公开(公告)号：US09381159B2

公开(公告)日：2016-07-05

申请号：US14362575

申请日：2012-12-05

Applicant: Tuo Jin ,  Zhenhua Hu ,  Weien Yuan

Inventor： Tuo Jin ,  Zhenhua Hu ,  Weien Yuan

IPC: A61K38/16 ,  A61K9/50 ,  A61P3/10 ,  A61K9/16 ,  A61K38/22 ,  A61K38/23 ,  A61K38/25 ,  A61K38/26 ,  A61K38/31

CPC classification number: A61K9/1647 ,  A61K9/1611 ,  A61K9/1694 ,  A61K38/22 ,  A61K38/23 ,  A61K38/25 ,  A61K38/26 ,  A61K38/31

Abstract: A new microsphere formulation (composition) for controlled- or sustained-release delivery of therapeutic ingredient(s), mainly peptides and proteins not over 10K in molecular weight, comprises at least a therapeutic ingredient, a helping agent (such as PH sensitive agent whose solubility is a function of pH) and a biodegradable polymer. The therapeutic ingredient(s) and the helping agent are in the form of fine particles, less than 1O um in diameter, encapsulated in the polymer which forms the microsphere matrix. A method for preparing the composition comprises a step of in-situ precipitating the therapeutic ingredient(s) and the helping agent to the fine particles and successive steps for forming the microspheres. Such a microsphere formulation offers a well-controlled release profile for prolonged period and encapsulation efficiency over 95%.

Abstract translation: 治疗成分（主要是分子量不超过10K的肽和蛋白质）的受控或持续释放递送的新微球制剂（组合物）至少包含治疗成分，助剂（例如PH敏感剂 溶解度是pH的函数）和可生物降解的聚合物。 治疗成分和助剂为直径小于10μm的细颗粒形式，包封在形成微球基质的聚合物中。 制备组合物的方法包括将治疗成分和辅助剂原位沉淀到细颗粒和用于形成微球的连续步骤的步骤。 这种微球制剂提供了良好控制的释放曲线，其延长的时间和包封效率超过95％。

公开(公告)号：US20130310536A1

公开(公告)日：2013-11-21

申请号：US13977973

申请日：2012-01-05

Applicant: Tuo Jin ,  Shiyue Duan

Inventor： Tuo Jin ,  Shiyue Duan

IPC: C08G12/06

CPC classification number: C08G12/06 ,  A61K9/5031 ,  A61K47/34 ,  C08G73/0273 ,  C08G73/18 ,  C12N15/87

Abstract: The present invention is directed to a design of and a method to synthesize polycations for gene (DNA and RNA) delivery. According to this design, the polycations (also said cationic polymers) are formed by polymerization of endogenous monomers bearing sufficient amino groups through degradable bonds with linker molecules. The amino group-bearing monomers are those naturally existing or nontoxic to human body. The linker molecules are those which are not only degradable to nontoxic fragments but also able to release the amino group-bearing monomers in their native state upon degradation. Some examples for the endogenous amino group-bearing monomers are spermine and spermidine (or their derivatives). Examples for the degradable chemical bonds formed between the amino group-bearing monomers are imines. In order to improve degradability or proton sponging effect, low pKa (

Abstract translation: 本发明涉及用于合成基因（DNA和RNA）递送聚阳离子的设计和方法。 根据该设计，聚阳离子聚合物（也称为阳离子聚合物）通过具有足够氨基的内源单体通过可降解键与连接分子的聚合形成。 含氨基的单体是天然存在的或对人体无毒的单体。 连接子分子是不仅可降解成无毒片段的那些，而且还能够在降解时以其天然状态释放含氨基的单体。 内源性含氨基单体的一些实例是精胺和亚精胺（或其衍生物）。 在含氨基的单体之间形成的可降解化学键的实例是亚胺。 为了提高降解性或质子海绵效应，低pKa（<8）氨基，通过聚合物降解产生的游离氨基（例如由亚胺键降解产生的那些）或其它给电子基团 因为咪唑，吡唑，吡啶，嘧啶或甚至苯被并入两个（或三个）反应性基团之间的接头中，用于连接含氨基的单体。 这些聚阳离子载体体系可用于纳米包封和转染基因材料。

公开(公告)号：US20110195124A1

公开(公告)日：2011-08-11

申请号：US13122873

申请日：2009-05-12

Applicant: Tuo Jin

Inventor： Tuo Jin

IPC: A61K9/00 ,  A61K38/00 ,  A61K39/00 ,  A61K48/00 ,  A61K38/28 ,  A61P3/10 ,  B29C39/42 ,  B29C35/16

CPC classification number: A61M37/0015 ,  A61K9/0021 ,  A61M2037/0023 ,  A61M2037/0046 ,  A61M2037/0053

Abstract: This invention discloses a novel microneedle system, phase-transition microneedle patch, which overcomes all the limitations that existing microneedles encountered. The microneedle patch is formed of an integrated polymeric piece consisting of a microneedle array and a plate (called holding plate) on which the needles stand. The microneedles of the patch are hard and strong enough to penetrate epidermis at dry state but turn to be hydrogel state soft and permeable to hydrophilic agents when absorbing body fluid. The hydrogel state of the patch is a hydrophilic network held by physical or chemical cross-linking junctions. The pores of the network are opened up by body fluid for drugs and macromolecules to diffuse through. The polymeric materials used to form the microneedle patch have been used in the pharmaceutical field for years and have proven compatibility with the skin and with proteins. The drugs may be stored in the matrix of the microneedle array as well as the holding plate so that the requirement for high dose applications may be full filled. In addition, molding (casting) of this type of microneedle patch is simple, easy to achieve and needs no microfabrication systems and organic solvents. By a programmed molding (casting), the patch may be assembled in a layered structure with desired drug concentration in each layer, respectively. Due to this design, a programmed pulse or a zero order release of drugs may easily be achieved. In addition, delicate proteins loaded in the patch are kept in a dry and hydrophilic glassy state before being released, the most favored state for protein storage. Finally, during the swelling-based drug release, the microneedle patch increases their thickness gradually between the skin and the back cover (which holds the needles) lo create a sustained pressure to ensure good contact of the microneedles inside epidermis.

Abstract translation: 本发明公开了一种新颖的微针系统，相变微针贴片，克服了现有微针遇到的所有限制。 微针贴片是由一个由微针阵列和针（所谓的保持板）组成的整体聚合物片形成的，针架在其上。 贴剂的微针硬度足够强，能够在干燥状态下穿透表皮，但是当吸收体液时，水凝胶状态变得柔软，可渗透亲水剂。 贴剂的水凝胶状态是由物理或化学交联结合物保持的亲水网络。 通过体液打开网络孔，使药物和大分子扩散通过。 用于形成微针贴片的聚合物材料已经在制药领域中使用了多年，并已经证明与皮肤和蛋白质的相容性。 药物可以储存在微针阵列以及保持板的基质中，使得高剂量应用的需求可以被充满。 此外，这种微针贴片的成型（铸造）简单，易于实现，不需要微细加工系统和有机溶剂。 通过编程成型（铸造），贴片可以分别以每层中所需药物浓度的层状结构组装。 由于该设计，可以容易地实现编程脉冲或零次释放药物。 此外，装载在贴片中的精细蛋白质在被释放之前保持在干燥和亲水的玻璃状态，这是最有利的蛋白质储存状态。 最后，在基于溶胀的药物释放期间，微针贴片在皮肤和后盖（其保持针头）之间逐渐增加其厚度，从而产生持续的压力，以确保表皮中的微针的良好接触。

公开(公告)号：US20090036417A1

公开(公告)日：2009-02-05

申请号：US12239847

申请日：2008-09-29

Applicant: Tuo JIN

Inventor： Tuo JIN

IPC: A61K31/555 ,  A61K31/28 ,  C07F5/00 ,  A61P43/00

CPC classification number: A61K31/555 ,  A61K9/0073 ,  A61K9/1274 ,  A61K31/28 ,  A61K38/00

Abstract: This invention provides a cochleate and nano-cochleate systems wherein the agents bridging lipid bilayer are organic multi-valent cations. This invention also provides a method for preparing the cochleate system comprising direct cochleation and hydrogel-isolated procedure. The preparation method comprises using the charge ration between the bridging agents and lipids to control the particle sizes. This cochleate or nano-cochleate system may be used for microencapsulation and delivery of therapeutics wherein the therapeutic agents are loaded in the cochleate structure as the bridging agents between lipid bilayers. Finally, this invention provides other uses of these new cochleate and nano- cochleate systems.

Abstract translation: 本发明提供了一种耳蜗和纳耳耳蜗系统，其中桥接脂质双层的试剂是有机多价阳离子。 本发明还提供了一种制备耳蜗系统的方法，其包括直接的耳蜗和水凝胶分离过程。 制备方法包括使用桥联剂和脂质之间的电荷比来控制颗粒尺寸。 该耳蜗或纳耳耳蜗系统可用于微囊化和递送治疗剂，其中治疗剂作为脂质双层之间的桥连剂加载在耳蜗结构中。 最后，本发明提供了这些新的耳蜗和纳耳耳蜗系统的其它用途。

公开(公告)号：US20090028904A1

公开(公告)日：2009-01-29

申请号：US12148942

申请日：2008-04-23

Applicant: Leila Zarif ,  Tuo Jin ,  Ignacio Segarra ,  Raphael J. Mannino

Inventor： Leila Zarif ,  Tuo Jin ,  Ignacio Segarra ,  Raphael J. Mannino

IPC: A61K9/00 ,  A61K31/70 ,  A61K38/02 ,  A61K39/00 ,  A61K31/7048 ,  A61K31/704 ,  A61K38/13 ,  A61K31/472 ,  A61K31/496 ,  A61K47/12 ,  A61K31/07 ,  A61K39/145 ,  A61K31/20 ,  A61K33/30 ,  A61K33/26 ,  A61K33/00 ,  A61K36/54

CPC classification number: A61K9/1274 ,  A61K31/07 ,  A61K31/11 ,  A61K31/20 ,  A61K31/472 ,  A61K31/496 ,  A61K31/704 ,  A61K31/7048 ,  A61K31/713 ,  A61K36/54 ,  A61K38/13 ,  Y10S436/829 ,  Y10S514/966 ,  Y10S514/967 ,  Y10T428/2984

Abstract: A process for producing a small-sized, lipid-based cochleate. Cochleates are derived from liposomes which are suspended in an aqueous two-phase polymer solution, enabling the differential partitioning of polar molecule based-structures by phase separation. The liposome-containing two-phase polymer solution, treated with positively charged molecules such as Ca2+ or Zn2+, forms a cochleate precipitate of a particle size less than one micron. The process may be used to produce cochleates containing biologically relevant molecules.

Abstract translation: 一种生产小型，基于脂质的耳蜗的方法。 耳蜗源自脂质体，其悬浮在水性两相聚合物溶液中，使得能够通过相分离差异分配极性分子基结构。 用带正电荷的分子如Ca2 +或Zn2 +处理的含脂质体的两相聚合物溶液形成粒度小于1微米的耳蜗沉淀物。 该方法可用于产生含有生物相关分子的耳蜗细胞。

公开(公告)号：US20060121121A1

公开(公告)日：2006-06-08

申请号：US10517122

申请日：2003-06-03

Applicant: Tuo Jin ,  Hua Zhu ,  Jiahao Zhu

Inventor： Tuo Jin ,  Hua Zhu ,  Jiahao Zhu

IPC: A61K9/16 ,  B29C39/10

CPC classification number: A61K9/0043 ,  A61K9/0024 ,  A61K9/0073 ,  A61K9/1075 ,  A61K9/113 ,  A61K9/1652 ,  A61K9/19 ,  A61K9/5031 ,  A61K9/5036 ,  A61K9/5073 ,  A61K38/00

Abstract: This invention provides method for sustained release delivery of structurally delicate agents such as proteins and peptides. Using unique emulsion system (Stable polymer aqueous-aqueous emulsion), proteins and peptides can be microencapsulated in polysacchride glassy particles under a condition free of any chemical or physical hazard such as organic solvents, strong interfacial tension, strong shears, elevated temperature, large amount of surfactants, and cross-linking agents. Proteins loaded in these glassy particles showed strong resistance to organic solvents, prolonged activity in hydrated state, and an excellent sustained release profile with minimal burst and incomplete release when being further loaded in degradable polymer microspheres. This invention provides a simple yet effective approach to address all the technical challenges raised in sustained release delivery of proteins.

Abstract translation: 本发明提供结构上精细的试剂例如蛋白质和肽的持续释放递送方法。 使用独特的乳液系统（稳定的聚合物水性乳液），蛋白质和肽可以在没有任何化学或物理危害的条件下，在有机溶剂，强界面张力，强剪切，高温，大量的条件下，微囊化在多糖玻璃状颗粒中 的表面活性剂和交联剂。 装载在这些玻璃状颗粒中的蛋白质显示出对有机溶剂的强烈抗性，水合状态下的延长的活性，以及​​当进一步负载在可降解聚合物微球体中时具有最小的突发和不完全释放的优异的持续释放特征。 本发明提供了一种简单但有效的方法来解决蛋白质持续释放递送中提出的所有技术挑战。

公开(公告)号：US06592894B1

公开(公告)日：2003-07-15

申请号：US09613840

申请日：2000-07-11

Applicant: Leila Zarif ,  Tuo Jin ,  Ignacio Segarra ,  Raphael J. Mannino

Inventor： Leila Zarif ,  Tuo Jin ,  Ignacio Segarra ,  Raphael J. Mannino

IPC: A61K9127

CPC classification number: A61K9/1274 ,  A61K31/07 ,  A61K31/11 ,  A61K31/20 ,  A61K31/472 ,  A61K31/496 ,  A61K31/704 ,  A61K31/7048 ,  A61K31/713 ,  A61K36/54 ,  A61K38/13 ,  Y10S436/829 ,  Y10S514/966 ,  Y10S514/967 ,  Y10T428/2984

Abstract: A process for producing a small-sized, lipid-based cochleate. Cochleates are derived from liposomes which are suspended in an aqueous two-phase polymer solution, enabling the differential partitioning of polar molecule based-structures by phase separation. The liposome-containing two-phase polymer solution, treated with positively charged molecules such as Ca2+ or Zn2+, forms a cochleate precipitate of a particle size less than one micron. The process may be used to produce cochleates containing biologically relevant molecules.

Abstract translation: 一种生产小型，基于脂质的耳蜗的方法。 耳蜗源自脂质体，其悬浮在水性两相聚合物溶液中，使得能够通过相分离差异分配极性分子基结构。 用带正电荷的分子如Ca2 +或Zn2 +处理的含脂质体的两相聚合物溶液形成粒度小于1微米的耳蜗沉淀物。 该方法可用于产生含有生物相关分子的耳蜗细胞。

公开(公告)号：US09163107B2

公开(公告)日：2015-10-20

申请号：US13977973

申请日：2012-01-05

Applicant: Tuo Jin ,  Shiyue Duan

Inventor： Tuo Jin ,  Shiyue Duan

IPC: C08G12/06 ,  C08G73/02 ,  A61K9/50 ,  A61K47/34 ,  C08G73/18 ,  C12N15/87 ,  C12N11/08 ,  A61K47/30 ,  A61K48/00

CPC classification number: C08G12/06 ,  A61K9/5031 ,  A61K47/34 ,  C08G73/0273 ,  C08G73/18 ,  C12N15/87

Abstract: The present invention is directed to a design of and a method to synthesize polycations for gene (DNA and RNA) delivery. According to this design, the polycations (also said cationic polymers) are formed by polymerization of endogenous monomers bearing sufficient amino groups through degradable bonds with linker molecules. The amino group-bearing monomers are those naturally existing or nontoxic to human body. The linker molecules are those which are not only degradable to nontoxic fragments but also able to release the amino group-bearing monomers in their native state upon degradation. Some examples for the endogenous amino group-bearing monomers are spermine and spermidine (or their derivatives). Examples for the degradable chemical bonds formed between the amino group-bearing monomers are imines. In order to improve degradability or proton sponging effect, low pKa (

Abstract translation: 本发明涉及用于合成基因（DNA和RNA）递送聚阳离子的设计和方法。 根据该设计，聚阳离子聚合物（也称为阳离子聚合物）通过具有足够氨基的内源单体通过可降解键与连接分子的聚合形成。 含氨基的单体是天然存在的或对人体无毒的单体。 连接子分子是不仅可降解成无毒片段的那些，而且还能够在降解时以其天然状态释放带氨基的单体。 内源性含氨基单体的一些实例是精胺和亚精胺（或其衍生物）。 在含氨基的单体之间形成的可降解化学键的实例是亚胺。 为了提高降解性或质子海绵效应，低pKa（<8）氨基，通过聚合物降解产生的游离氨基（例如由亚胺键降解产生的那些）或其它给电子基团 因为咪唑，吡唑，吡啶，嘧啶或甚至苯被并入两个（或三个）反应性基团之间的接头中，用于连接含氨基的单体。 这些聚阳离子载体体系可用于纳米包封和转染基因材料。

公开(公告)号：US20080248098A1

公开(公告)日：2008-10-09

申请号：US12065310

申请日：2006-07-20

Applicant: Tuo Jin ,  Fei Wu ,  Weien Yuan

Inventor： Tuo Jin ,  Fei Wu ,  Weien Yuan

IPC: A61K9/127 ,  A61K47/36 ,  A61K38/02 ,  A61K38/16 ,  A61K47/38 ,  A61P43/00 ,  A61K9/14 ,  A61K31/7052 ,  A61K39/00 ,  A61K39/395

CPC classification number: A61K9/1694 ,  A61K9/0024 ,  A61K9/1623 ,  A61K9/1647 ,  A61K9/1652 ,  A61K9/19 ,  A61K9/7007 ,  A61K39/00 ,  A61L27/48 ,  A61L31/10 ,  A61L31/129

Abstract: A method of preparing polysaccharide glassy microparticles which are less than 10 μum in diameter and contain structurally delicate agents, such as proteins, peptides, gene materials, vaccines, antibodies, viruses and liposomes using low-temperature aqueous-aqueous emulsification (free of polyelectrolytes) and freezing-induced phase separation. When delicate agents are added to a polysaccharide-PEG two phase system followed by homogenization (or other shear adding process), the agents partition into the polysaccharide dispersed phase preferentially. These processes help to avoid aggregation of proteins caused by interaction with charged polyelectrolytes used for stabilizing the polysaccharide dispersed phase in our previously reported aqueous-aqueous emulsion. When this system is frozen and lyophilized, glassy particles less than 10 μm in diameter containing delicate agents can be formed. These fine polysaccharide particles protect proteins within their hydrophilic glassy matrix, and can therefore be easily suspended in hydrophobic polymer solutions and formulated to various forms of sustained release devices such microsphere, sheets, fibers, coating layers, and scaffolds. The particles can also be dispersed in hydrophilic gels to improve releasing kinetics and to deliver vaccines and antibodies for immune therapy.

Abstract translation: 一种制备多糖玻璃状微粒的方法，其使用低温水性乳化（不含聚电解质），其直径小于10um，并含有结构上脆弱的物质，例如蛋白质，肽，基因材料，疫苗，抗体，病毒和脂质体。 和冷冻诱导相分离。 当将精制剂加入到多糖-PEG两相体系中，随后进行均质化（或其他剪切加料法）时，试剂优先分配到多糖分散相中。 这些过程有助于避免与我们以前报道的水性乳液中稳定多糖分散相的带电聚电解质相互作用引起的蛋白质聚集。 当该系统被冷冻和冻干时，可以形成含有微细剂的直径小于10微米的玻璃状颗粒。 这些细多糖颗粒保护其亲水性玻璃质基质内的蛋白质，因此可以容易地悬浮在疏水性聚合物溶液中并配制成各种形式的缓释装置如微球，片，纤维，涂层和支架。 颗粒也可以分散在亲水性凝胶中，以改善释放动力学和递送用于免疫治疗的疫苗和抗体。

公开(公告)号：US6153217A

公开(公告)日：2000-11-28

申请号：US235400

申请日：1999-01-22

Applicant: Tuo Jin ,  Leila Zarif ,  Raphael Mannino

Inventor： Tuo Jin ,  Leila Zarif ,  Raphael Mannino

IPC: C07D233/60 ,  A61K9/00 ,  A61K9/127 ,  A61K31/05 ,  A61K31/192 ,  A61K31/198 ,  A61K31/216 ,  A61K31/337 ,  A61K31/405 ,  A61K31/4174 ,  A61K31/436 ,  A61K31/4422 ,  A61K31/48 ,  A61K31/522 ,  A61K31/568 ,  A61K31/704 ,  A61K31/7042 ,  A61K31/7048 ,  A61K45/00 ,  A61K47/02 ,  A61K47/24 ,  A61K47/30 ,  A61K47/34 ,  A61K47/36 ,  A61K47/42 ,  A61K47/44 ,  A61P9/10 ,  A61P23/00 ,  A61P25/20 ,  A61P29/00 ,  A61P31/04 ,  A61P31/10 ,  A61P31/12 ,  A61P35/00 ,  A61P37/06 ,  C07D209/26 ,  C07D211/90 ,  C07D305/00 ,  C07D473/18 ,  C07D519/00 ,  C07J1/00

CPC classification number: A61K9/1274 ,  A61K31/07 ,  A61K31/11 ,  A61K31/20 ,  A61K31/472 ,  A61K31/496 ,  A61K31/704 ,  A61K31/7048 ,  A61K31/713 ,  A61K36/54 ,  A61K38/13 ,  Y10S436/829 ,  Y10S514/966 ,  Y10S514/967 ,  Y10T428/2984

Abstract: A process for producing a small-sized, lipid-based cochleate is described. Cochleates are derived from liposomes which are suspended in an aqueous two-phase polymer solution, enabling the differential partitioning of polar molecule based-structure by phase separation. The liposome-containing two-phase polymer solution, treated with positively charged molecules such as Ca.sup.2+ or Zn.sup.2+, forms a cochleate precipitate of a particle size less than one micron. The process may be used to produce cochleates containing pharmaceutical agents or biologically relevant molecules. Small-sized cochleates may be administered orally or through the mucosa to obtain an effective method of treatment.

Abstract translation: 描述了一种生产小型脂质类耳蜗的方法。 耳蜗源自脂质体，其悬浮在水性两相聚合物溶液中，使得能够通过相分离差异分配极性分子基结构。 用带正电荷的分子如Ca2 +或Zn2 +处理的含脂质体的两相聚合物溶液形成粒度小于1微米的耳蜗沉淀物。 该方法可用于制备含有药剂或生物相关分子的耳蜗细胞。 可以口服或通过粘膜给予小尺寸的耳蜗以获得有效的治疗方法。