CN1138528C - 肽/蛋白质悬浮调和物 - Google Patents
肽/蛋白质悬浮调和物 Download PDFInfo
- Publication number
- CN1138528C CN1138528C CNB961944943A CN96194494A CN1138528C CN 1138528 C CN1138528 C CN 1138528C CN B961944943 A CNB961944943 A CN B961944943A CN 96194494 A CN96194494 A CN 96194494A CN 1138528 C CN1138528 C CN 1138528C
- Authority
- CN
- China
- Prior art keywords
- temper
- peptide
- protein
- suspension
- utensil
- 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.)
- Expired - Fee Related
Links
Images
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
-
- 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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
-
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
Abstract
本发明提供改善肽和蛋白质的化学和物理稳定性用的改良组合物。本发明提供含液体悬浮液的液体有益剂调和物,所述悬浮液包括至少5wt%的有益剂,且悬浮液粘度和有益剂大小可使有益剂在持久递送期间在悬浮液中的沉降程度减至最小。
Description
本发明涉及稳定化、浓缩了的肽和蛋白质悬浮液调和物。更确切地说,本发明涉及新的改进型组合物,用以提供药用肽/蛋白质的浓缩化非水悬浮液,它具有合适的化学、物理和生物活性稳定性,适于由持续释放施药系统长期递送。
蛋白质和许多其它生物活性化合物长期在水溶液中会降解。由于这种化学不稳定性,蛋白质溶液通常不适用于施药器具。蛋白质在其中不溶解而是悬浮着的载体常可提供改进的化学稳定性。此外,当药剂在所要求的载体中溶解度低时,有效的办法是将此有益剂悬浮于载体中。但是,由于悬浮有益剂的沉降和凝聚,悬浮液的物理稳定性就差。随着活性化合物浓度的提高,非水载体的这些问题会更为严重。
就施药植入物来说,持续施药达一年是常有的。治疗性递送速率低的有益剂是用于植入物的主要候选物。当该器具被植入或贮存时,有益剂可能在液体调和物中产生沉降,这种不均匀性会不利地影响配成的有益剂的浓度。植入的有益剂储器(reservoir)的尺寸是解决该问题的关键,植入的储器通常约为25-250μl。受该体积限制,高浓度(大于或等于10%)、最小量悬浮载体以及其它赋形剂的调和物是优选的。
有益剂的一个实例是α-干扰素(α-IFN),它在低剂量下就有疗效。此干扰素由于其抗病毒活性而可治疗慢性肝炎。目前规定的疗法需要注射每剂约含3.0×106IU(15微克)药物的α-IFN溶液,每周三次,疗程为4~6个月。需要经常注射,因为α-IFN的消失半衰期短;在注射后8~10小时内,多数药物就全部从血浆中消失了。
Yim等公开的U.S.Pat.No 4,871,538;Kwan等公开的U.S.Pat.No.4,847,079;Yamashira等公开的U.S.Pat.No.5,081,156和Yim等公开的European Publication No.0,281,299描述了浓度在104~108IU/ml之间的IFN/肽组合物。在Kwan等的报导中,描述了α-IFN浓度为103~108IU/ml的药物溶液。Yim描述的剂量范围为104~108IU α-IFN/ml。在Yim II的报导中,描述了悬浮于磷酸盐缓冲液中含α-IFN、锌和鱼精蛋白的不溶性复合物。但是,Yim I、Yim II和Kwan部分启示了水溶性缓冲剂在其组合物中的应用。这导致化合物可能的水解,引起化学降解和不稳定性。Yamashira启示了干扰素在含可生物降解的载体的混合物中的干扰素持续释放制剂。每1mg载体中掺入IFN的浓度为103~108IU,或每个剂量形式含104~108IU的干扰素。此外,虽然专利和公开出版物描述了前述104~108IU/ml的浓度,但未报导109~1011IU/ml数量级的浓度。
需要用于植入、持续释放器具的新型组合物,它包括非水悬浮液载体和作为有益剂的浓缩化蛋白质/肽。尽管本技术中已知浓度高达108IU/ml时可实现稳定的αIFN,而本发明利用新的组合,其组合效果使有益剂化合物比其它调和物在物理和化学稳定性方面得到显著而惊人的改善。
图1表示与本发明的浓缩化悬浮液组合使用的可植入、持续释放渗透性递送器具的剖面图。
图2阐明了细胞色素c悬浮液的稳定性。
图3阐明了α-干扰素悬浮液的稳定性。
本发明的一个方面涉及高浓度下长期稳定肽和蛋白质的制剂。
本发明的另一个方面涉及人α-IFN的稳定化制剂。
本发明的又一个方面涉及浓度至少为1×109IU/ml的人α-IFN稳定化制剂。
本发明的又一个方面涉及稳定的有益剂调和物,它包括粒子大小为0.3~50微米、优选1~10微米的有益剂和悬浮液载体配方,该配方的粘度在37℃下为100~100,000泊。
这种新调和物是物理稳定的悬浮液,它赋予水敏化合物以化学稳定性且可用于稳定高浓度的活性化合物。载体组分能用于可植入的系统。
本发明的浓缩化有益剂悬浮液提供长期大为稳定的浓度,适用于持续递送、植入物应用。本发明的悬浮液可使因水解引起的粒子降解和持久递送期间的粒子沉降减至最小。这类“持久期间”表示一周至两年,优选至少约为一个月,最优选是三个月至一年。
持续的非肠道递送药物具有很多优点。典型的持续释放可植入渗透性递送器具被描述于U.S.Pat.Nos.5,034,229;5,057,318和5,110,596,将它们并入本文作参考。如图1所示,这类器具10通常包括外壳12,外壳12包括流体不透性壁部分14和流体渗透性壁部分6,这两部分限定并包围内腔18。出口通道20形成于流体不透性壁部分,通过流体将内腔18与外界环境连接。为了将与环境流体的接触降至最小,使有益剂22含于流体不透性部分内。含于流体渗透性部分内的膨胀性推动元件24,由吸入穿过流体渗透性壁部分的流体而引起膨胀。一般由活塞26将有益剂22与膨胀性推动元件24分开,这就迫使药剂从出口通道出去而进入应用环境。如文中揭示的非水性施用悬浮液调和物中的有益剂,可用这些种类的植入器具来实现。
依本发明,高浓度的有益剂悬浮于非水悬浮液载体中,可保持物理和化学稳定。“高浓度”定义为有益剂浓度值至少应为调和物的约0.5wt%,优选至少约5wt%,更优选0.5~70wt%以及5~70wt%,而最优选约10~70w/w。例如,“高浓度”的α-IFN是109~1011IU;至于鲑鱼降钙素,2×104IU~2.8×106IU间的浓度就是“高浓度”。有益剂粒子直径大小为0.3~50微米,优选约为1~10微米。一般可通过研磨、筛分、喷雾干燥、超临界流体提取所选择的特定有益剂来实现所需粒子大小。用于这种器具和组合物的典型有益剂包括干扰素和降钙素。可被施药的其它代表性有益剂包括药理活性的肽和蛋白质,组成代谢的激素,促生长激素,与内分泌系统相关的激素,包括猪促生长激素、牛促生长激素、马促生长激素、羊促生长激素、人促生长激素,从垂体和下丘脑腺提取和浓缩而得的促生长激素,由重组DNA方法生产的促生长激素,牛促生长激素如
Nucleic Acid Res.,Vol.10,p.7197(1982)中所述,羊促生长激素如Arch.Biochem.Biophys.,Vol.156,p.493(1973)中所述,以及猪促生长激素如DNA,Vol.2,pp37,45,(1983)中所述。代表性的有益剂还包括cochicine、α124-促肾上腺皮质激素和赖氨加压素。多肽还包括生长激素(growth hormone),生长激素(somat-ropin),生长激素(somatotropin),生长激素类似物,修饰的猪生长激素,修饰的牛生长激素,猪和牛生长激素二者的衍生物,生长调节素-C,促性腺素释放激素,促滤泡激素,促黄体素,LH-RH,LH-RH类似物,生长激素释放因子,促性腺素释放因子,胰岛素,绒毛膜促性腺激素,缩宫素,生长激素加氨基酸,加压素,促肾上腺皮质激素,表皮生长因子,催乳激素,生长抑素,生长激素加蛋白质,多肽如促甲状腺素释放激素,促甲状腺素,胰泌素,促胰酶素,脑啡肽,胰高血糖素,内部分泌并借助血流分布于动物内的内分泌剂,等等。有益剂及其剂量单位量是下述报导的现有技术中已知的:
The Pharmacological Basis of Therapeutics,by Gilman,Goodman,Rall and Murad,7thEd.,(1985)published by MacMillan Publishing Co.,NY;Pharma-ceutical Sciences,Remington,17th Ed.,(1985)published by MackPublishing Co.,Easton,PA,以及U.S.Pat.No.4,526,938。特别优选的是在低递送速率/剂量下产生所需疗效的有益剂,例如,需要数皮克至数毫克药剂的蛋白质/肽。
药物上可接受的悬浮液载体被用于将固体有益剂粒子悬浮于有益剂调和物中。非水载体被用于将有益剂与水隔离,并防止悬浮液中的有益剂水解或其它降解。此外,药物上可接受的悬浮液载体能为植入物中的组分起增稠剂作用。作为从植入物转运有益剂的载体,它保护有益剂以防分解,而且它赋予调和物中的组分以物理和化学稳定性。可利用增稠剂来提高调和物的粘度,防止植入环境中的流体与植入物的有益剂调和物混合。调和物中增稠剂的量依所需调节的粘度为1%~99.9%之间,且优选为5-60%。
典型的非水悬浮液载体包括:蜡,其软化点不高于体温;氢化植物油(如花生油、棉籽油、芝麻油、蓖麻油、橄榄油、玉米油、碘化罂粟籽油),硅油,中链脂肪酸单酸甘油酯,或多元醇。其中多元醇是优选的。
适于悬浮液载体的多元醇例如包括二醇、三醇、多元醇等等。更具体的多元醇包括聚乙二醇(平均分子量为200~1000,优选200~600),丙二醇,聚乙二醇1,5-戊二醇;1,6-己二醇;1,7-庚二醇;1,9-壬二醇;1,2-二甲基-1,6-己二醇;1,2,3-丙三醇;1,2,5-戊三醇;1,3,5-戊三醇;1,2,4-丁三醇;一缩二季戊四醇(dipentaerythriol)等等。在另一个实施方案中,药物上可接受的悬浮液载体包括丙三醇单(低级烷基)醚和丙三醇二(低级烷基)醚如丙三醇1-甲基醚、丙三醇1-乙基醚、丙三醇1,2-二甲基醚、丙三醇1,3-二甲基醚等等。在另一个实施方案中,药物上可接受的载体包括混合物如丙二醇和甘油基(glycero),等等。
在整个持久递送期间,需要足够的粘度使粒子悬浮于载体中。沉降与粒子大小和载体粘度有关。如果递送期更短,则粘度可以更低,因为需要进行悬浮的时间更短。所要求的粘度例如可由Stokes-Einstein方程测定,它是悬浮液中粒子移动多远的量度
V=沉降速率
μ=载体的粘度
g=重力加速度
Pp=粒子密度
Pc=载体密度式中R=有益剂的平均粒子半径。有益剂悬浮调和物的粘度可通过应用增稠剂提高粘度至所需值来改变。用于本发明的组合物中的典型增稠剂包括合适的水凝胶如羟丙基纤维素、羟丙基甲基纤维素(HPMC)、羧甲基纤维素钠、聚丙烯酸、聚(甲基异丁烯酸)(PM-MA)。优选的水凝胶是纤维素醚如羟烷基纤维素和羟烷基烷基-纤维素化合物。最优选的羟烷基纤维素是羟丙基纤维素(HPC)和聚维酮(PVP)。羟丙基纤维素可商购,以商品名KlucelTM出售宽粘度级范围产品(Hercules,Ltd.,London,England)。羟烷基纤维素的浓度取决于所用的具体粘度级和所需液体组合物的粘度。例如,如果所需粘度小于约1000泊(cps),则可用平均分子量约60,000道尔顿的羟丙基纤维素(即Klucel EFTM)。如果所需粘度为约1000~约2500cps,则可用更高粘度级的羟丙基纤维素(即Klucel LFTM和Lu-cel GFTM)。除了用不同粘度的不同增稠剂之外,也可用不同量相同特定增稠剂来改变粘度。羟丙基纤维素的浓度优选为载体的5%w/w以上,更优选为5~20%w/w,且最优选为8~18%w/w。如果用油作载体,就可用一硬脂酸铝为增稠剂。
羟烷基烷基纤维素醚是一类由纤维素醚化得到的水溶性水凝胶。用于本文有关这类水凝胶的术语“烷基”指C1-C6烷基,其中的烷基表示含1~6个碳原子的直链或支链,如文中规定那样,它可被任选取代。代表性的烷基包括甲基、乙基、丙基、异丙基、丁基、戊基、己基等等。
羟烷基烷基纤维素的实例有:羟丙基甲基纤维素、羟乙基甲基纤维素和羟丁基甲基纤维素。羟丙基甲基纤维素(HPMC)是优选的。HPMC可以宽范围的粘度级商购(即,Aldrich Chem.Co.,Ltd.Dorset,England and Dow Chem.Co.,Midland,Mich.,USA)。除了提高粘度外,羟烷基烷基纤维素可用作稳定剂、悬浮剂和乳化剂。本发明的液体组合物中羟烷基烷基纤维素的浓度尤其取决于其应用目的(即稳定剂、乳化剂、粘度增高剂)及其粘度级别。
为确保悬浮液载体的粘度在所需递送期间足以维持悬浮液中的药剂,可往悬浮液载体中加入增稠剂。优选的增稠剂包括聚维酮和羟丙基纤维素。在一个实施方案中,当用到低分子量如400的PEG时,平均分子量为1000的5%羟丙基纤维素或40-60%聚维酮可与聚乙二醇协调组合应用。如果用于悬浮液载体的聚乙二醇分子量大于600,例如分子量为1000,则优选用聚维酮作增稠剂。
提供以下实施例以阐述本发明的实施,但并不想以任何方式限定本发明。
实施例1
制备含50wt%PEG 400和50wt%聚维酮(PVP)的粘性载体。将PEG 400(Union Carbide)称入烧杯,再加入等量聚维酮K29-32(GAF)。用刮勺搅拌混合该PEG和聚维酮约5分钟,将掺混后的载体放置过夜以保证聚维酮的全部溶解。然后将此载体置于真空烘箱(National Appliance Company)内脱气,方法是抽真空并将载体于50℃下保温30分钟。
将细胞色素c(Sigma,得自马心脏)置于瓷制球磨罐内磨碎,然后通过400目筛而得直径小于37微米的粒子。在烧杯中,将0.5566克细胞色素c加入4.9970克PEG400/聚维酮载体中以配制10%细胞色素c于50∶50 PVP∶PEG400载体中的悬浮液。用刮勺彻底混合此悬浮液约5分钟使之掺混,然后将此细胞色素c悬浮液装入11个渗透性兽医用植入物(如图1所示)。
通过释放入盛有去离子水的培养管而体外测试此植入物。为了监测细胞色素c从植入物释放情况,将释放介质样品置于UV分光光度计(Shimadzu UV 160U)上在409nm的波长处进行测定。在预定的植入期间(42天),植入物成功地释放了细胞色素c。图2的曲线图表明释放的蛋白质(mg)随时间延长而渐增。在后一半释放期中,从试管中取出数个植入物并检查是否发生细胞色素c的沉降。将这些植入物切开,从植入物的顶部和底部取出蛋白质悬浮液样品。称取蛋白质悬浮液样品,在容量瓶内用DI(去离子)水稀释,通过UV分光光度计分析。结果表明,细胞色素c悬浮液是均匀的。
实施例2
标准样:20μl的8.0mg/ml标准物被稀释至160μg/ml。每个HPLC样用蒸馏水稀释10倍。HPLC的操作条件如下:柱: POROS RH 2.1mm×3.0cm流动相:A:95%H2O,0.1%TFA,5%ACN
B:95%ACN,5%H2O,0.083%TFA梯度: 在5分钟内20%B~50%B流速: 2.0ml/min检测器: 280nm @ 0.002AUFS
IRMA标准样:工作标准是通过用含0.5%牛血清白蛋白(BSA)的磷酸缓冲盐水(PBS)释释IRMA标准物而配制的。用含0.5%BSA的PBS进行稀释来配制样本:对于干扰素调和物,稀释400倍,对于标样,则稀释2000倍。
图3示出HPLC分析和IRMA分析的结果。HPLC测定表明即使在37℃下5天后也未损失α-IFN,说明该蛋白质在非水载体中是稳定的。由IRMA分析的活性相对于初始贮存液来说,在t=0时为78%;在t=5天时,室温下调和物的活性为87%,37℃下为90%。与原贮存液相比时,由HPLC测定此调和物未损失α-IFN。该分析表明了37℃下干扰素在PEG中达5天时的稳定性。不过,维持了初始贮存液活性的约80-90%。IRMA结果表明,时间和温度未引起活性损失。
本发明特别参照其某些优选的实施方案进行了详细描述,但应懂得可在本发明的实质和范围内作变更和修改。
Claims (16)
1.在持久递送期间递送调和物的器具中用的肽/蛋白质调和物,所述调和物包括含5-70wt%固体粒子形式肽/蛋白质的悬浮液,该肽/蛋白质粒子大小为0.3~50微米,该悬浮液还包括分子量为200~1000的多元醇和增稠剂,而悬浮液粘度于37℃下为100~100,000泊。
2.权利要求1的调和物,其中的粒子大小为1~10微米。
3.权利要求1的调和物,其中的持久递送期至少约为1个月。
4.权利要求1的调和物,其中的多元醇是聚乙二醇。
5.权利要求4的调和物,其中的增稠剂包括聚维酮。
6.权利要求1的调和物,其中的聚乙二醇分子量为200~600。
7.权利要求6的调和物,其中的增稠剂包括聚维酮或羟丙基纤维素。
8.权利要求1的调和物,其中的肽/蛋白质是人α-干扰素。
9.权利要求8的调和物,其中干扰素的浓度至少是1×109IU。
10.权利要求1的调和物,其中所述肽/蛋白质是水敏化合物。
11.含权利要求1的调和物的肽/蛋白质递送器具。
12.权利要求11的肽/蛋白质递送器具,其中的器具适于植入动物体内。
13.用于在持久递送期间持续控制的递送的组合物,该组合物包括:
(a)0.5wt%~70wt%粒子大小为0.3~50微米的肽/蛋白质;和
(b)非水液体悬浮液调和物,其特征在于37℃下的粘度为100~100,000泊,该调和物还包括分子量为200~1000的聚乙二醇和增稠剂。
14.权利要求13的组合物,其中的增稠剂包括聚维酮或羟丙基纤维素。
15.含权利要求13的组合物的肽/蛋白质递送器具。
16.权利要求15的肽/蛋白质递送器具,其中的器具适于植入动物体内。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/475,238 US5904935A (en) | 1995-06-07 | 1995-06-07 | Peptide/protein suspending formulations |
US08/475,238 | 1995-06-07 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1187119A CN1187119A (zh) | 1998-07-08 |
CN1138528C true CN1138528C (zh) | 2004-02-18 |
Family
ID=23886776
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB961944943A Expired - Fee Related CN1138528C (zh) | 1995-06-07 | 1996-05-22 | 肽/蛋白质悬浮调和物 |
Country Status (14)
Country | Link |
---|---|
US (2) | US5904935A (zh) |
EP (1) | EP0831773B1 (zh) |
JP (2) | JPH11506730A (zh) |
KR (1) | KR100460653B1 (zh) |
CN (1) | CN1138528C (zh) |
AT (1) | ATE187062T1 (zh) |
AU (1) | AU706318B2 (zh) |
CA (1) | CA2220871C (zh) |
DE (1) | DE69605417T2 (zh) |
DK (1) | DK0831773T3 (zh) |
ES (1) | ES2139360T3 (zh) |
FI (1) | FI119464B (zh) |
NZ (1) | NZ308843A (zh) |
WO (1) | WO1996040049A1 (zh) |
Families Citing this family (94)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6063910A (en) * | 1991-11-14 | 2000-05-16 | The Trustees Of Princeton University | Preparation of protein microparticles by supercritical fluid precipitation |
US6290991B1 (en) * | 1994-12-02 | 2001-09-18 | Quandrant Holdings Cambridge Limited | Solid dose delivery vehicle and methods of making same |
MY125870A (en) * | 1997-07-25 | 2006-08-30 | Alza Corp | Osmotic delivery system flow modulator apparatus and method |
US20060165606A1 (en) | 1997-09-29 | 2006-07-27 | Nektar Therapeutics | Pulmonary delivery particles comprising water insoluble or crystalline active agents |
EP2311436A1 (en) | 1998-04-27 | 2011-04-20 | Altus Pharmaceuticals Inc. | Stabilized protein crystals, formulations containing them and methods of making them |
US8052982B2 (en) | 1998-07-20 | 2011-11-08 | Peptech Animal Health Pty Limited | Bioimplant formulation comprising lecithin and stearin |
NZ510020A (en) * | 1998-09-09 | 2003-06-30 | Alza Corp | Membrane coated capsule for sustained release of a drug formulation, and a granulated composition, in liquid form |
US6194006B1 (en) | 1998-12-30 | 2001-02-27 | Alkermes Controlled Therapeutics Inc. Ii | Preparation of microparticles having a selected release profile |
CA2361424C (en) † | 1999-02-08 | 2009-04-28 | Alza Corporation | Stable non-aqueous single phase viscous vehicles and formulations utilizing such vehicles |
US7258869B1 (en) * | 1999-02-08 | 2007-08-21 | Alza Corporation | Stable non-aqueous single phase viscous vehicles and formulations utilizing such vehicle |
US7919109B2 (en) | 1999-02-08 | 2011-04-05 | Intarcia Therapeutics, Inc. | Stable non-aqueous single phase viscous vehicles and formulations utilizing such vehicles |
KR20090007504A (ko) | 2000-02-24 | 2009-01-16 | 몬산토 테크놀로지 엘엘씨 | 소마토트로핀의 지속적인 방출을 위한 비수성 주사제제들 |
EP1274459B1 (en) | 2000-04-19 | 2005-11-16 | Genentech, Inc. | Sustained release formulations comprising growth hormone |
US7871598B1 (en) | 2000-05-10 | 2011-01-18 | Novartis Ag | Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery and methods of use |
US6264987B1 (en) | 2000-05-19 | 2001-07-24 | Alkermes Controlled Therapeutics Inc. Ii | Method for preparing microparticles having a selected polymer molecular weight |
US6495164B1 (en) | 2000-05-25 | 2002-12-17 | Alkermes Controlled Therapeutics, Inc. I | Preparation of injectable suspensions having improved injectability |
AU2001271491A1 (en) | 2000-06-26 | 2002-01-08 | Monsanto Technology Llc | Non-aqueous surfactant-containing formulations for extended release of somatotropin |
US6664234B1 (en) * | 2000-06-30 | 2003-12-16 | Monsanto Technology Llc | Non-aqueous injectable formulation preparation with pH adjusted for extended release of somatotropin |
US6824822B2 (en) | 2001-08-31 | 2004-11-30 | Alkermes Controlled Therapeutics Inc. Ii | Residual solvent extraction method and microparticles produced thereby |
US6471995B1 (en) | 2000-09-27 | 2002-10-29 | Alkermes Controlled Therapeutics, Inc. Ii | Apparatus and method for preparing microparticles using liquid-liquid extraction |
US20020114843A1 (en) | 2000-12-27 | 2002-08-22 | Ramstack J. Michael | Preparation of microparticles having improved flowability |
IL156618A0 (en) | 2000-12-28 | 2004-01-04 | Altus Biologics Inc | Crystals of whole antibodies and fragments thereof, methods for the preparation thereof and diagnostic kits utilizing the same |
CA2439120C (en) * | 2001-02-23 | 2011-07-05 | Genentech, Inc. | Erodible polymers for injection |
CA2451185A1 (en) * | 2001-06-21 | 2003-01-03 | Altus Biologics, Inc. | Spherical protein particles and methods of making and using them |
US7318931B2 (en) * | 2001-06-21 | 2008-01-15 | Genentech, Inc. | Sustained release formulation |
ES2364636T3 (es) | 2001-12-19 | 2011-09-08 | Novartis Ag | Administración pulmonar de aminoglucósidos. |
CN1668279A (zh) * | 2002-06-17 | 2005-09-14 | 阿尔萨公司 | 具有包含分散在液体载体中的渗透物质的早期零级推动力动力系统的渗透递送体系 |
US7731947B2 (en) * | 2003-11-17 | 2010-06-08 | Intarcia Therapeutics, Inc. | Composition and dosage form comprising an interferon particle formulation and suspending vehicle |
BR0317421A (pt) * | 2002-12-19 | 2005-11-08 | Alza Corp | Géis de fase única não-aquosa estável e formulações destes para liberação a partir de um dispositivo implantável |
US7772188B2 (en) | 2003-01-28 | 2010-08-10 | Ironwood Pharmaceuticals, Inc. | Methods and compositions for the treatment of gastrointestinal disorders |
JP2006521897A (ja) * | 2003-03-31 | 2006-09-28 | アルザ・コーポレーション | 内部圧力を放散する手段を備える浸透ポンプ |
AU2004227986A1 (en) * | 2003-03-31 | 2004-10-21 | Alza Corporation | Osmotic delivery system and method for decreasing start-up times for osmotic delivery systems |
AR047552A1 (es) | 2003-06-26 | 2006-01-25 | Control Delivery Sys Inc | Sistemas de suministro de farmacos de liberacion sostenida biodegradables |
US20050048123A1 (en) | 2003-06-26 | 2005-03-03 | Control Delivery System, Inc. | In situ gelling drug delivery system |
WO2005021841A2 (en) | 2003-09-03 | 2005-03-10 | Bioforms | Methods and apparatus for rapid crystallization of biomolecules |
CA2537811A1 (en) * | 2003-10-31 | 2005-05-19 | Alza Corporation | Osmotic pump with self-retaining, fast-start membrane plug |
CA2545027A1 (en) * | 2003-11-06 | 2005-05-26 | Alza Corporation | Modular imbibition rate reducer for use with implantable osmotic pump |
MXPA06011924A (es) | 2004-04-15 | 2007-06-11 | Alkermes Inc | Dispositivo de liberacion continua base polimeros. |
US20050266087A1 (en) * | 2004-05-25 | 2005-12-01 | Gunjan Junnarkar | Formulations having increased stability during transition from hydrophobic vehicle to hydrophilic medium |
US7772182B2 (en) * | 2004-08-05 | 2010-08-10 | Alza Corporation | Stable suspension formulations of erythropoietin receptor agonists |
US20060029551A1 (en) * | 2004-08-05 | 2006-02-09 | Kui Liu | Stable particle formulations of erythropoietin receptor agonists |
US20060045891A1 (en) * | 2004-08-24 | 2006-03-02 | Lovalenti Phillip M | Density-matched suspension vehicles and pharmaceutical suspensions |
US11246913B2 (en) | 2005-02-03 | 2022-02-15 | Intarcia Therapeutics, Inc. | Suspension formulation comprising an insulinotropic peptide |
WO2006083761A2 (en) | 2005-02-03 | 2006-08-10 | Alza Corporation | Solvent/polymer solutions as suspension vehicles |
EP2361630A1 (en) * | 2005-02-03 | 2011-08-31 | Intarcia Therapeutics, Inc | Implantable drug delivery device comprising particles and an osmotic pump |
US7759312B2 (en) | 2005-03-11 | 2010-07-20 | Endo Pharmaceuticals Solutions Inc. | Delivery of dry formulations of octreotide |
WO2006099288A2 (en) * | 2005-03-11 | 2006-09-21 | Indevus Pharmaceuticals, Inc. | Controlled release formulations of octreotide |
US7959938B2 (en) | 2005-03-15 | 2011-06-14 | Intarcia Therapeutics, Inc. | Polyoxaester suspending vehicles for use with implantable delivery systems |
CN101453982B (zh) * | 2006-05-30 | 2011-05-04 | 精达制药公司 | 两件式内部通道渗透递送系统流动调节器 |
NZ573174A (en) * | 2006-06-01 | 2012-01-12 | Msd Consumer Care Inc | Sustained release pharmaceutical dosage form containing phenylephrine |
ES2422864T3 (es) * | 2006-08-09 | 2013-09-16 | Intarcia Therapeutics, Inc | Sistemas de liberación osmótica y unidades de pistón |
RU2440097C2 (ru) | 2007-04-23 | 2012-01-20 | Интарсия Терапьютикс, Инк. | Способ лечения диабета ii типа и ожирения, осмотическое устройство для доставки и способ его изготовления |
WO2008134475A2 (en) | 2007-04-27 | 2008-11-06 | Endo Pharmaceuticals Solutions Inc., 33 | Implant device release agents and methods of using same |
EP2152245B1 (en) | 2007-04-30 | 2015-12-02 | Novo Nordisk A/S | Method for drying a protein composition, a dried protein composition and a pharmaceutical composition comprising the dried protein |
HUE043228T2 (hu) | 2007-06-22 | 2019-08-28 | Univ Texas | Stabil szubmikron peptid vagy protein részecskék képzése vékonyfilm fagyasztással |
EP2240155B1 (en) | 2008-02-13 | 2012-06-06 | Intarcia Therapeutics, Inc | Devices, formulations, and methods for delivery of multiple beneficial agents |
US8071537B2 (en) | 2008-06-25 | 2011-12-06 | Endo Pharmaceuticals Solutions Inc. | Implantable device for the sustained release of a polypeptide |
JP5536053B2 (ja) | 2008-06-25 | 2014-07-02 | エンド ファーマスーティカルズ ソリューションズ インコーポレイテッド. | 離型剤を有するオクトレオチドインプラント |
KR20200000462A (ko) | 2008-08-15 | 2020-01-02 | 아이언우드 파마슈티컬스, 인코포레이티드 | 경구 투여를 위한 리나클로타이드-함유 제형 |
NZ592113A (en) * | 2008-10-15 | 2012-04-27 | Intarcia Therapeutics Inc | Highly concentrated drug particles, formulations, suspensions and uses thereof |
EP2376522A4 (en) | 2008-11-16 | 2013-12-25 | Univ Texas | LOW VISCOSIS HIGHLY CONCENTRATED SUSPENSIONS |
US8682440B2 (en) | 2009-08-03 | 2014-03-25 | Incube Labs, Llc | Swallowable capsule and method for stimulating incretin production within the intestinal tract |
JP2013501071A (ja) | 2009-08-06 | 2013-01-10 | アイロンウッド ファーマシューティカルズ, インコーポレイテッド | リナクロチドを含む処方物 |
EP3323423B1 (en) * | 2009-09-28 | 2020-06-17 | Intarcia Therapeutics, Inc | Rapid establishment and/or termination of substantial steady-state drug delivery |
US8562589B2 (en) | 2009-12-24 | 2013-10-22 | Rani Therapeutics, Llc | Swallowable drug delivery device and method of delivery |
TR201711271T4 (tr) | 2010-02-17 | 2019-02-21 | Ironwood Pharmaceuticals Inc | Gastrointestinal Bozukluklar İçin Tedaviler |
US9072668B2 (en) | 2010-03-09 | 2015-07-07 | Janssen Biotech, Inc. | Non-aqueous high concentration reduced viscosity suspension formulations of antibodies |
PL2603232T3 (pl) | 2010-08-11 | 2020-05-18 | Ironwood Pharmaceuticals, Inc. | Stabilne formulacje linaklotydu |
US9283179B2 (en) | 2010-12-23 | 2016-03-15 | Rani Therapeutics, Llc | GnRH preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US9402806B2 (en) | 2010-12-23 | 2016-08-02 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US8764733B2 (en) * | 2010-12-23 | 2014-07-01 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US8734429B2 (en) | 2010-12-23 | 2014-05-27 | Rani Therapeutics, Llc | Device, system and methods for the oral delivery of therapeutic compounds |
US8809271B2 (en) | 2010-12-23 | 2014-08-19 | Rani Therapeutics, Llc | Therapeutic agent preparations comprising liraglutide for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US9284367B2 (en) | 2010-12-23 | 2016-03-15 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US8969293B2 (en) | 2010-12-23 | 2015-03-03 | Rani Therapeutics, Llc | Therapeutic agent preparations comprising exenatide for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US9415004B2 (en) | 2010-12-23 | 2016-08-16 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US8980822B2 (en) | 2010-12-23 | 2015-03-17 | Rani Therapeutics, Llc | Therapeutic agent preparations comprising pramlintide for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US9629799B2 (en) | 2010-12-23 | 2017-04-25 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US9149617B2 (en) | 2010-12-23 | 2015-10-06 | Rani Therapeutics, Llc | Device, system and methods for the oral delivery of therapeutic compounds |
US10639272B2 (en) | 2010-12-23 | 2020-05-05 | Rani Therapeutics, Llc | Methods for delivering etanercept preparations into a lumen of the intestinal tract using a swallowable drug delivery device |
US9259386B2 (en) | 2010-12-23 | 2016-02-16 | Rani Therapeutics, Llc | Therapeutic preparation comprising somatostatin or somatostatin analogoue for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US9402807B2 (en) | 2010-12-23 | 2016-08-02 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US8809269B2 (en) | 2010-12-23 | 2014-08-19 | Rani Therapeutics, Llc | Therapeutic agent preparations comprising insulin for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US8846040B2 (en) | 2010-12-23 | 2014-09-30 | Rani Therapeutics, Llc | Therapeutic agent preparations comprising etanercept for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US9861683B2 (en) | 2010-12-23 | 2018-01-09 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US20120208755A1 (en) * | 2011-02-16 | 2012-08-16 | Intarcia Therapeutics, Inc. | Compositions, Devices and Methods of Use Thereof for the Treatment of Cancers |
EP2776055B1 (en) | 2011-08-17 | 2016-12-14 | Ironwood Pharmaceuticals, Inc. | Treatments for gastrointestinal disorders |
US9889085B1 (en) | 2014-09-30 | 2018-02-13 | Intarcia Therapeutics, Inc. | Therapeutic methods for the treatment of diabetes and related conditions for patients with high baseline HbA1c |
EP3302354B1 (en) | 2015-06-03 | 2023-10-04 | i2o Therapeutics, Inc. | Implant placement systems |
WO2017200943A1 (en) | 2016-05-16 | 2017-11-23 | Intarcia Therapeutics, Inc. | Glucagon-receptor selective polypeptides and methods of use thereof |
USD860451S1 (en) | 2016-06-02 | 2019-09-17 | Intarcia Therapeutics, Inc. | Implant removal tool |
USD840030S1 (en) | 2016-06-02 | 2019-02-05 | Intarcia Therapeutics, Inc. | Implant placement guide |
KR20190104039A (ko) | 2017-01-03 | 2019-09-05 | 인타르시아 세라퓨틱스 인코포레이티드 | Glp-1 수용체 효능제의 연속적인 투여 및 약물의 동시-투여를 포함하는 방법 |
USD933219S1 (en) | 2018-07-13 | 2021-10-12 | Intarcia Therapeutics, Inc. | Implant removal tool and assembly |
Family Cites Families (43)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3732865A (en) * | 1971-01-13 | 1973-05-15 | Alza Corp | Osmotic dispenser |
US3833725A (en) * | 1972-12-08 | 1974-09-03 | Syntex Corp | Dialkylated glycol compositions and medicament preparations containing same |
US4036954A (en) * | 1973-11-02 | 1977-07-19 | Yamanouchi Pharmaceutical Co., Ltd. | Stable prostaglandin E group-containing formulation |
US4180560A (en) * | 1976-10-26 | 1979-12-25 | Syntex Corporation | Inert core implant pellet |
US4215691A (en) * | 1978-10-11 | 1980-08-05 | Alza Corporation | Vaginal contraceptive system made from block copolymer |
US4237885A (en) * | 1978-10-23 | 1980-12-09 | Alza Corporation | Delivery system with mated members for storing and releasing a plurality of beneficial agents |
US4389414A (en) * | 1981-05-11 | 1983-06-21 | Syntex (U.S.A.) Inc. | Prostaglandin compositions |
US4507281A (en) * | 1981-10-13 | 1985-03-26 | Exovir, Inc. | Interferon-containing compositions |
US4475916A (en) * | 1982-03-18 | 1984-10-09 | Merck & Co., Inc. | Osmotic drug delivery system |
EP0092918B1 (en) * | 1982-04-22 | 1988-10-19 | Imperial Chemical Industries Plc | Continuous release formulations |
US4483849A (en) * | 1983-01-07 | 1984-11-20 | Carter William A | Stabilization and purification of interferon with propylene glycol, resulting in a non-toxic product |
EP0130935B1 (fr) * | 1983-07-01 | 1987-04-15 | Battelle Memorial Institute | Polypeptide biodégradable et son utilisation pour le relargage progressif de médicaments |
US4855134A (en) * | 1983-10-14 | 1989-08-08 | Sumitomo Pharmaceuticals Company, Limited | Sustained-release preparation |
GB2155889B (en) * | 1984-03-21 | 1988-03-02 | Alza Corp | Dispenser-capsule |
US5032572A (en) * | 1984-07-18 | 1991-07-16 | Medical College Of Ohio | Polymers containing cross-linked azo bonds, which polymers are useful for releasing therapeutic agents into the lower gastrointestinal tract |
US4847079A (en) * | 1985-07-29 | 1989-07-11 | Schering Corporation | Biologically stable interferon compositions comprising thimerosal |
GB8613688D0 (en) * | 1986-06-05 | 1986-07-09 | Euro Celtique Sa | Pharmaceutical composition |
US4853218A (en) * | 1987-02-24 | 1989-08-01 | Schering Corporation | Zinc-protamine-alpha interferon complex |
JPS63281299A (ja) * | 1987-05-13 | 1988-11-17 | Hitachi Ltd | 連想メモリ装置 |
EP0294160A1 (en) * | 1987-06-02 | 1988-12-07 | Schering Corporation | Treatment of chronic type b hepatitis with a combination of recombinant human alpha and gamma interferons |
US4871538A (en) * | 1987-07-13 | 1989-10-03 | Schering Corporation | Insoluble copper-alpha interferon complex |
IT1222734B (it) * | 1987-09-25 | 1990-09-12 | Scalvo S P A | Formulaziopne farmaceutiche e forme di dosaggio per la somminaistarzione rettale di calcitonina |
US4855141A (en) * | 1988-03-25 | 1989-08-08 | Alza Corporation | Device comprising means for protecting and dispensing fluid sensitive medicament |
HU201567B (en) * | 1988-07-21 | 1990-11-28 | Gyogyszerkutato Intezet | Process for production of intravenous medical compositions containing cyclosphorin |
US5342625A (en) * | 1988-09-16 | 1994-08-30 | Sandoz Ltd. | Pharmaceutical compositions comprising cyclosporins |
US5110596A (en) * | 1988-12-13 | 1992-05-05 | Alza Corporation | Delivery system comprising means for delivering agent to livestock |
EP0374120A3 (en) * | 1988-12-13 | 1991-07-31 | Monsanto Company | Comosition for controlled release of polypeptides |
US5034229A (en) * | 1988-12-13 | 1991-07-23 | Alza Corporation | Dispenser for increasing feed conversion of hog |
US5057318A (en) * | 1988-12-13 | 1991-10-15 | Alza Corporation | Delivery system for beneficial agent over a broad range of rates |
IT8920486A0 (it) * | 1989-05-12 | 1989-05-12 | Isf Spa | Composizioni farmaceutiche. |
JP2514249B2 (ja) * | 1989-05-23 | 1996-07-10 | 帝人株式会社 | 安定化されたカルシトニン類医薬組成物 |
US5100392A (en) * | 1989-12-08 | 1992-03-31 | Biosynthesis, Inc. | Implantable device for administration of drugs or other liquid solutions |
IT1242642B (it) * | 1990-04-17 | 1994-05-16 | Alfa Wassermann Spa | Formulazioni iniettabili contenenti naproxen sale sodico. |
FR2663223B1 (fr) * | 1990-06-14 | 1994-12-02 | Af Aplicaciones Far Lab | Forme galenique parenterale. |
US5137727A (en) * | 1991-06-12 | 1992-08-11 | Alza Corporation | Delivery device providing beneficial agent stability |
US5236707A (en) * | 1991-11-08 | 1993-08-17 | Dallas Biotherapeutics, Inc. | Stabilization of human interferon |
JP3730667B2 (ja) * | 1991-12-27 | 2006-01-05 | 武田薬品工業株式会社 | 注射用組成物 |
US5223265A (en) * | 1992-01-10 | 1993-06-29 | Alza Corporation | Osmotic device with delayed activation of drug delivery |
US5221278A (en) * | 1992-03-12 | 1993-06-22 | Alza Corporation | Osmotically driven delivery device with expandable orifice for pulsatile delivery effect |
US5614487A (en) * | 1993-05-28 | 1997-03-25 | Genentech, Inc. | Sustained release pharmaceutical composition |
WO1995010989A1 (en) * | 1993-10-19 | 1995-04-27 | Scimed Life Systems, Inc. | Intravascular stent pump |
EP0768867B1 (en) * | 1994-06-13 | 2002-10-09 | Alza Corporation | Dosage form for administering drug in liquid formulation |
WO1999008832A1 (de) * | 1997-08-20 | 1999-02-25 | Mikron Sa Agno | Vorrichtung zum bewegen und positionieren eines gegenstandes in einer ebene |
-
1995
- 1995-06-07 US US08/475,238 patent/US5904935A/en not_active Expired - Lifetime
-
1996
- 1996-05-22 AT AT96920358T patent/ATE187062T1/de not_active IP Right Cessation
- 1996-05-22 WO PCT/US1996/007377 patent/WO1996040049A1/en active IP Right Grant
- 1996-05-22 ES ES96920358T patent/ES2139360T3/es not_active Expired - Lifetime
- 1996-05-22 CN CNB961944943A patent/CN1138528C/zh not_active Expired - Fee Related
- 1996-05-22 NZ NZ308843A patent/NZ308843A/xx not_active IP Right Cessation
- 1996-05-22 KR KR1019970708967A patent/KR100460653B1/ko not_active IP Right Cessation
- 1996-05-22 DK DK96920358T patent/DK0831773T3/da active
- 1996-05-22 CA CA2220871A patent/CA2220871C/en not_active Expired - Fee Related
- 1996-05-22 AU AU58694/96A patent/AU706318B2/en not_active Ceased
- 1996-05-22 DE DE69605417T patent/DE69605417T2/de not_active Expired - Lifetime
- 1996-05-22 JP JP9500644A patent/JPH11506730A/ja not_active Withdrawn
- 1996-05-22 EP EP96920358A patent/EP0831773B1/en not_active Expired - Lifetime
-
1997
- 1997-12-05 FI FI974429A patent/FI119464B/fi active IP Right Grant
-
1999
- 1999-01-28 US US09/238,159 patent/US5972370A/en not_active Expired - Lifetime
-
2008
- 2008-10-22 JP JP2008271657A patent/JP2009057389A/ja active Pending
Also Published As
Publication number | Publication date |
---|---|
WO1996040049A1 (en) | 1996-12-19 |
AU5869496A (en) | 1996-12-30 |
KR100460653B1 (ko) | 2005-08-05 |
EP0831773A1 (en) | 1998-04-01 |
EP0831773B1 (en) | 1999-12-01 |
CN1187119A (zh) | 1998-07-08 |
KR19990022486A (ko) | 1999-03-25 |
ES2139360T3 (es) | 2000-02-01 |
NZ308843A (en) | 2000-01-28 |
DE69605417T2 (de) | 2000-03-23 |
CA2220871A1 (en) | 1996-12-19 |
DK0831773T3 (da) | 2000-05-08 |
ATE187062T1 (de) | 1999-12-15 |
FI119464B (fi) | 2008-11-28 |
AU706318B2 (en) | 1999-06-17 |
CA2220871C (en) | 2011-02-08 |
DE69605417D1 (de) | 2000-01-05 |
FI974429A0 (fi) | 1997-12-05 |
US5904935A (en) | 1999-05-18 |
JPH11506730A (ja) | 1999-06-15 |
JP2009057389A (ja) | 2009-03-19 |
FI974429A (fi) | 1997-12-05 |
US5972370A (en) | 1999-10-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1138528C (zh) | 肽/蛋白质悬浮调和物 | |
EP1610765B1 (en) | Non-aqueous single phase vehicles and formulations utilizing such vehicles | |
US20170319662A1 (en) | Stable non-aqueous single phase viscous vehicles and formulations utilizing such vehicles | |
US20110160708A1 (en) | Stable non-aqueous single phase viscous vehicles and formulations utlizing such vehicles | |
US20050118206A1 (en) | Surfactant-based gel as an injectable, sustained drug delivery vehicle | |
KR20050088196A (ko) | 안정한 비수성 단일 상 겔 및 이식가능한 장치로부터전달하기 위한 이의 제형 | |
NO178564B (no) | Framgangsmåte for framstilling av et system for administrering av aktive medikamenter gjennom slimhinner | |
JPH07165613A (ja) | 経鼻吸収薬物用キャリヤおよび生理活性ペプチド組成物 | |
TWI715520B (zh) | 用於持續釋放蘭瑞肽之醫藥組成物 | |
US20230346877A1 (en) | Pharmaceutical Compositions having a Selected Release Duration | |
JPH09315953A (ja) | 経鼻吸収用生理活性ペプチド組成物 | |
JP3263598B2 (ja) | 経鼻吸収用生理活性ペプチド組成物 | |
JPH06199681A (ja) | 生理活性ペプチド組成物 |
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 | ||
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20040218 Termination date: 20130522 |