/DPPC、DLPC/DPPC/CH、DLPC/DMPC、DLPC/DMPC/CH、DOPC/DSPC、DPSM/DMSM、蛋黄卵磷脂/胆固醇和大豆卵磷脂/胆固醇，除以上脂质外，还可以包括带电脂质如二肉豆蔻酰基磷脂酰甘油(DMPG)、二棕榈酰基磷脂酰甘油(DPPG)、二肉豆蔻酰基磷脂酸(DMPA)、二棕榈酰基磷脂酸(DPPA)或硬脂酰胺(SA)。
在本发明中，尤其有益的脂质是DPPC和/或DMPC。优选含有至少10％(w/w)DMPC的DPPC和DMPC的混合物。例如，10-50％ DMPC。特别优选还含有至少一种例如其量高达5％(w/w)的带电脂质例如DMPG、DPPG、DMPA或SA的DPPC和DMPC的混合物。其它优选的混合物包括任选地含有至少一种带电脂质的DPSM和DMSM，和任选地含有至少一种带电脂质和具有低于37℃的Tc胆固醇与蛋黄卵磷脂或大豆卵磷脂的混合物。其它的混合物可由本领域中的技术人员参考例如Gregor Cevc，磷脂手册(Phospholipids Handbook)，Marcel Dekker，NewYork(1993)pp 427-435而容易地选出。
优选地，活性组分具有能够掺入到脂质双层中的分子结构，从而有助于在水合过程中脂质体中的包封。这样的一个实例是脂肪酸酯，其具有足以起到疏水固定作用的长烃基链。
适宜的活性组分可以由本领域中的技术人员容易地确定，可以包括例如抗炎症和支气管扩张药物以及抗组织胺、环氧合酶抑制剂、白细胞三烯合成抑制剂、白细胞三烯拮抗剂、磷脂酶-A2(PLA2)抑制剂、血小板凝聚因子(PAF)拮抗剂和气喘预防剂。抗心率失常药、安神药、强心苷、激素、抗高血压药、抗糖尿病药、抗扁桃体炎药和抗癌药、镇静剂、止痛药、抗菌素、抗风湿药、免疫治疗药、抗真菌药、抗低血压药、疫苗、抗病毒药、蛋白质、肽和维生素也是有益的。
具体地，糖肾上腺皮质激素甾族化合物例如布地奈德、地塞米松、β-米松、肤轻松、氟甲松、曲安奈德、氟尼缩松、氯地米松和孕烷衍生物的16，17-缩醛和由此衍生而来的化合物；和β-2激动剂如叔丁喘宁、甲氧苯舒喘宁、沙丁胺醇、福莫特罗、芬忒醇、双氯喘安、异丙喹喘宁、双甲苯喘定和broxaterol也可用于本发明中。活性组分也可以是药物活性物质的混合物；例如可以使用糖肾上腺皮质激素甾族化合物与支气管扩张剂如福莫特罗、甲氧苯舒喘宁、叔丁喘宁或沙丁胺醇的混合物。为了避免疑问，在本文中所指的任何活性组分均包括药物可接受的酯、盐和其水合物。
当活性组分是类固醇时，优选类固醇酯。
活性组分优选类固醇，优选的类固醇用至少8个，例如至少10个或至少12个碳原子的脂肪酸在21位上酯化，脂肪酸可以具有例如高达24个碳原子，例如高达20个碳原子或高达18个碳原子，更优选的活性组分是类固醇-21-棕榈酸酯、肉豆蔻酸酯、月桂酸酯、癸酸酯、辛酸酯或硬脂酸酯，根据本发明最优选的活性组分是化合物(22R)-16α，17α-亚丁基二氧-6α，9α-二氟-11β-羟基-21-棕榈酰氧基孕-4-烯-3，20-二酮、若佛来普奈德(rofleponide)棕榈酸酯。
当活性组分是酯时，它必须能够水解成活性主药。令人惊奇地是，本发明的单相原脂质体粉末有助于所需的就地水解，而结晶状态的酯不水解。
当期望通过吸入法输送时，尽可能多的本发明的原脂质体粉末应由直径小于10微米，例如0.01-10微米或0.1-6微米，例如0.1-5微米的颗粒或该颗粒的附聚物构成。优选地，至少50％的粉末由所需尺寸范围内的颗粒构成。例如至少60％，优选至少70％，更优选至少80％和最优选至少90％的粉末由所需尺寸范围内的颗粒或该颗粒的附聚物构成。
本发明的原脂质体粉末不必包含其它成分。但是包含本发明粉末的药物组合物也可包括其它的药物可接受的添加剂，例如药物可接受的辅助剂、稀释剂和载体。如果完全去除溶剂，那么这些添加剂可在微粉化后或微粉化前添加到原脂质体组合物中。载体优选是结晶的、亲水性的物质。一种优选的载体是结晶乳糖单水合物。其它适宜的载体包括葡萄糖、果糖、半乳糖、海藻糖、蔗糖、麦芽糖、棉子糖、麦芽糖醇、松三糖、水苏糖、乳糖醇、直辉中基性岩、淀粉、木糖醇、甘露糖醇、肌醇等和其水合物，以及氨基酸例如丙氨酸和甜菜碱。
存在于制剂中的添加剂的量可以在非常大的范围内变化。在某些情况下，需要很少或不需要添加剂，而例如一般优选地是用添加剂稀释粉末，从而改进用于吸入器的粉末性质。在后一种情况下，例如至少50％，例如至少70％或至少80％的制剂可由添加剂构成，其余的是原脂质体粉末。添加剂的百分比也可根据生物活性化合物的效力和粉末吸入的最佳量而定。
在使用添加剂例如载体的情况下，整个组合物可以是颗粒的形式，颗粒的尺寸在适于吸入的颗粒尺寸范围内。另外，载体也可包含例如质量平均直径大于20微米的粗粒子，或者它可包含更小颗粒例如质量平均直径小于10微米的附聚物、具有的质量平均直径例如大于20微米的附聚物，从而在任何情况下均形成一种原脂质体和载体的有序混合物。
本发明的另一个目的是提供本发明的原脂质体粉末的制备方法，即得到单相原脂质体粉末的方法。
因此，本发明还提供了用于吸入法的原脂质体粉末的制备方法，该方法包括在一种溶剂中溶解一种脂质或脂质混合物以及一种亲脂生物活性组分，该脂质或脂质混合物具有低于37℃的相转变温度；通过冷冻溶液而得到结晶的溶剂基体和玻璃态单一脂质相；该冷冻在低于脂质相的相转变温度的温度下进行；并且在低于脂质相的相转变温度的温度下蒸发冷冻溶剂。
本发明还提供了含有原脂质体粉末的药物组合物的制备方法，该方法包括在制备原脂质体粉末后，紧接着将结晶的亲水性可药用载体加入到如此获得的原脂质体粉末中的步骤；和任选地将粉末和载体的混合物微粉化从而得到适于吸入的颗粒范围内的颗粒的步骤。
冷冻溶液和溶剂的蒸发可通过常规方法完成，例如在常规冷冻干燥器中。例如可以将脂质和生物活性组分的溶液倾入冷冻干燥器的搁板上并且降低温度以冷冻溶液。然后溶剂的蒸发可例如通过降低冷冻干燥箱中的压力而实现；得到的粉末可从箱体的搁板上刮下来并且任选地过筛。
如果必要，冻干粉末可以进行进一步处理从而得到在适于吸入的颗粒尺寸范围内的颗粒；例如冻干粉末可以例如应用空气喷射磨进行微粉化而得到适于吸入的颗粒。
生物活性组分和脂质的溶液的冷冻以能在冷冻溶剂基体中制备单一脂质相的方式进行。单一脂质相的生产由最终温度和溶液的冷冻速率控制，任何具体溶液的最佳冷冻速率可在必要的该溶剂的结晶时间和必要的脂质和活性组分的结晶时间之间的某处，并且可由本领域的技术人员简单地通过逐次逼近法而确定。最佳的最终温度应低于脂质相的玻璃化温度10-20℃。例如可以用粉末X-射线法检测结晶度和可用差示扫描量热计检测生物活性组分掺入到水合后的脂质体中的程度。
由于所有成分必须在冷冻前存在于溶液中，为了避免可导致粉末多相的沉淀或相分离，所以溶剂必须具有完全溶解脂质和生物活性组分的能力。此外，溶剂应是毒性上可接受的，具有适宜的凝固点，并优选具有高蒸汽压。溶剂可以是例如有机溶剂，例如醇或水和有机溶剂的混合物。优选用于本发明的溶剂是叔丁醇。
粉末可任选地附聚成小球，从而控制粉末的粘结性。球直径优选地不大于1mm，大于这个标准的球可以例如通过筛分除去。任何附聚物是脆的，因此它们可以例如在粉末吸入器中容易地解聚集。
本发明的原脂质体粉末可用于疾病的局部或全身治疗，并且可以例如经上和下的呼吸道施药，包括鼻内施药。所以，本发明还提供了原脂质体粉末在治疗中的用途和在生产经呼吸道治疗疾病的药物中的用途，和治疗需要治疗的病人的方法，该方法包括给所说的病人施用治疗有效量的本发明的原脂质体粉末。
例如，本发明的原脂质体粉末可以用于呼吸道炎性疾病的治疗，例如气喘、鼻炎、牙槽炎、细支气管炎和支气管炎。
对呼吸道施药可以例如使用干粉末吸入器或加压气溶胶吸入器来完成。
适宜的干粉末吸入器包括剂量吸入器，例如已知的商标为Monohaler的单剂量吸入器和多剂量吸入器例如多剂量呼吸驱动的干粉吸入器，如已知的商标为Turbuhaler的吸入器。
尽管本发明的原脂质体粉末特别适合于通过吸入法施药，但是它还可以包含于适于其它输送形式的制剂中。例如可以制备口服、局部和注射制剂，用在例如与发炎相关的疾病例如关节炎、皮肤病和肠病的治疗中。
以下实施例说明本发明的范围，但并不限制本发明的范围。
实施例1
将若佛来普奈德棕榈酸酯(10份)、DPPC(63份)、DMPC(24份)和NaDPPG(3份)在80℃下溶解于叔丁醇(1300份)中。将溶液倒入冻干器搁板上，冷却至-35℃。溶液在30分钟后达到此温度，然后降低冻干器中的压力从而导使溶剂升华。当通过降低压力和升高温度而调节升华速率时，在整个过程中温度不允许超过-10℃。冻干继续进行直至除去全部溶剂。从冻干器的搁板上刮下得到的粉末并且穿过筛子。
将此粉末在空气喷射磨中微粉化成尺寸小于5μm的粉末颗粒。通过筛分的方法，将粉碎后的粉末与乳糖单水合物(20份粉末：80份乳糖单水合物)混合并且混合物在低压下在喷射磨中通过微粉化而进一步均匀化。
使用标准技术，将粉末混合物附聚成不大于1mm的球。大一些的球通过筛分除去。将附聚的粉末填充到Turbuhaler干粉吸入器中。
实施例2
在6小时、17小时和24小时的冷冻时间下重复实施例1的过程。
对比实施例
将实施例1的脂质与活性组分简单地干混合在一起。所得的粉末是包含活性组分和脂质的分离颗粒的多相体系。
实施例3
应用下面具有低于37℃的相转变温度的脂质混合物重复实施例1的过程：
DPSM/DPSM
蛋黄卵磷脂/胆固醇
大豆卵磷脂/胆固醇
实施例4
应用下面的活性组分重复实施例1的过程：
若佛来普奈德-21-肉豆蔻酸酯
若佛来普奈德-21-月桂酸酯
若佛来普奈德-21-癸酸酯
若佛来普奈德-21-辛酸酯
若佛来普奈德-21-硬脂酸酯
粉末分析
对实施例1和2的粉末混合物进行的X-射线粉末衍射显示粉末中不存在结晶状态。对比实施例的粉末含有结晶状态的活性组分。
活性组分掺入脂质体中
将实施例1和2的原脂质体粉末水合并且应用差示扫描量热法测量活性组分的混合程度。DSC显示活性组分完全掺入到脂质体中。对对比实施例粉末进行的DSC显示活性组分基本上没有掺入到脂质体中。
酯水解
研究了实施例1和对比实施例的原脂质体粉末水解成活性主要成分的程度，实施例1和2以及对比实施例(每一种情况下50μM类固醇酯)的原脂质体粉末用水水合并加热到50℃持续15分钟。然后，将样品在37℃下在猪胰脂肪酶(2mg/mL)的存在下，在一种缓冲剂(1mM EDTA，80mM KCL，10mM HEPES，pH7.4)中孵育，并且周期性地进行超声处理，变换每次的处理时间长度，其最高达120分钟。将样品通过HPLC方法分析以测定多少酯已水解成活性主要成分。
与仅有2％的对比实施例粉末相比，有94％的实施例1的原脂质体粉末水解成活性主要成分。
药理研究
抗水肿效力应用Sephadex模型对小鼠进行测定，如L.Kallstrom等人于试剂和作用(Agent and Action)17(3/4)355(1985)中所述。
将实施例1和对比实施例的粉末样品悬浮于冷盐水中并通过气管内注射进入雄Spargue-Dawley小鼠的左肺中。1小时后通过气管内滴注Sephadex滴(5mg/kg)到左肺和右肺中而引发了炎症过程。所得的间隙水肿在20小时后通过测量左肺和右肺的重量而定量。肺重量的减少是由粉末的药理效能导致。用实施例1的原脂质体粉末处理过的小鼠的肺重量比用对比实施例的原脂质体粉末处理过的小鼠的肺重量减少了40倍：即根据本发明的原脂质体粉末的效能比对比实施例粉末的效能高了40倍。
吸入法研究
麻醉Beagle狗，插管，并且置于实施例1或对比实施例制剂的粉末气溶胶中。气溶胶由粉末片剂用Wright Dust Feed仪器在1800rpm下进行操作而产生。在吸入过程中记录气溶胶浓度(Casella 950 AMS)、潮体积、吸气潮体积和呼吸频率。目标吸入剂量是25μg若佛来普奈德棕榈酸酯/Kg体重。吸入后，有规律地采取血浆样品。通过比较静脉用药后的若佛来普奈德血浆浓度而计算生物利用率。给予根据实施例1的粉末后，若佛来普奈德的生物利用率接近100％，而给予对比实施例的粉末后，若佛来普奈德的生物利用率是无法测量到。
Claims (37)
1、一种药物组合物，其包含一种原脂质体粉末，所说的粉末包含一种结合具有低于37℃的相转变温度的脂质或脂质混合物的单相的生物活性组分分散颗粒，和一种结晶的和亲水性的药物可接受的载体。
2、一种权利要求1中要求保护的药物组合物，其中粉末包含一种或多种选自天然和合成的磷酸甘油脂类、鞘脂类和二半乳糖甘油脂类的脂质。
3、一种权利要求1或2中要求保护的药物组合物，其中粉末包含选自混合物SM/PC、SM/胆固醇、ePC/胆固醇、sPC/胆固醇、PC/PS/胆固醇、DMPC/DPPC、DMPC/DPPC/CH、DMPC/CH、DPPC/DOPC、DPPC/DOPC/CH、DLPC/DPPC、DLPC/DPPC/CH、DLPC/DMPC、DLPC/DMPC/CH、DOPC/DSPC的脂质混合物。
4、一种权利要求3中要求保护的药物组合物，其中粉末包含DPPC、DMPC或DPPC和DMPC的混合物。
5、一种权利要求4中要求保护的药物组合物，其中混合物含有至少10％的DMPC。
6、一种权利要求1、2、4或5中任一项要求保护的药物组合物，其中粉末还包含一种带电的脂质。
7、一种权利要求6中要求保护的药物组合物，其中带电的脂质选自DMPG、DPPG、DMPA和SA。
8、一种权利要求1、2、4、5或7中任一项要求保护的药物组合物，其中活性组分选自抗炎症药物、支气管扩张药物、抗组织胺、环氧合酶抑制剂、白细胞三烯拮抗剂、PLA2抑制剂、PAF拮抗剂和气喘预防剂。
9、一种权利要求1、2、4、5或7中任一项要求保护的药物组合物，其中活性组分包含一种糖肾上腺皮质激素甾族化合物。
10、一种权利要求1、2、4、5或7中任一项要求保护的药物组合物，其中活性组分包含β-2激动剂。
11、一种权利要求1、2、4、5或7中任一项要求保护的药物组合物，其中活性组分包含用至少8个碳原子的脂肪酸在21位上酯化的类固醇。
12、一种权利要求11中要求保护的药物组合物，其中活性组分包含用至少10个碳原子的脂肪酸在21位上酯化的类固醇。
13、一种权利要求12中要求保护的药物组合物，其中活性组分包含用至少12个碳原子的脂肪酸在21位上酯化的类固醇。
14、一种权利要求1、2、4、5、7、12或13中任一项要求保护的药物组合物，其中活性组分包含一种类固醇-21-棕榈酸酯。
15、一种权利要求1或2中要求保护的药物组合物，其中活性组分包含若佛来普奈德棕榈酸酯。
16、一种权利要求1、2、4、5、7、12或13中任一项要求保护的药物组合物，其中至少50％的粉末包含直径小于10微米的颗粒。
17、一种权利要求16中要求保护的药物组合物，其中至少60％的粉末包含直径小于10微米的颗粒。
18、一种权利要求17中要求保护的药物组合物，其中至少70％的粉末包含直径小于10微米的颗粒。
19、一种权利要求18中要求保护的药物组合物，其中至少80％的粉末包含直径小于10微米的颗粒。
20、一种权利要求19中要求保护的药物组合物，其中至少90％的粉末包含直径小于10微米的颗粒。
21、一种在前面权利要求17-20的任之一项中要求保护的药物组合物，其中颗粒直径为0.01-10微米。
22、一种权利要求21中要求保护的药物组合物，其中颗粒直径为0.1-6微米。
23、一种权利要求22中要求保护的药物组合物，其中颗粒直径为0.1-5微米。
24、一种权利要求1、2、4、5、7、12、13、17-20、22或23中任一项要求保护的药物组合物，其包含附聚的颗粒。
25、一种权利要求1、2、4、5、7、12、13、17-20、22或23中任一项要求保护的药物组合物，其中载体是结晶乳糖单水合物。
26、一种权利要求1、2、4、5、7、12、13、17-20、22或23中任一项要求保护的药物组合物，其中载体选自葡萄糖、果糖、半乳糖、海藻糖、蔗糖、麦芽糖、棉子糖、麦芽糖醇、松三糖、水苏糖、乳糖醇、直辉中基性岩、淀粉、木糖醇、甘露糖醇、肌醇和其水合物，以及氨基酸。
27、一种权利要求1、2、4、5、7、12、13、17-20、22或23中任一项要求保护的药物组合物，其中载体包含质量平均直径大于20微米的颗粒。
28、一种权利要求1、2、4、5、7、12、13、17-20、22或23中任一项要求保护的药物组合物，其中载体包含质量平均直径小于10微米的颗粒。
29、一种生产权利要求1-28中任一项要求保护的药物组合物方法，其中所述原脂质体粉末是如此生产的：在一种溶剂中溶解一种脂质或脂质混合物以及一种亲脂性生物活性组分，所说的脂质或脂质混合物具有低于37℃的相转变温度；通过冷冻溶液而得到结晶的溶剂基体和玻璃态单一脂质相，所说的冷冻过程在低于脂质相的相转变温度的温度下进行；和在低于脂质相的相转变温度的温度下蒸发冷冻溶剂。
30、一种权利要求29中要求保护的方法，其还包括将冻干粉末微粉化以得到适于吸入的颗粒尺寸范围内的颗粒的步骤。
31、一种权利要求29或30中要求保护的方法，其中冷冻和溶剂蒸发在冻干器中完成。
32、一种权利要求29或30中要求保护的方法，其中溶剂包含一种有机溶剂。
33、一种权利要求32中要求保护的方法，其中溶剂包括醇。
34、一种权利要求33中要求保护的方法，其中溶剂包括叔丁醇。
35、一种生产权利要求1-28中任一项的药物组合物的方法，该方法包括根据权利要求29、30、33或34中任一项的方法，紧接着将结晶的亲水性可药用载体加入到如此获得的原脂质体粉末中的步骤；和任选地将粉末和载体的混合物微粉化从而得到适于吸入的颗粒范围内的颗粒的步骤。
36、一种权利要求35中要求保护的方法，其还包括使颗粒附聚成直径为1mm或更小的球的步骤。
37、一种权利要求1-28中任一项要求保护的药物组合物在生产用于经呼吸道治疗疾病的药物中的用途。
Applications Claiming Priority (4)
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| SE9502369A SE9502369D0 (sv) | 1995-06-30 | 1995-06-30 | Process for the preparation of compositions for inhalation |
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Country Status (32)
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Families Citing this family (109)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR002009A1 (es) * | 1994-12-22 | 1998-01-07 | Astra Ab | Composicion farmaceutica, procedimiento para la manufactura de un polvo de proliposoma como el utilizado en dicha composicion, procedimiento para lamanufactura de dicha composicion, uso de dicha composicion farmaceutica en la manufactura de un medicamento y dispositivo inhalador de polvo seco. |
| US20020052310A1 (en) * | 1997-09-15 | 2002-05-02 | Massachusetts Institute Of Technology The Penn State Research Foundation | Particles for inhalation having sustained release properties |
| TW497974B (en) * | 1996-07-03 | 2002-08-11 | Res Dev Foundation | High dose liposomal aerosol formulations |
| EP0927025A4 (en) * | 1996-09-18 | 2001-07-25 | Dragoco Inc | DRY POWDER COMPOSITION WITH ACTIVE INGREDIENT ENCLOSED IN LIPOSOMES |
| US20030203036A1 (en) * | 2000-03-17 | 2003-10-30 | Gordon Marc S. | Systems and processes for spray drying hydrophobic drugs with hydrophilic excipients |
| IL133597A0 (en) * | 1997-06-27 | 2001-04-30 | Astra Ab | New combination of antiasthma medicaments |
| JP2002510311A (ja) * | 1997-06-27 | 2002-04-02 | アストラ・アクチエボラーグ | トコフェロールにより安定化された吸引用プロリポソーム粉末 |
| US7052678B2 (en) * | 1997-09-15 | 2006-05-30 | Massachusetts Institute Of Technology | Particles for inhalation having sustained release properties |
| US7348025B2 (en) | 1997-09-23 | 2008-03-25 | Research Development Foundation | Small particle liposome aerosols for delivery of anticancer drugs |
| US6090407A (en) | 1997-09-23 | 2000-07-18 | Research Development Foundation | Small particle liposome aerosols for delivery of anti-cancer drugs |
| US6433040B1 (en) | 1997-09-29 | 2002-08-13 | Inhale Therapeutic Systems, Inc. | Stabilized bioactive preparations and methods of use |
| US6946117B1 (en) | 1997-09-29 | 2005-09-20 | Nektar Therapeutics | Stabilized preparations for use in nebulizers |
| US20020017295A1 (en) * | 2000-07-07 | 2002-02-14 | Weers Jeffry G. | Phospholipid-based powders for inhalation |
| US20060165606A1 (en) | 1997-09-29 | 2006-07-27 | Nektar Therapeutics | Pulmonary delivery particles comprising water insoluble or crystalline active agents |
| US6309623B1 (en) | 1997-09-29 | 2001-10-30 | Inhale Therapeutic Systems, Inc. | Stabilized preparations for use in metered dose inhalers |
| US6565885B1 (en) | 1997-09-29 | 2003-05-20 | Inhale Therapeutic Systems, Inc. | Methods of spray drying pharmaceutical compositions |
| SE9704833D0 (sv) * | 1997-12-22 | 1997-12-22 | Astra Ab | New formulation |
| US6956021B1 (en) * | 1998-08-25 | 2005-10-18 | Advanced Inhalation Research, Inc. | Stable spray-dried protein formulations |
| EP1839648A3 (en) * | 1998-11-12 | 2007-11-21 | Transave, Inc. | An inhalation system |
| KR20010111564A (ko) * | 1998-11-12 | 2001-12-19 | 프랭크 쥐. 필키윅즈 | 흡입 시스템 |
| GB9912639D0 (en) | 1999-05-28 | 1999-07-28 | Britannia Pharmaceuticals Ltd | Improvements in and relating to treatment of respiratory conditions |
| GB2359749B (en) * | 1998-11-26 | 2004-05-05 | Britannia Pharmaceuticals Ltd | Anti-asthmatic combinations comprising surface active phospholipids |
| HUP0200185A3 (en) * | 1999-03-05 | 2006-07-28 | Chiesi Farma Spa | Improved powdery pharmaceutical compositions for inhalation |
| EP1043016B1 (en) * | 1999-03-30 | 2014-08-20 | Sodic Sa | A plant extract based on glycerides,phospholipids and phytosphingolipids, a method for the preparation of this extract and a cosmetic composition containing the same |
| DE60026982T2 (de) * | 1999-04-05 | 2006-11-16 | Mannkind Corp., Danbury | Verfahren zur bildung von feinem pulver |
| US7300667B1 (en) | 1999-05-27 | 2007-11-27 | Euro-Celtique, S.A. | Preparations for the application of anti-inflammatory, especially antiseptic agents and/or agents promoting the healing of wounds, to the lower respiratory tract |
| PT1180017E (pt) | 1999-05-27 | 2010-05-28 | Euro Celtique Sa | Preparações com povidona-iodo para o tratamento de feridas |
| US9006175B2 (en) | 1999-06-29 | 2015-04-14 | Mannkind Corporation | Potentiation of glucose elimination |
| US20010036481A1 (en) * | 1999-08-25 | 2001-11-01 | Advanced Inhalation Research, Inc. | Modulation of release from dry powder formulations |
| US6749835B1 (en) | 1999-08-25 | 2004-06-15 | Advanced Inhalation Research, Inc. | Formulation for spray-drying large porous particles |
| US7678364B2 (en) | 1999-08-25 | 2010-03-16 | Alkermes, Inc. | Particles for inhalation having sustained release properties |
| WO2001013891A2 (en) * | 1999-08-25 | 2001-03-01 | Advanced Inhalation Research, Inc. | Modulation of release from dry powder formulations |
| US6156294A (en) | 1999-11-28 | 2000-12-05 | Scientific Development And Research, Inc. | Composition and method for treatment of otitis media |
| GB9928311D0 (en) * | 1999-11-30 | 2000-01-26 | Novartis Ag | Organic compounds |
| DE10012151A1 (de) * | 2000-03-13 | 2001-09-27 | Gsf Forschungszentrum Umwelt | Mittel zur Behandlung von Erkrankungen des Tracheo-Brochialtraktes, insbesondere der COPD |
| GB0008660D0 (en) * | 2000-04-07 | 2000-05-31 | Arakis Ltd | The treatment of respiratory diseases |
| US7871598B1 (en) | 2000-05-10 | 2011-01-18 | Novartis Ag | Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery and methods of use |
| TWI290473B (en) | 2000-05-10 | 2007-12-01 | Alliance Pharma | Phospholipid-based powders for drug delivery |
| CN1294141C (zh) | 2000-08-05 | 2007-01-10 | 葛兰素集团有限公司 | 作为抗炎剂的6α，9α－二氟-17α－[(2－呋喃基羧基)氧基]－11β－羟基－16α－甲基－3－氧代-雄甾－1，4-二烯－17－硫代羧酸S－氟甲酯 |
| US6858596B2 (en) | 2000-08-05 | 2005-02-22 | Smithkline Beecham Corporation | Formulation containing anti-inflammatory androstane derivative |
| GB0019172D0 (en) | 2000-08-05 | 2000-09-27 | Glaxo Group Ltd | Novel compounds |
| US6787532B2 (en) | 2000-08-05 | 2004-09-07 | Smithkline Beecham Corporation | Formulation containing anti-inflammatory androstane derivatives |
| US6777399B2 (en) | 2000-08-05 | 2004-08-17 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative compositions |
| US6759398B2 (en) | 2000-08-05 | 2004-07-06 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative |
| US6777400B2 (en) | 2000-08-05 | 2004-08-17 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative compositions |
| US6858593B2 (en) | 2000-08-05 | 2005-02-22 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative compositions |
| US6750210B2 (en) | 2000-08-05 | 2004-06-15 | Smithkline Beecham Corporation | Formulation containing novel anti-inflammatory androstane derivative |
| PT2283817T (pt) | 2000-11-30 | 2016-08-22 | Vectura Ltd | Método de fabrico de partículas para utilização numa composição farmacêutica |
| US20020141946A1 (en) * | 2000-12-29 | 2002-10-03 | Advanced Inhalation Research, Inc. | Particles for inhalation having rapid release properties |
| UA77656C2 (en) | 2001-04-07 | 2007-01-15 | Glaxo Group Ltd | S-fluoromethyl ester of 6-alpha, 9-alpha-difluoro-17-alpha-[(2-furanylcarbonyl)oxy]-11-beta-hydroxy-16- alpha-methyl-3-oxoandrosta-1,4-dien-17-beta-carbothioacid as anti-inflammatory agent |
| MXPA03009940A (es) | 2001-04-30 | 2004-01-29 | Glaxo Group Ltd | DERIVADOS ANTI-INFLAMATORIOS DE 17. BETA-CARBOTIOATO ESTER DE ANDROSTANO CON UN GRUPO DE ESTER CICLICO EN LA POSICIoN 17.ALFA. |
| AU2002352836B2 (en) * | 2001-11-20 | 2005-09-29 | Alkermes, Inc. | Improved particulate compositions for pulmonary delivery |
| ES2364636T3 (es) | 2001-12-19 | 2011-09-08 | Novartis Ag | Administración pulmonar de aminoglucósidos. |
| NZ534142A (en) * | 2002-01-21 | 2007-08-31 | Vasogen Ireland Ltd | Pharmaceutically acceptable phosphate-glycerol carrying bodies comprising phospatidylglycerol and/or phosphatidylcholine and/or phosphatidylglycerol |
| US20030224039A1 (en) * | 2002-03-05 | 2003-12-04 | Transave, Inc. | Methods for entrapment of bioactive agent in a liposome or lipid complex |
| AU2003220125B2 (en) | 2002-03-20 | 2006-06-15 | Mannkind Corporation | Inhalation apparatus |
| GB2389530B (en) | 2002-06-14 | 2007-01-10 | Cipla Ltd | Pharmaceutical compositions |
| US7718189B2 (en) | 2002-10-29 | 2010-05-18 | Transave, Inc. | Sustained release of antiinfectives |
| US7879351B2 (en) * | 2002-10-29 | 2011-02-01 | Transave, Inc. | High delivery rates for lipid based drug formulations, and methods of treatment thereof |
| DK2363114T3 (da) * | 2002-10-29 | 2015-06-22 | Insmed Inc | Opretholdt afgivelse af anti-infektionsmidler |
| CN1208052C (zh) | 2003-03-20 | 2005-06-29 | 上海家化联合股份有限公司 | 一种辅酶q10前体脂质体及其制备方法 |
| US20040204439A1 (en) * | 2003-04-14 | 2004-10-14 | Staniforth John Nicholas | Composition, device, and method for treating sexual dysfunction via inhalation |
| US20060147389A1 (en) * | 2004-04-14 | 2006-07-06 | Vectura Ltd. | Devices and pharmaceutical compositions for enhancing dosing efficiency |
| JP2006522634A (ja) * | 2003-04-14 | 2006-10-05 | ベクトゥラ・リミテッド | 投与効率を向上させるデバイス及び製薬組成 |
| CN100427064C (zh) * | 2003-04-16 | 2008-10-22 | 沈阳药科大学 | 一种制备脂质体的新方法 |
| ES2362038T3 (es) * | 2003-09-02 | 2011-06-27 | Norton Healthcare Limited | Procedimiento para preparar un medicamento. |
| US20050214224A1 (en) * | 2003-11-04 | 2005-09-29 | Nektar Therapeutics | Lipid formulations for spontaneous drug encapsulation |
| DE602005024413D1 (de) | 2004-08-20 | 2010-12-09 | Mannkind Corp | Katalyse der diketopiperazinsynthese |
| EP2322180B1 (en) | 2004-08-23 | 2015-05-27 | MannKind Corporation | Diketopiperazine salts for drug delivery |
| GB0425758D0 (en) | 2004-11-23 | 2004-12-22 | Vectura Ltd | Preparation of pharmaceutical compositions |
| CN102614131A (zh) | 2005-09-14 | 2012-08-01 | 曼金德公司 | 以提高结晶微粒表面对活性试剂的亲和力为基础的药物配制方法 |
| CA2631872C (en) | 2005-12-08 | 2014-04-01 | Transave, Inc. | Lipid-based compositions of antiinfectives for treating pulmonary infections and methods of use thereof |
| BRPI0707991B8 (pt) | 2006-02-22 | 2021-05-25 | Mannkind Corp | métodos de preparação de um medicamento em pó seco com uma propriedade farmacêutica melhorada, dito pó seco e uso de uma quantidade efetiva do pó seco |
| CN1895223B (zh) * | 2006-04-05 | 2012-06-27 | 沈阳药科大学 | 一种新的脂质体制备方法 |
| US9814672B2 (en) * | 2007-03-09 | 2017-11-14 | Susan T. Laing | Echogenic vehicle for clinical delivery of plasminogen activator and other fibrin-binding therapeutics to thrombi |
| EP2146692A1 (en) * | 2007-03-19 | 2010-01-27 | Fresenius Kabi Oncology Limited | Proliposomal and liposomal compositions |
| US20100196455A1 (en) * | 2007-05-04 | 2010-08-05 | Transave, Inc. | Compositions of Multicationic Drugs for Reducing Interactions with Polyanionic Biomolecules and Methods of Use Thereof |
| US9333214B2 (en) | 2007-05-07 | 2016-05-10 | Insmed Incorporated | Method for treating pulmonary disorders with liposomal amikacin formulations |
| US9114081B2 (en) | 2007-05-07 | 2015-08-25 | Insmed Incorporated | Methods of treating pulmonary disorders with liposomal amikacin formulations |
| US9119783B2 (en) | 2007-05-07 | 2015-09-01 | Insmed Incorporated | Method of treating pulmonary disorders with liposomal amikacin formulations |
| US20090047336A1 (en) * | 2007-08-17 | 2009-02-19 | Hong Kong Baptist University | novel formulation of dehydrated lipid vesicles for controlled release of active pharmaceutical ingredient via inhalation |
| IL313823A (en) | 2008-06-13 | 2024-08-01 | Mannkind Corp | A dry powder inhaler and system for drug delivery |
| US8485180B2 (en) * | 2008-06-13 | 2013-07-16 | Mannkind Corporation | Dry powder drug delivery system |
| AU2009259883B2 (en) | 2008-06-20 | 2015-02-05 | Mannkind Corporation | An interactive apparatus and method for real-time profiling of inhalation efforts |
| TWI494123B (zh) | 2008-08-11 | 2015-08-01 | Mannkind Corp | 超快起作用胰島素之用途 |
| US8314106B2 (en) | 2008-12-29 | 2012-11-20 | Mannkind Corporation | Substituted diketopiperazine analogs for use as drug delivery agents |
| ES2994042T3 (en) | 2009-02-26 | 2025-01-16 | Glaxo Group Ltd | Pharmaceutical formulations comprising 4-{(1 r)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol |
| CA2754595C (en) | 2009-03-11 | 2017-06-27 | Mannkind Corporation | Apparatus, system and method for measuring resistance of an inhaler |
| KR20190090092A (ko) | 2009-06-12 | 2019-07-31 | 맨카인드 코포레이션 | 한정된 비표면적을 갖는 디케토피페라진 마이크로입자 |
| EP2496295A1 (en) | 2009-11-03 | 2012-09-12 | MannKind Corporation | An apparatus and method for simulating inhalation efforts |
| GB0921075D0 (en) | 2009-12-01 | 2010-01-13 | Glaxo Group Ltd | Novel combination of the therapeutic agents |
| KR20130117755A (ko) | 2010-06-21 | 2013-10-28 | 맨카인드 코포레이션 | 건조 분말 약물 운반 시스템 및 방법 |
| MX353285B (es) | 2011-04-01 | 2018-01-05 | Mannkind Corp | Paquete de blister para cartuchos farmaceuticos. |
| WO2012174472A1 (en) | 2011-06-17 | 2012-12-20 | Mannkind Corporation | High capacity diketopiperazine microparticles |
| BR112014009686A2 (pt) | 2011-10-24 | 2018-08-07 | Mannkind Corp | composição analgésica inalável, pó seco e método para tratar dor |
| EP4331675A3 (en) | 2012-05-21 | 2024-05-29 | Insmed Incorporated | Systems for treating pulmonary infections |
| BR112015000529B1 (pt) | 2012-07-12 | 2022-01-11 | Mannkind Corporation | Inalador de pó seco |
| EA035868B1 (ru) * | 2012-08-17 | 2020-08-24 | Смартек Интернэшнл Эл-Эл-Си | Приготовление высушенных липосом для применения в системах выпуска в прессованном виде |
| US10159644B2 (en) | 2012-10-26 | 2018-12-25 | Mannkind Corporation | Inhalable vaccine compositions and methods |
| CN104884047A (zh) | 2012-11-29 | 2015-09-02 | 英斯梅德股份有限公司 | 稳定的万古霉素制剂 |
| US9603799B2 (en) * | 2013-03-15 | 2017-03-28 | Htd Biosystems Inc. | Liposomal vaccine adjuvants and methods of making and using same |
| KR102391750B1 (ko) | 2013-03-15 | 2022-04-28 | 맨카인드 코포레이션 | 미세결정성 디케토피페라진 조성물 및 방법 |
| BR112016000937A8 (pt) | 2013-07-18 | 2021-06-22 | Mannkind Corp | formulações farmacêuticas de pó seco, método para a fabricação de uma formulação de pó seco e uso de uma formulação farmacêutica de pó seco |
| CA2920488C (en) | 2013-08-05 | 2022-04-26 | Mannkind Corporation | Insufflation apparatus and methods |
| WO2015148905A1 (en) | 2014-03-28 | 2015-10-01 | Mannkind Corporation | Use of ultrarapid acting insulin |
| ME03536B (me) | 2014-05-15 | 2020-04-20 | Insmed Inc | Postupci za lečenje netuberkuloznih mikobakterijskih infekcija pluća |
| US10561806B2 (en) | 2014-10-02 | 2020-02-18 | Mannkind Corporation | Mouthpiece cover for an inhaler |
| CN109152735B (zh) * | 2016-05-09 | 2022-03-11 | 阿斯利康(瑞典)有限公司 | 包含亲脂性抗炎剂的脂质纳米颗粒及其使用方法 |
| WO2019191627A1 (en) | 2018-03-30 | 2019-10-03 | Insmed Incorporated | Methods for continuous manufacture of liposomal drug products |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US514674A (en) * | 1894-02-13 | Ejector for breakdown guns | ||
| EP0026241A2 (en) * | 1978-10-12 | 1981-04-08 | Bowater-Scott Limited | Holder and dispenser for stacked rolls |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2135647A (en) * | 1983-02-15 | 1984-09-05 | Squibb & Sons Inc | Method of preparing liposomes and products produced thereby |
| US4744989A (en) * | 1984-02-08 | 1988-05-17 | E. R. Squibb & Sons, Inc. | Method of preparing liposomes and products produced thereby |
| JPH0753661B2 (ja) * | 1984-03-08 | 1995-06-07 | フアレス フアーマスーチカル リサーチ エヌブイ | プロ―リポソーム組成物及びリポソームの水性分散物を作る方法 |
| SE8601457D0 (sv) * | 1986-04-01 | 1986-04-01 | Draco Ab | Compositions of liposomes and b?712-receptor active substances for inhalation |
| SE8603812D0 (sv) * | 1986-09-12 | 1986-09-12 | Draco Ab | Administration of liposomes to mammals |
| US5096629A (en) * | 1988-08-29 | 1992-03-17 | 501 Nippon Fine Chemical Co., Ltd. | Method for preparing lipid powder for use in preparing liposomes and method for preparing liposomes |
| CA2087902C (en) * | 1992-02-05 | 2006-10-17 | Narendra Raghunathji Desai | Liposome compositions of porphyrin photosensitizers |
| JPH09501168A (ja) * | 1993-08-06 | 1997-02-04 | オパーバス ホールディング ビー ヴィ | 生物構造体、生体ポリマー及び／又はオリゴマーを充填した小胞の調製方法 |
| US5635206A (en) * | 1994-01-20 | 1997-06-03 | Hoffmann-La Roche Inc. | Process for liposomes or proliposomes |
| AR002009A1 (es) * | 1994-12-22 | 1998-01-07 | Astra Ab | Composicion farmaceutica, procedimiento para la manufactura de un polvo de proliposoma como el utilizado en dicha composicion, procedimiento para lamanufactura de dicha composicion, uso de dicha composicion farmaceutica en la manufactura de un medicamento y dispositivo inhalador de polvo seco. |
-
1995
- 1995-12-18 AR ARP950100614A patent/AR002009A1/es unknown
- 1995-12-18 SA SA95160463A patent/SA95160463B1/ar unknown
- 1995-12-19 TW TW084113555A patent/TW508248B/zh not_active IP Right Cessation
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- 1995-12-20 CA CA002208517A patent/CA2208517A1/en not_active Abandoned
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- 1995-12-20 DE DE69530792T patent/DE69530792T2/de not_active Expired - Lifetime
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- 1995-12-20 AU AU43605/96A patent/AU693632B2/en not_active Ceased
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- 1995-12-20 EE EE9700134A patent/EE03592B1/xx not_active IP Right Cessation
- 1995-12-20 NZ NZ298180A patent/NZ298180A/xx unknown
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- 1995-12-21 EG EG106095A patent/EG23683A/xx active
-
1997
- 1997-06-06 IS IS4500A patent/IS1978B/is unknown
- 1997-06-19 FI FI972653A patent/FI972653L/fi not_active Application Discontinuation
- 1997-06-19 NO NO19972847A patent/NO320434B1/no unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US514674A (en) * | 1894-02-13 | Ejector for breakdown guns | ||
| EP0026241A2 (en) * | 1978-10-12 | 1981-04-08 | Bowater-Scott Limited | Holder and dispenser for stacked rolls |
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