CN101124003A - Novel methods for administration of drugs and devices useful thereof - Google Patents

Novel methods for administration of drugs and devices useful thereof Download PDF

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CN101124003A
CN101124003A CN 200480015184 CN200480015184A CN101124003A CN 101124003 A CN101124003 A CN 101124003A CN 200480015184 CN200480015184 CN 200480015184 CN 200480015184 A CN200480015184 A CN 200480015184A CN 101124003 A CN101124003 A CN 101124003A
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novel
methods
administration
drugs
devices
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CN 200480015184
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N·哈维
P·E·劳伦特
P·阿尔查斯
R·J·佩蒂斯
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贝克顿·迪金森公司
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Abstract

本发明涉及用于将物质施用到患者皮肤的接合层,即皮肤的真皮网织层和皮下层的下真皮之间的过渡组织的方法。 The present invention relates to a material for administering to the patient's skin bonding layer, i.e., the dermal tissue reticulocytes and a transition between the subcutaneous layer of subdermal layer method. 本发明提供了肠胃外给药的改进方法,其中,它所提供的优点包括减弱不希望的免疫反应和由所施用的物质引起的意外的免疫毒性作用。 The present invention provides an improved process for parenteral administration, which includes the advantages it offers unexpected weakened immune undesirable toxic effects of a substance by the immune response caused by administration. 另外,通过采用本发明方法可以获得改善了的药物动力学特征。 Further, by employing the method of the present invention can obtain an improved pharmacokinetic characteristics. 本发明还披露了可用于本发明方法的装置。 The present invention also discloses a device may be used in the methods of the present invention.

Description

施用药物的新方法和用于该方法的装置1. 发明领域本发明涉及用于将物质施用到患者皮肤的接合层,即皮肤的真皮网织层和皮下层的真皮之间的过渡组织的方法。 The method and new methods of administration of drugs for the apparatus 1. Field of the Invention The present invention relates to a method for administering a substance to the bonding layer of the patient's skin, i.e. the dermal layer, and a transition reticular dermis tissue between the subcutaneous layer . 本发明提供了肠胃外给药的改进方法,其中,它所提供的优点包括减少不希望的免疫反应和由施用所述物质引起的意外的免疫毒性作用。 The present invention provides an improved process for parenteral administration, which includes the advantages it offers to reduce undesirable immune responses and immune unexpected toxic effects caused by the administration of the substance. 另外,通过使用本发明方法可以获得改善了的药物动力学特征。 Further, by using the method of the present invention can be obtained an improved pharmacokinetic characteristics. 还披露了用于本发明方法中的装置。 Also discloses a method for apparatus according to the present invention. 2. 发明背景有效地和安全地施用诸如诊断制剂和药物的药用物质的重要性长久以来就已经认识到了。 2. Background of the Invention efficiently and safely administering pharmaceutical importance, such as diagnostics and pharmaceutical substances have long been recognized. 传统针形物的使用,长期以来提供了一种通过皮肤施用将药用物质经由传统针形物输送到人体和动物体内的方法。 Using a conventional needle has long provided a method of transporting a drug substance through the skin was administered via a conventional needle to humans and animals. 为了实现通过皮肤的可再现的和有效的输送,同时改进注射的方便性并且减轻患者的担心和/或与常规针形物相关的疼痛,业已作出了相当多的努力。 Through the skin in order to achieve reproducible and efficacious delivery, while improving the ease of injection and reduce the fear of the patient and / or pain associated with conventional needle it was already made considerable efforts. 另外,某些输送系统完全取消了针形物, 并且依赖于化学介体或外部驱动力,如离子电渗电流或电穿孔,或热穿孔或超声波导入,以便破坏角质层,即皮肤的最外层,通过皮肤表面输送物质。 Further, some of the delivery system was completely abolished needle, and is dependent on chemical mediators or external driving forces such as iontophoretic currents or electroporation or thermal perforation or sonophoresis, in order to destroy the stratum corneum, i.e. the outermost skin layer, transporting substance through the skin surface. 不过,所迷输送系统不能总是可再现地打破皮肤屏障或将所述药物物质输送到皮肤表面下面的特定深度,因此,临床结果可能是搏动的。 However, the delivery system of the fans can not always reproducible or break the skin barrier to deliver the drug substance to a certain depth below the surface of the skin, and therefore, clinical results may be pulsating. 因此,对角质层的机械破坏,如使用针形物, 被认为提供了通过皮肤表面施用物质的可再现性最高的方法,并且提供了对所施用的物质定位的控制和可靠性。 Therefore, the mechanical damage to the stratum corneum, such as using a needle-shaped material, is believed to provide the most reproducible method of administration of substances through the skin surface, and provides a substance administered positioning control and reliability. 将物质输送到皮肤表面下面的方法几乎只能通过经皮施用,即通过皮肤将物质输送到皮肤下面的部位。 Delivery of a substance to the skin surface by following the method used almost exclusively transdermal administration, i.e. delivery of substances through the skin site beneath the skin. 经皮给药包括皮下,肌内或静脉内施用途径,其中,肌内和皮下注射是最常用的。 Transdermal administration includes subcutaneous administration, intramuscular or intravenous routes, wherein, intramuscular and subcutaneous injection are most commonly used. 从解剖学上看,身体的外表面由两种主要组织层组成,外面的表皮和下面的真皮,它们共同构成了皮肤(有关综述参见Physiology, Biochemistry, and Molecular Biology of the Skin, Second Edition, LA Goldsmith, Ed. , Oxford University Press, New York, 1991)。 Anatomically, the outer surface of the body composed of two major tissue layers, the outer epidermis and the underlying dermis, which together constitute the skin (for review, see Physiology, Biochemistry, and Molecular Biology of the Skin, Second Edition, LA Goldsmith, Ed., Oxford University Press, New York, 1991). 表皮被细分成五层,总厚度为75 - 150jam。 Epidermis is subdivided into five layers with a total thickness of 75 - 150jam. 真皮在表皮下面,它包括两层,最外面的部分被称作真皮乳头层,较深层的被称作真皮网织层。 In the dermis beneath the epidermis, which comprises two layers, an outermost portion referred to as the papillary dermis, it referred to as dermis deeper plexiform layer. 真皮乳头层包括大量的微循环血管和淋巴管丛。 Papillary dermis comprising a large number of micro-vascular and lymphatic plexus. 相反,真皮网织层是相对无细胞和无血管的,并且由致密的胶原和弹性结締组织组成。 In contrast, the dermal plexiform layer are relatively avascular and acellular, and a dense connective tissue composed of collagen and elastin. 在表皮和真皮下面是皮下组织,又被称作下真皮,它由结締组织和脂肪组织组成。 In the subcutaneous tissue below the epidermis and dermis, also called the dermis, which consists of connective tissue and adipose tissue. 肌肉组织位于皮下组织下面。 Muscle tissue is located beneath the subcutaneous tissue. 真皮网织层和皮下组织是通过被称作接合层的界面分开的。 Dermis and subcutaneous tissue plexiform layer are separated by a bonded layer at the interface is called. 接合层以若干胶原束为边界,它构成了紧挨着接合层上面的真皮网织层。 Some collagen bundles in the bonding layer as a boundary, which constitutes the bonding layer immediately above the dermis reticular layer. 这些胶原束是以平行于皮肤表面的方式排列的,固定真皮乳头层的弹性纤维。 The collagen bundles are parallel to the skin surface of the arrangement, the elastic fibers in the papillary dermis fixed. 在接合层中,构成光滑的,弹性的和分散的胶原纤维的纤维状结締组织是相对于真皮网织层而垂直取向的。 Bonding layer constituting a smooth, elastic and fibrous connective tissue collagen fibers are dispersed with respect to the dermis reticular layer of the vertical alignment. 这种结締组织与糖胺聚糖和蛋白聚糖结合,并且支撑成纤维细胞,少量的脂肪细胞和来自血管的浸润细胞。 Such binding connective tissue and proteoglycans and glycosaminoglycans, fibroblasts and the support, small amounts of fat cells and infiltrating cells from blood vessels. 所述接合层的另一个特征是存在形成真皮的毛细管袢的血管的致密网络。 Another feature of the bonding layer is a loop of the capillary blood vessels present in the dermis forming a dense network. 重要的是,集中毛细血管后微静脉的深静脉丛位于接合层中。 Importantly, the concentration of capillary venules located deep venous plexus bonding layer. 在皮肤接合层下面,是脂肪组织,它构成了皮下层。 Bonding layer beneath the skin, adipose tissue, which forms the skin layer. 接合层的厚度估计为1.9-3mm。 The estimated thickness of the bonding layer of 1.9-3mm. 这些数据是基于对健康自愿者的临床研究,采用了X-光CT扫描和高频(20MHz)超声波成像技术。 These data are clinical studies on healthy volunteers, using X- ray CT scans and high frequency (20MHz) ultrasonic imaging techniques. 如上文所述,皮下组织和肌肉组织通常都被用作施用药用物质的部位。 As described above, the subcutaneous tissue and muscle tissue are generally administered as parts of pharmaceutical substances. 不过,在将药用物质施用到这些部分时所遇到的最严重的问题之一是,在受试者体内引起不希望的免疫反应的潜在危险。 However, one of the most serious problems in the administration of the medicinal substance to these parts encountered is that in a subject causing potentially dangerous unwanted immune response. 在某些情况下,这种不希望的免疫反应可能导致受试者死亡。 In some cases, this unwanted immune response may lead to death of the subject. 因此, 尽管一直需要能导致改善了的药物动力学的施用物质的方法,同时还存在对减弱了通过用药导致的有害作用,如不希望的免疫反应的施用物质的方法的特征需要。 Therefore, although lead has been a need for a method of administering a substance to improve pharmacokinetics, there is also diminished deleterious effects caused by medication, method of administration of substances undesired immune response desired characteristics.

3.发明概述本发明提供了通过选择性地和专一性地靶定患者皮肤的接合层的新的肠胃外施用方法,以便导致所输送的物质具有较高的治疗效力。 3. SUMMARY The present invention provides a new parenteral predetermined outer bonding layer of the skin of the patient by selectively target and specificity to the method of application, so as to cause the material delivered has a high therapeutic efficacy. 相对包括真皮内和皮下给药方法在内的其他方法而言,按照本发明方法输送的物质具有改善了的临床用途和治疗效力。 Relative to other methods include intradermal and subcutaneous methods of administration, including, substance delivery method according to the present invention have improved clinical utility and therapeutic efficacy. 本发明提供了好于常规给药方法的优点,包括,但不局限于改善了的药物动力学,不希望的和有害的副作用的减轻,受试者对疼痛感觉的减轻或消除,没有对注射体积的限制。 The present invention provides the advantage of better than conventional methods of administration, including, but not limited to improved pharmacokinetics, and mitigate undesired harmful side effects, the subject to reduce or eliminate the perception of pain, no injection size restrictions. 本发明在一定程度上是基于发明人的意外发现,即将物质输送到患者皮肤的接合层,提供了改善了的输送方法。 The present invention is based on the inventors surprisingly found that a certain degree, the bonding layer is about delivering a substance to the patient's skin, there is provided an improved method of delivery. 在本文中,接合层表示皮肤的真皮的深层,即,真皮网织层和皮下层的真皮之间的过渡组织区。 Herein, the bonding layer represents the skin deep dermis, i.e., the transition zone between the dermal tissue reticular dermis layer and the subcutaneous layer. 在本文中,施用于接合层中意在包括以如下方式将物质施用到接合层,使所述物质沉积在接合层中,以便它能方便地到达接合层的静脉丛和毛细血管后微静脉的稠密的网络,并且被快速吸收和系统地分配。 As used herein, applied to the bonding layer comprises the following manner in Italy substance applied to the bonding layer, the bonding layer material is deposited, so that it can easily reach a dense bonding layer after venules and capillaries venous plexus network and is rapidly absorbed and distributed systems. 根据本发明方法,物质在接合层中的沉积主要是在至少大约1.5mm的深度上,优选至少大约2 mm,最多不超过大约3 mm, 优选不超过大约2.5mm,由此导致了所述物质的快速吸收,并且减弱了免疫反应。 The method according to the present invention, the bonding layer material is deposited primarily on the depth of at least about 1.5mm, preferably at least about 2 mm, no more than about 3 mm, preferably no more than about 2.5mm, which led to the substance the rapid absorption, and weakened immune response. 因此,按照本发明方法输送的物质可以比包括ID和IM在内的其他施用途径更快地产生它们的有利效果。 Thus, they can produce advantageous effects than other routes of administration, including IM and ID include faster method according to the present invention the substance delivered. 优选的是,按照本发明方法输送的物质能够进入患者皮肤的接合层,而又不穿过它。 Preferably, the substance delivery method according to the present invention can be brought into engagement with the patient's skin layer, without passing through it. 将所述物质放入皮下层(例如,超过2.5 mm 的深度)可能不仅会导致所述物质的緩慢吸收,并且还可能与不希望的免疫反应相关,并因此是本发明方法所不希望的。 The material was placed in the subcutaneous layer (e.g., over a 2.5 mm depth) may not only result in a slow absorption of the substance, and also may be associated with undesirable immune response, and thus the method of the present invention is not desirable. 本发明提供了用于将物质导入并且沉积在皮肤接合层中的方法。 The present invention provides a method for depositing a material into the skin and the bonding layer. 根据本发明方法将物质输送到受试者接合层中,导致了改善了的药物动力学,例如,改善了的药物动力学特征。 The method of the present invention will be delivered to the subject matter in the bonding layer, resulting in an improved pharmacokinetics, e.g., an improved pharmacokinetic characteristics. 尽管不希望受特定理论的约束,据信,由于渗入接合层的静脉丛和毛细血管后微静 While not wishing to be bound by a particular theory, it is believed, because the venous plexus and capillaries infiltrated layer bonded micro static

脉的稠密网络,直接将所述物质用于接合层,会导致所述物质比皮下或肌内施用更有效的吸收,反过来,又会导致改善了的药物动力学。 Pulse dense network, directly to the bonding layer material will result in the substance than subcutaneous or intramuscular administration more efficient absorption, in turn, will lead to improved pharmacokinetics. 另外,通过专一性地和选择性地靶定用于给药的接合层,由所述物质表现出来的药物动力学始终是可再现的,导致了相对其他输送方法而言PK参数的个体间差异的减弱。 Further, the specificity and selectively targeted for administration of the bonding layer, manifested by the substance always reproducible pharmacokinetics, resulting in inter-individual relative to other delivery methods PK parameters weakened differences. 本发明方法不仅提供了相对常规给药方法而言的改善了的药物动力学,而且还提供了其他优点,包括减少了通过施用一种物质所导致的有害的副作用,如针对所述物质的活性成分的不希望的免疫反应和意外的免疫毒性作用。 The method of the present invention not only provides improved over conventional methods of administration in terms of the pharmacokinetics, but also offers other advantages, including reducing the detrimental side effects caused by administration of a substance, as for the active substance undesired immune response component of the immune and unexpected toxic effects. 在本文中,术语"不希望的免疫反应" 表示接受本发明物质的受试者的天然免疫反应,其中,在施用时, 不希望所述物质引起这样的反应。 As used herein, the term "unwanted immune response" acceptance of the innate immune response of the subject matter of the present invention, wherein, when administered, the substance cause such undesired reactions. 可以用本发明方法预防的不希望的免疫反应的例子包括,但不局限于,IgE-介导的过敏性,正如所披露的,具有局部和/或系统过敏性反应的风险,例如,在肠胃外注射胰岛素或肝素和很多其他药物之后,所述药物以具有蛋白或多糖作为活性成分为基础;抗体-介导的细胞毒性过敏性,以及免疫复合物介导的过敏性,它会导致系统性负面事件,如由于循环免疫复合物的沉积而导致的肾和/或肝和/或微脉管改变;细胞-介导的过敏性,存在在注射部位诱导迟发类型的反应和活性成分的免疫中和的风险,或任何系统性负面事件,如由肝素治疗引起的血小板减少症。 Examples of an immune response by the method of the present invention is preventing undesired may include, but are not limited to, IgE- mediated allergy, as disclosed, with the risk of local and / or systemic allergic reactions, e.g., in the stomach and external injection of insulin or heparin after many other drugs, the drug is a protein or a polysaccharide having as an active ingredient basis; antibody - mediated cytotoxic hypersensitivity, allergic and immune complex-mediated, it causes systemic renal adverse events, such as due to the deposition of circulating immune complexes caused by and / or liver and / or microvascular changes; cell - mediated hypersensitivity, delayed type induction in the presence of injection site reactions and immunological active ingredient and risk, or any systemic adverse events, such as thrombocytopenia caused by heparin.

因此,本发明方法特别适用于输送这样的治疗性物质,即所诱导的针对它的免疫反应对于要输送的所述物质的治疗效果来说是不利的。 Thus, the method of the present invention is particularly suitable for delivering such a therapeutic substance, i.e., induced responses to the therapeutic effect of the substance to be delivered is disadvantageous immune against it. 所述物质的例子包括低分子量肝素,五糖,a和p干扰素,促红细胞生成素,抗体,多肽激素,生长激素,和白介素。 Examples of the materials include low molecular weight heparin, pentasaccharide, a and p interferons, erythropoietin, antibodies, polypeptide, growth hormone, and interleukins. 本发明的给药方法的较小的免疫毒性作用的风险在某种程度上是由于在接合层中较低的免疫活性细胞的比例。 Less risk of toxic effects of immunization methods of administration of the present invention in part because the ratio of the immunocompetent cells of the lower bonding layer. 因此,本发明方法在输送所述物质时好于真皮内输送。 Thus, the method of the present invention when delivering the substance intradermally to the conveying better. 在后一种情况下,不希望的免疫反应的风险较大,因为真皮内空间以高浓度的免疫活性细胞,例如,树突细胞, 单核细胞,淋巴细胞,巨噬细胞等为特征。 In the latter case, a greater risk of undesirable immune response, since the intradermal space to a high concentration of immune cells, e.g., dendritic cells, monocytes, lymphocytes, macrophages is characterized. 在具体实施方案中,要根据本发明方法施用的所述物质不是疫苗,因为用它产生的免疫反 In a particular embodiment, to be administered according to the invention the substance is not a vaccine, because it produces counter-immunized with

应减弱可能是不利的。 Should decrease may be a disadvantage.

根据本发明方法输送物质,减少或消除了受试者感受到的疼痛。 Transporting substance according to the invention, reduce or eliminate the pain felt by the subject. 因此,本发明方法优于包括真皮内输送的其它肠胃外给药方法。 Thus, the method of the present invention is superior to other parenteral methods of administration include intradermal delivery. 尽管不希望受到特定作用机制的限制,真皮内层是以神经末稍和神经触觉小体为特征的感觉器官。 Although not wishing to be bound by a particular mechanism of action, the dermis is the inner nerve endings and nerve corpuscles characterized by sensory organs. 相反,接合层具有较少的神经末稍和感觉小体,因此,通过将物质施用到接合层所导致的疼痛感觉比通过将所述物质输送到真皮内层所产生的疼痛感觉弱。 In contrast, the bonding layer having a less sensory nerve endings bodies and, therefore, the substance is administered by the bonding layer to the pain caused by sensory feel weaker than delivering the substance into the dermis inner pain produced.

根据本发明方法输送物质的另一个优点是,与将所述物质输送到其他组织腔室相比,不存在对所述物质的注射体积的限制。 Another advantage of transporting substance according to the invention, as compared to the other tissues delivering the substance into the chamber, injection volume limit of the material is not present. 因此, 与真皮内输送相比,本发明方法是特别有利的,因为真皮内输送注射物质的体积被限制为大约50 - 250jjL,这在某种程度上是由于真皮层的胶原束和弹性蛋白纤维的高度网络和真皮组织可变形性所限。 Thus, as compared with intradermal delivery, the method of the present invention is particularly advantageous because delivery volume intradermal injection of the substance is limited to about 50 - 250jjL, which in part due to the dermal layer of collagen bundles and the elastin fibers deformability highly limited network and dermal tissues. 尽管不希望受到由于接合层结締组织的柔韧性和高度可变形性的特征机制的约束,在将物质输送到接合层中时,对注射体积没有限制,特别是通过快速浓注。 While not wishing to be bound due to the high degree of flexibility and deformability characteristics of the connective tissue engagement mechanism, when delivery of a substance into the bonding layer, there is no restriction on injection volume, especially by bolus injection. 可用于本发明方法的物质的体积可以与用于皮下施用的注射体积相同。 Volume of material can be used in the methods of the present invention may be the same injection volume for subcutaneous administration. 因此,使用本发明方法,所述物质的体积可以为大约0. 5 mL或以上,更优选大约1. 0 mL或以上。 Thus, using the method of the present invention, the volume of the substance may be about 0. 5 mL or more, more preferably about 1. 0 mL or more.

本发明涉及用于精确地和选择性地靶定患者的皮肤的接合层的任何装置。 The present invention relates to any apparatus for accurately bonding layer and selectively targeted to the patient's skin. 所使用的装置的性质并不重要,只要它能穿透患者的皮肤到接合层区内的目标深度,而又不穿透该区就行。 Properties of the device used is not critical, as long as it penetrates the patient's skin to a depth of the target layer bonded area, the area on the line without penetration. 所述装置优选刺入皮肤至少大约2 mm的深度,至多不超过大约3 mm,最优选不超过大约2. 5 mm。 The device is preferably at least approximately the skin depth of penetration of 2 mm, up to no more than about 3 mm, most preferably no more than about 2. 5 mm. 在某些实施方案中,本发明涉及使用包括至少一个针形物,优选微型操作针的装置将物质输送到患者皮肤的接合层。 In certain embodiments, the present invention relates to a composition comprising at least one needle, preferably a micro-needle means of delivering a substance to the skin of the patient using a bonding layer. 优选的是, 所述针形物的长度足以刺入接合层,并且出口深度在接合层内,以便所述物质被输送到并且分布在接合层中。 Preferably, the length of the piercing needle has sufficient bonding layer, and the depth of the outlet within the bonding layer, so that the substance to be delivered and distributed to the bonding layer. 在某些实施方案中,所述针形物的长度为大约2 mm-大约5 mm,优选大约2 mm-大约3 mm。 In certain embodiments, the needle has a length of about 2 mm- about 5 mm, preferably from about about 2 mm- 3 mm. 在其他实施方案中,在插入所述针形物时,所述针形物的出口位于大约2 mm-大约3mm的深度,优选大约2 mm-大约2. 5 mm。 In other embodiments, the needle during insertion thereof, said needle outlet was located at a depth of about 2 mm- about 3mm, preferably about 2 mm- about 2. 5 mm.

本发明涉及用于接合层处给药的包括一种或多种物质的药用制剂。 The present invention relates to materials comprising one or more layers of the pharmaceutical formulation is administered for engaging. 在某些实施方案中,包括本发明的物质的制剂包括治疗或预防有效量的所述物质。 In certain embodiments, the present invention comprises a substance said substance formulations include therapeutically or prophylactically effective amount. 在其他实施方案中,本发明的制剂包括一种或多种其他添加剂。 In other embodiments, the formulations of the invention include one or more other additives. 可以按照本发明方法施用的制剂可以是适合接合层处给药的任何形式。 The method of the present invention may be administered according to the formulation may be in any form suitable for the administration of the bonding layer. 使用本发明方法,物质可以作为快速浓注施用,或通过输液施用。 Using the method of the present invention, a substance may be administered as a bolus, or by infusion administration. 在本文中,术语"快速浓注"表示在少于IO分钟的时间内输送的药物量。 As used herein, the term "bolus" represents the amount of drug delivered in less than IO minutes. "输液"表示用超过io分钟的时间输送物质。 "Infusion" is represented by more than io minutes transporting substance. 可以理解的是,施用或输送的快速浓注可以通过速度控制装置进行,例如泵, 或没有特殊的速度控制装置,例如,用户自己注射。 It will be appreciated that the administration or delivery can be by bolus injection speed control device, such as a pump, with or without special speed control means, e.g., the user's own injection. 4. 附图的简要说明图1显示皮肤解剖学:示意性地示出了皮肤的各个层以及它们的相应的边界。 4. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the anatomy of the skin: schematically shows the various layers of the skin and their respective boundaries. 图2注射装置:给药装置的针形物长度取决于要靶定的皮肤的区室。 FIG 2 the injection device: a needle-shaped drug delivery device depends on the length thereof compartment to a targeted skin. 用于真皮内,接合层和浅皮下组织注射的最佳针形物长度分另'J为1. 5 mm, 2-3mm, 和4-5 mm。 For intradermal, subcutaneous injection bonding layer and shallow optimal needle length was the other points' J is 1. 5 mm, 2-3mm, and 4-5 mm. 图3抗体的几何平均效价:比较了不同注射途径在D0, D7, D14 通过注射单一剂量的狂犬病疫苗所产生的抗体效价。 Geometric mean antibody titers Figure 3: Comparison of different routes of injection at D0, D7, D14 antibody titers generated by injection of a single dose of rabies vaccine. 狂犬病疫苗是通过IM, ID或接合层途径施用的。 Rabies vaccine by IM, ID or route of administration of the bonding layer. 图4抗体的几何平均效价:随时间监测相继的两次和三次注射之后的抗体效价。 Geometric mean antibody titers in FIG. 4: Monitoring antibody titer after two and three successive injections over time. 通过IM, ID或接合层途径施用狂犬病疫苗。 By IM, ID or bonding layer rabies vaccine administration routes. 5. 发明的详细说明本发明部分涉及用于给患者皮肤施用物质的方法,包括输送所述物质,优选选择性地和专一性地输送到患者皮肤的接合层。 The method described invention relates in part to the skin of a patient for administering the substance 5. The invention in detail, including transporting the material, and preferably is selectively delivered to specific patient's skin bonding layer. 在一种实施方案中,所述受试者是人或动物,优选人。 In one embodiment, the subject is a human or an animal, preferably a human. 在本文中,接合层表示真皮的最深层,即真皮网织层,和皮下层的下真皮之间的过渡组织空间。 Herein, the bonding layer represents the deepest dermis, reticular dermis layer, i.e., the space between the tissue and the transition subdermal subcutaneous layer. 接合层由若干胶原束定界,它构成了恰好位于接合层 The bonding layer delimited by a number of collagen bundles, which constitutes the bonding layer is located just

上方的真皮网织层。 Woven mesh layer above the dermis. 在所述接合层中.由光滑的,柔软的和分散的胶原纤维组成的纤维状结締组织是垂直于真皮网织层方向的。 The bonding layer. Fibrous connective tissue by a smooth, soft and dispersed collagen fibers is a direction perpendicular to the dermis layer woven mesh. 接合层的另一个特征是,存在分解为真皮的毛细血管袢的血管的稠密网络。 Another feature of the bonding layer, the presence of the decomposition vessel dermal capillary loops dense network. 重要的是,集中后毛细血管的深静脉丛位于接合层中。 Importantly, the concentration of deep venous plexus capillary bonding layer located. 本发明提供了通过选择性地和专一性地靶定患者皮肤的接合层的新的肠胃外施用方法,以便导致所输送的物质具有增强的治疗效力。 The present invention provides a new parenteral predetermined outer bonding layer of the skin of the patient by selectively target and specificity to the method of application, so as to cause the material delivered with enhanced therapeutic efficacy. 在某些实施方案中,直接靶定所述接合层。 In certain embodiments, the bonding layer is directly targeted. 在本文中,施用到接合层中表示包括以如下方式将一种物质施用到接合层,使所述物质沉积在接合层中,以便它能够方便地到达接合层的静脉丛和毛细血管后微静脉的稠密的网络,并且被快速地吸收和系统性分布。 Herein, the applied bonding layer comprising the following manner represented a substance applied to the bonding layer, the bonding layer material is deposited, so that it can easily reach the bonding layer and the venous plexus capillary venules the dense network, and are rapidly absorbed and systemic distribution. 根据本发明方法,物质在接合层中的沉积主要是在至少大约1. 5 mm的深度上,优选至少大约2 mm,最多深度不超过大约3mm,优选不超过大约2.5 mm,这样导致了所述物质的快速吸收和免疫反应减弱。 The method according to the present invention, the bonding layer material is deposited primarily on the depth of at least about 1. 5 mm, preferably at least about 2 mm, up to a depth of no more than about 3mm, preferably no more than about 2.5 mm, this has led to the rapid absorption and weakened immune reactive substances. 因此,按照本发明方法输送的物质与包括SC和IM的其他施用途径相比,能快速地产生它们的有利效果。 Thus, the method according to the present invention, the substance delivery compared to other routes of administration including SC and IM, and they can quickly produce advantageous effects. 本发明方法与传统给药方法相比,其优点是,例如,改善了所施用物质的药物动力学,减弱了不希望的和有害副作用,减弱或消除了疼痛感受,以及不存在对注射体积的体积限制。 The method of the present invention as compared to conventional methods of administration, the advantage that, for example, improve the kinetics of the drug substance administered, and reduce the undesirable adverse side effects, reducing or eliminating the pain perception, as well as the injection volume is not present volume constraints. 按照本发明方法施用的物质产生的药物动力学与通过常规给药方法施用的相同物质获得的动力学相比更好并且临床上更理想。 Kinetic pharmacokinetic comparison substance according to the method of the present invention produced by the administration of the same substance administered by conventional methods of administration to obtain better and more clinically desirable. 尽管不希望受特定理论的约束,据信由于浸入接合层的静脉丛和毛细血管后微静脉的稠密网络,将所述物质直接施用到接合层会导致所述物质比皮下或肌内施用更有效的吸收,反过来,会导致改善了的药物动力学。 While not wishing to be bound by a particular theory, it is believed that due to the dense network of venules bonding layer after immersion in venous plexus and capillaries, the substance applied directly to the bonding layer material will lead to more effective than the subcutaneous or intramuscular administration absorption, in turn, will lead to improved pharmacokinetics. 另外,通过专一性地和选择性地靶定接合层,由所述物质表现出来的药物动力学可一致性地再现,导致PK参数相对其他常规给药方法而言个体间的差异较小。 Further, the specificity and selectively targeting the bonding layer, manifested by the substance can be consistently reproduced pharmacokinetics, resulting in PK parameters relative to other conventional methods of administration little difference among individuals. 根据本发明,改善了的药物动力学表示与常规施用方法相比具有提高了的生物利用率、降低了的延迟时间(Tlag)、降低了的乙x、 更快的吸收速度、特定量的施用物质的更快的发作和/或提高了的 According to the present invention, showing improved pharmacokinetics compared to conventional methods of administration having improved bioavailability, reducing the delay time (Tlag), a reduced B x, a faster rate of absorption, the amount of administration of a particular faster onset of substance and / or improve the

所述生物利用率表示到达血管腔室的所施用物质的特定剂量的总量。 It represents the total amount reaches the bioavailability of specific dosage administered substances vessel chamber. 它通常是作为浓度与时间曲线下面的面积衡量的。 It is usually a concentration area under the curve measured time. "延迟时间"表示施用所述物质到可测定或可检测血液或血浆含量之间的延迟。 "Delay time" indicates a delay between the contents of the blood or plasma may be measured, or the detectable substance to be administered. 乙x是表示获得所述物质的最大血液浓度的时间值,而C^是用特定剂量和施用方法所达到的最大血液浓度。 B x is a substance obtained the maximum blood concentration time value, C ^ is the specific dosage and method of application of the maximum blood concentration reached. 发作时间是Tlag, Tmax,和C„ax的函数,因为所有这些参数都影响达到实现生物学效果所必需的血液(或目标组织)浓度时必需的时间,Tnax和C眼可以通过对图表结果的目测检查测定,并且通常可以提供足够的信息,用于比较两种施用物质的方法。不过,可以使用本领域技术人员所公知的数学模型和/或其他方法通过动力学分析更精确地测定数值。药物动力学参数和最低有效浓度的测定是按照本领域常规方法进行的。通过与标准施用途径相比确认所获得的值是否提高了,例如,皮下,真皮内或肌内施用。在这种比较中,优选,但不是必需的是,施用到接合层和施用到参考部位,如皮下施用涉及到相同的剂量水平,即,相同用量和浓度的药物,以及相同的载体,和相同的施用速度,该速度以单位时间的量和体积表示。因此,举例来说, 以诸如100pg/mL的浓 Onset time is Tlag, Tmax, and C "ax function, since all these parameters influence the time necessary to achieve to achieve the necessary biological effect of blood (or target tissue) concentration time, and C Tnax chart by eye can result Determination of visual inspection, and typically provides sufficient information to compare two methods of administration of the substance used. However, a mathematical model may be used to those skilled in known and / or other numerical methods more accurately measured by a kinetic analysis. pharmacokinetic parameters are determined and the lowest effective concentration is carried out according to conventional methods in the art. compared with the standard value is confirmed whether the obtained route of administration increased, e.g., subcutaneous, intradermal or intramuscular administration. in this comparison preferably, but not necessarily is applied to the bonding layer and administration into the reference site such as subcutaneous administration involve the same dose levels, i.e., the same amounts and concentrations of the drug, and the same vector, and the same rate of application, the speed indicates an amount and volume per unit time. Thus, for example, such as to 100pg / mL of concentrated 和每分钟100nL的速度用5分钟时间将特定药用物质施用到接合层,优选与相同浓度的100pg/mL和每分钟100uL的速度用5分钟施用相同药用物质到皮下空间进行比较。本发明方法不仅提供了与传统给药方法相比的输送物质的改善了的药物动力学,而且还提供了其他优点,包括减轻通过施用物质所导致的有害副作用,如不希望的免疫反应和对所述物质的活性成分的意外的免疫毒性作用。在本文中,术语"不希望的免疫反应"表示接受本发明的物质的受试者的天然免疫反应,其中,所述物质在施用时不希望引起这样的反应。可以通过本发明方法预防的不希望的免疫反应的例子包括,但不局限于,IgE-介导的过敏性,抗体-介导的细胞毒性过敏性,免疫复合物介导的过敏性,和细胞介导的过敏性,抗体对活性成分的免疫中和,以及针对所述活性成分针对天然化合物形 100nL per minute and with a speed of 5 minutes to a particular pharmaceutical substances applied to the bonding layer, preferably at the same concentration 100pg / mL and 100uL per minute administration of the same pharmaceutical substance into the subcutaneous space of 5 minutes were compared. The present invention the method not only provides improved transporting substance compared to conventional methods of administration of the pharmacokinetics, but also offers other advantages, including alleviating adverse side effects caused by the administration of substances, such as unwanted immune reaction and the immune unexpected toxic effects of the active ingredient substances. As used herein, the term "unwanted immune response" acceptance of the innate immune response of the subject matter of the present invention, wherein the undesirable substance when administered cause such . examples of reactive immune response may be prevented by the method of the present invention is not intended to include, but not limited to, allergic IgE- mediated, antibody - mediated cytotoxic hypersensitivity, allergic immune complex-mediated , and cell-mediated hypersensitivity, immune antibodies and the active ingredient, and natural shape for the active ingredient compound against 的抗体的最终交叉反应性,所述天然化合物与所述施用的物质具有相同的抗原基序。因此,本发明方法特别适用于治疗性物质,其所诱导的针对它的免疫反应对于所输送的物质的治疗效果来说是不利的。用于本发明方法的治疗性物质的例子,包括低分子量肝素,五糖,oc和p干扰素,促红细胞生成素,抗体,多肽激素,生长激素和白介素。用于本发明方法的治疗性物质包括重组蛋白。在本文的以下5.1部分披露可用于本发明方法的物质的其他非限定性例子。本发明给药方法对免疫毒性作用风险的降低在某种程度上是由于免疫活性细胞在接合层中的低的比例。因此,本发明方法比所述物质的真皮内输送更好,在真皮内不希望的免疫反应的风险更高, 因为真皮内间隙以高浓度的免疫活性细胞为特征,例如,树突细胞, 单核细胞,淋巴细胞,巨噬细胞等。 The final antibody cross-reactivity with the natural substance of the compound administered has the same antigenic motifs. Thus, the method of the present invention is particularly suitable for treating material, the reaction for which it is delivered induced immunity against it treatment substance is unfavorable. examples of therapeutic substance the method of the present invention, include low molecular weight heparin, pentasaccharide, and p OC interferons, erythropoietin, antibodies, polypeptide hormones, growth hormone and interleukin therapeutic substances for the method of the present invention comprises recombinant proteins. non-limiting examples of other disclosed materials can be used in the methods of the present invention is described herein in the following section 5.1. the method of administration of the present invention reduces the risk of toxic effects on the immune to some partly due to the low proportion of immunocompetent cells in the bonding layer. Thus, the method of the present invention is better than intradermal delivery of the substance, higher risk intradermal undesired immune response, because the gap to intradermal high concentration of immunocompetent cells is characterized, e.g., dendritic cells, monocytes, lymphocytes, macrophages, and the like. 在具体实施方案中,要根据本发明方法施用的物质不是疫苗,因为降低它的免疫反应可能是不利的。 In a particular embodiment, the method according to the present invention a substance is not administered the vaccine, because it reduced the immune response may be disadvantageous. 另外,选择性地靶定用于输送物质的接合层可导致其他临床效果,如减弱了的疼痛感觉。 Additionally, targeted selectively transporting substance used for the bonding layer can lead to other clinical effects such as a reduced pain sensation. 尽管不希望受理论的约束,由于接合层具有较少的神经末稍和感觉小体,通过将物质施用到接合层所诱导的疼痛感觉可能低于通过施用到其他组织区室所导致的疼痛。 While not wishing to be bound by theory, because the bonding layer having a less sensory nerve endings and bodies, by administering the substance to the bonding layer may be lower than induced pain sensation of pain by administering to the other resulting tissue compartments. 根据本发明方法输送物质,减轻或消除了由受试者所感受到的疼痛。 Transporting substance according to the invention, reduce or eliminate the pain felt by the subject. 因此,本发明方法比其他给药方法,包括真皮内输送更好。 Thus, the method of the present invention, including intradermal delivery better than other methods of administration. 与将所述物质输送到其他组织区室中相比,根据本发明方法输送物质的另一个优点是,不存在对所述物质注射体积的限制。 Compared with the substance delivered to other tissue compartments, the further advantage transporting substance according to the invention is to limit the volume of material injected does not exist. 因此, 本发明方法特别优于真皮内输送,其中,后者注射物质的体积被局限于大约50 - 250 pL,这部分是由于真皮层的胶原束和弹性蛋白纤维的高度网络和真皮组织可变形性的原因。 Thus, the method of the present invention is particularly superior intradermal delivery, wherein the injection volume of the latter substance is limited to about 50 - 250 pL, partly due to highly organized collagen bundles network and dermal layers and dermal elastin fibers deformable of reasons. 尽管不希望受特定机制的约束,由于接合层结締组织的弹性和高度可变形性,在靶定接合层时,对注射体积没有限制,特别是快速浓注注射。 While not wishing to be bound by a particular mechanism, since the engagement and highly deformable elastic connective tissue layer, the bonding layer when the targeted, there is no limit on the volume of injection, especially bolus injection. 可用于本发明方法的物质的体积可以是与皮下施用相同的注射体积。 Volume of material can be used in the methods of the present invention may be administered subcutaneously with the same injection volume. 因此,使用本发明方法,所述物质的注射体积可以为大约0. 5 mL或以上,更优选大约1. 0 mL或以上。 Thus, using the method of the present invention, the volume of the injected substance may be about 0. 5 mL or more, more preferably about 1. 0 mL or more. 因此,本发明方法提供了用于治疗,预防或緩解与疾病,失调或感染相关的一种或多种症状的方法,包括将本发明的一种或多种物质输送到患者皮肤的接合层。 Accordingly, the present invention provides a method for treating, preventing or ameliorating the disease, disorder or infection by one or more symptoms associated with a method comprising delivering one or more substances to the bonding layer of the present invention, the patient's skin. 与其他输送方法相比,按照本发明方法输送的物质具有增强了的临床效用和治疗效力。 Compared with other delivery methods, delivery of a substance according to the method of the present invention having enhanced clinical utility and therapeutic efficacy. 5.1用于施用的物质本发明包括通过选择性地靶定受试者的接合层施用多种物质。 5.1 for the administration of the subject matter of the present invention comprises a bonding layer is applied more substances by selectively targeting. 可以用本发明方法施用的物质的例子包括,但不局限于,药理学或生物学活性物质,包括诊断制剂,药物,和其他物质,这些物质能提供治疗或保健效果,例如,但不局限于neutriceuticals。 Examples of substance administered by the method of the present invention may include, but are not limited to, pharmacologically or biologically active substances including diagnostic agents, drugs, and other substances which provide therapeutic or health benefits, such as, but not limited to, neutriceuticals. 本发明涉及施用任何蛋白,特别是治疗性蛋白,以及所有的盐,多晶型物, 类似物,衍生物,片段,模拟物和其他的肽,这些物质可以通过本领域技术人员所公知的标准方法获得。 The present invention relates to administration of any proteins, particularly therapeutic proteins, as well as all salts, polymorphs, analogs, derivatives, fragments, mimetics and other peptides, these materials may be well known by those skilled in the standard methods available. 特别适用于本发明方法的物质是那些不希望的免疫反应和免疫毒性作用风险降低而具有有利效果,并且因为具有改善了的药物动力学特征而获益的物质,所述物质包括,但不局限于低分子量肝素, 五糖,ot和P干扰素,促红细胞生成素,抗体,多肽激素,生长激素,和白介素。 The method is particularly suitable for the present invention are those substances undesirable immune response and reduce the risk of toxic effects of immunization has advantageous effects, and because having improved pharmacokinetic characteristics and benefits of substances which include, but are not limited to low molecular weight heparin, pentasaccharide, OT and P interferons, erythropoietin, antibodies, polypeptide, growth hormone, and interleukins. 本发明方法特别适用于输送抗-血栓形成药,如低分子量肝素和合成的五糖。 The method of the present invention is particularly applicable to the delivery of anti - thrombotic drugs such as heparin and low molecular weight synthetic pentasaccharide. 这些物质能够因本发明方法使不希望的免疫反应降低而具有巨大优点。 These materials can be due to that the method of the present invention to reduce undesired immune response has great advantage. 在本领域中,业已报道了施用低分子量肝素, 如依诺肝素⑧的负面免疫反应。 In the present art, it has been reported that administration of low molecular weight heparin, such as enoxaparin adverse immune response to ⑧. 例如,业已报道了在SC施用依诺肝素⑧时产生的过敏性反应(例如,参见Pharmacotherapy, 2002, 22 (11) : 1511-5)以及在接受LMW肝素治疗的患者体内的迟发型过敏性(DTH)反应(例如,参见Dermatol. Surg, 2001 27( 1 ): 47-52 )。 For example, it has been reported that allergic reaction when administered SC enoxaparin ⑧ (e.g., see Pharmacotherapy, 2002, 22 (11): 1511-5) and delayed-type hypersensitivity in a patient receiving a LMW heparin ( DTH) reaction (e.g., see, Dermatol Surg, 2001 27 (1.): 47-52). 另外,业已报道了由肝素诱导的血小板减少症(HIT),它是使用肝素的主要副作用;HIT是严重的和威胁生命的综合症,它是针对血 In addition, it has been reported by the heparin-induced thrombocytopenia (HIT), which is the main side effect of heparin; HIT is a serious and life-threatening syndrome, it is for the blood

小板因子4/肝素复合物形成的抗体所导致的。 Platelet factor 4 antibody complex formed by heparin / it caused. 据估计,HIT业已在1-3%的所有接受肝素治疗的患者中出现(参见Perfusion, 2003, 18(1 ): 47-53; Eur. J. Pediatr. 158(Suppl. 3): S130-1 33 ( 1999 )。 尽管合成的五糖,如Fondaparinux⑧业已被报道与较低的(和低分子量肝素相比)免疫毒素风险相关,但仍然存在明显的潜在威胁(Clin. Ther. 24 ( 11 ) : 1757-1769 ( 2002 )。 因此,本发明方法提供了用于抗血栓治疗的替代的和更完善的方法,因为输送诸如肝素的抗血栓药,包括低分子量肝素,能减弱或消除不希望的免疫反应,这种反应与现有抗血栓治疗相关,如DTH和HIT。本发明涉及输送用于治疗和/或预防与血栓形成相关的疾病的任何制剂。四种主要类型的治疗方法被用于预防或治疗血栓形成: 抗血小板剂,抗凝剂(肝素),维生素K拮抗剂(香豆素衍生物) 和血栓溶解剂。每一种类型的制剂能够在凝固途径的不同部位干扰凝固(参见G It is estimated that, HIT has occurred in 1-3% of all patients receiving heparin (see Perfusion, 2003, 18 (1): 47-53; Eur J. Pediatr 158 (Suppl 3): S130-1... 33 (1999) although synthetic pentasaccharide, such as Fondaparinux⑧ have been reported to be associated with a lower (compared to heparin and low molecular weight) immunotoxin risk, but there are still significant potential threat (Clin Ther 24 (11)..: 1757-1769 (2002). Accordingly, the present invention provides a method of alternative and better methods for antithrombotic therapy, because the delivery of an antithrombotic agent such as heparin, including low molecular weight heparin, can reduce or eliminate unwanted immune response, which associated with the conventional antithrombotic therapy, such as the HIT and DTH. the present invention relates to delivery for the treatment and / or prophylaxis of any of the formulations associated with thrombotic diseases. four main types of method of treatment is for the prevention or treatment of thrombotic: anti-platelet agent, an anticoagulant (heparin), vitamin K antagonists (coumarin derivatives), and each type of thrombolytic agent formulation can be in different parts of the interference coagulation coagulation pathway (see G. oodman & Gilman, The Pharmacological Basis of Therapeutics, 9th ed. , McGraw-Hill, NY ( 1996 ))。 双嘧达莫是有时被用于预防或治疗血栓形成的另一种制剂;它是血管扩张剂, 与华法灵(香豆素衍生物)组合,能抑制人造心脏瓣膜的栓塞,并且与阿斯匹林组合能减少患有血栓性疾病的患者的血栓形成。本发明还涉及细胞表面糖蛋白GPIIb/IIIA的抑制剂,它属于抗-血栓形成药的新家族,大多用于冠心病,以及凝血抑制因子,这些因子被鉴定为具有抗-血栓形成作用。本发明方法可用于治疗和/或预防与疾病相关的血栓形成,包括,但不局限于,深静脉血栓形成,肺栓塞,血栓性静脉炎,由血栓形成或栓塞造成的动脉闭阻,在血管成形术或血栓溶解期间或之后的动脉再闭阻,在动脉损伤或侵入性心脏手术之后的再狭窄,手术后静脉血栓形成或栓塞,急性或慢性动脉硬化症,中风 oodman & Gilman, The Pharmacological Basis of Therapeutics, 9th ed, McGraw-Hill, NY (1996)) are sometimes dipyridamole another formulation for the prevention or treatment of thrombosis;.. It is a vasodilator, Warfarinanion composition (coumarin derivatives) and can inhibit the artificial heart valve plug, and in combination with aspirin can reduce thrombosis in patients suffering from thrombotic diseases is formed. the present invention further relates to a cell surface glycoprotein GPIIb / IIIA inhibitors, anti it belongs - a new family of antithrombotic drugs, mostly for coronary heart disease, and inhibition of blood coagulation factor that is identified as having an anti - thrombogenic effect of the method of the present invention is useful for the treatment and / or prevention of thrombosis associated with a disease, including, but not limited to, deep vein thrombosis, pulmonary embolism, thrombophlebitis, arterial embolism caused by thrombosis or closed resistance caused during angioplasty or thrombolysis or after arteries then closed resistance, then after arterial injury or invasive cardiac surgery stenosis, postoperative venous thrombosis or embolism, acute or chronic atherosclerosis, stroke ,心肌梗塞,癌和肿瘤转移,以及神经退化病。可用于本发明方法的诊断物质包括,但不局限于,胰岛素,ACTH(例如,促肾上腺皮质激素注射剂),促黄体素-释放激素(例如, 盐酸促性腺激素释放因子),生长激素-释放激素(例如,乙酸舍莫瑞林),胆嚢收缩素(辛卡利特),甲状旁腺激素和它的片段(例如,醋酸特立帕肽),甲状腺释放激素和它的类似物(例如,普罗瑞林)和分泌素等。 Diagnostic substances, myocardial infarction, cancer and metastasis, and neurodegenerative diseases may be used in the methods of the present invention include, but are not limited to, insulin, of ACTH (e.g., corticotropin injection), luteinizing hormone - releasing hormone (e.g. , gonadotropin releasing factor hydrochloride), growth hormone - releasing hormone (e.g., acetic acid Shemoruilin), bile Nang angiotensin (Sincalide), parathyroid hormone and fragments thereof (e.g., teriparatide acetate ), thyroid releasing hormone and its analogs (e.g., protirelin) and secretin and the like. 可用于本发明的治疗性物质包括,但不局限于al抗-胰蛋白酶;抗-血管生成药;反义制剂;布托啡诺;降血钩素和类似物;西利酶;Cox-II抑制剂;皮肤学制剂;二氢麦角胺;多巴胺刺激剂和拮抗剂;脑啡肽和其他吗啡样肽;表皮生长因子;促红细胞生成素和类似物;促卵泡激素;G-CSF;胰高血糖素;GM-CSF;格拉司琼; 生长激素和类似物(包括生长激素-释放激素);生长激素拮抗剂; 肝素;水蛭素和水蛭素类似物,如水蛭肽;IgE抑制剂;胰岛素;胰岛素调理素和类似物;胰岛素-样生长因子;干扰素;白介素;促黄体素;促黄体素-释放激素和类似物;低分子量肝素和其他天然改性或合成的糖胺聚糖;M-CSF;甲氧氯普胺;咪哒唑仑;单克隆抗体, 聚乙二醇化(pegylated)的抗体,聚乙二醇化的蛋白或用亲水性或疏水性聚合物或其他官能团修饰过的任何蛋白,融 Substance useful for the treatment of the present invention include, but are not limited to, al anti - trypsin; anti - angiogenic agents; antisense agents; butorphanol; hook lowering blood hormone and the like; Sealy enzyme; Cox-II inhibition agents; dermatological preparations; dihydroergotamine; stimulators and dopamine antagonist; and other morphine-like peptide enkephalin; epidermal growth factor; erythropoietin, and the like; follicle stimulating hormone; G-CSF; glucagon Su; GM-CSF; granisetron; growth hormone and analogs (including growth hormone - releasing hormone); growth hormone antagonist; heparin; hirudin and hirudin analogs such as hirulog; of IgE inhibitors; insulin; insulin opsonin and the like; insulin - like growth factor; interferons; interleukins; luteinizing hormone; luteinizing hormone - releasing hormone and the like; low molecular weight heparins and other natural or modified synthetic glycosaminoglycans; M-CSF ; metoclopramide; midazolam; monoclonal antibody, pegylation (of pegylated) an antibody, or pegylated proteins modified with hydrophilic or hydrophobic polymers or other functional groups of any protein ,melt 蛋白,单链抗体片段或它们与任何结合的蛋白的组合,大分子或它的其他官能团, 麻药镇痛剂;烟碱;非类固醇抗炎制剂;寡糖;昂丹司琼;曱状旁腺激素和类似物;曱状旁腺激素拮抗剂,前列腺素拮抗剂;前列腺素;重组可溶性受体;东茛菪碱;五羟色胺刺激剂和拮抗剂;西地那非;叔丁喘宁;沙丁胺醇;莫达芬尼;溶血栓药;组织血纤维蛋的溶酶原激活剂;TNF和它的拮抗剂;以及疫苗。 Proteins, single-chain antibody fragment, or any combination thereof with the binding protein, macromolecule or its other functional groups, a narcotic analgesic; nicotine; non-steroidal anti-inflammatory agents; oligosaccharide; ondansetron; Yue next gland hormones, and the like; Yue adjacent thyroid hormone antagonists, prostaglandin antagonists; prostaglandin; recombinant soluble receptor; scopolamine; serotonin antagonists and stimulants; sildenafil; terbutaline; salbutamol; modafinil; thrombolytics; tissue plasminogen activator fibrin eggs; of TNF and its antagonists; and vaccines. 在某些实施方案中,可以用本发明方法施用的物质是这样的物质,它们的理想特征是快速见效,随后是所述药物的较长的循环水平。 In certain embodiments, the substance may be administered by the method of the present invention is a substance, which is the desirable feature of rapid results, followed by a longer circulating levels of the drug. 所述物质的例子是胰岛素,需要它的快速的和高峰的启动水平, 以便克服通过对糖或其他非复合碳水化合物的消化和吸收而获得的高的葡萄糖水平,同时,需要将血糖迅速降低到正常水平。 Examples of the material is insulin, which requires rapid startup and peak level, in order to overcome by high levels of glucose or other non-sugar complex carbohydrate digestion and absorption is obtained, while the need to quickly lower the blood glucose normal level. 本发明涉及胰岛素,胰高血糖素样肽,它们所有的盐,多晶型物,类似物, 衍生物,片段,模拟物和肽的用途。 The present invention relates to insulin, glucagon-like peptide, the use of all their salts, polymorphs, analogs, derivatives, fragments, mimetics and peptides. 可用于本发明方法的物质的另 Substances can be used in the methods of the invention further

一个例子是疼痛緩解制剂(例如,Cox抑制剂,吗啡,阿片样物质和其他麻药镇痛剂和曲普坦类);勃起功能障碍制剂,例如,西地那非;抗-凝血因子(例如,肝素,低分子量肝素,GPIIb/IIa拮抗剂, fondaparine);抗急性-焦虑疾病,如惊恐发作(例如,咪唑安定, 安定,三环分子);急性白天嗜睡(例如,莫达芬尼);癫痫发作(例如,安定)。 One example is pain relief preparations (e.g., Cox inhibitors, morphine, opioid and other narcotic analgesics and triptans); erectile dysfunction formulations, e.g., sildenafil; anti - coagulation factors (e.g., heparin, low molecular weight heparin, GPIIb / IIa antagonist, fondaparine); acute anti - anxiety disorders, such as panic attacks (e.g., midazolam, diazepam, tricyclic molecules); acute daytime sleepiness (e.g., modafinil); seizure seizures (eg, diazepam). 另外,对于在通过常规输送方法,例如SC施用时通常緩慢吸收的物质来说,较快的吸收可能是有利的。 Further, the material for delivery by conventional methods, for example, typically administered slowly absorbed SC, the faster the absorption may be advantageous. 传统SC施用高分子量药物是緩慢吸收的,因为吸收与分子量成反比。 SC administration of the conventional high molecular weight drugs are slow-absorbing, because the absorption is inversely proportional to molecular weight. 所述物质的例.子包括,但不局限于高分子量或疏水性药物化合物。 Examples of the substance. Promoters include, but are not limited to, high molecular weight or hydrophobic pharmaceutical compounds. 5.2用于接合层给药的制剂本发明涉及包括一种或多种用于接合层给药的物质的制剂。 5.2 formulations of the invention relates to administration for the bonding layer comprising one or more materials for the bonding layer of the formulation for administration. 在某些实施方案中,含有本发明的物质的制剂包括治疗或预防有效量的所述物质。 In certain embodiments, a formulation containing a substance according to the present invention comprises a therapeutically or prophylactically effective amount of the substance. 在其他实施方案中,本发明的制剂包括一种或多种其他添加剂。 In other embodiments, the formulations of the invention include one or more other additives. 在本文中,除非另有说明,"治疗有效量"表示足以在治疗或控制疾病时提供治疗效果或推迟或减弱与所述疾病相关的症状的本发明的物质或其他活性成分的用量。 As used herein, unless otherwise indicated, a "therapeutically effective amount" means an amount sufficient to provide a therapeutic effect in treating or controlling a disease or to delay or reduce the amount of material or other active ingredients of the invention with the associated disease symptoms. 另外,本发明物质的治疗有效量表示所述其单独或者与其他治疗组合,在疾病的治疗或控制方面产生治疗效果的量。 Further, a therapeutically effective amount of the agent of the invention alone or represents the amount of generated therapeutic effect in combination with other treatments or treatment of disease control aspect. 在用于表示本发明物质的量时,该术语可以包括能改善总体治疗,减轻或避免症状或导致疾病的原因,或增强治疗效力或与另一种治疗剂的协同作用增强的量。 When the amount of substance used in the present invention, the term may comprise improve overall treatment, alleviation or avoids symptoms or causes of disease, or enhances the therapeutic efficacy of another therapeutic agent or synergy enhanced. 在本文中,除非另有说明,"预防有效量"表示足以产生预防疾病复发或扩散的本发明的物质或其他活性成分的用量。 As used herein, unless otherwise indicated, a "prophylactically effective amount" denotes an amount sufficient to produce a substance preventing or other active ingredient of the present invention recurrence or spread of the disease. 预防有效量可以表示足以预防最初的疾病,疾病的复发或扩散或个体内疾病发生,包括但不局限于有发病倾向的用量。 A prophylactically effective amount may represent sufficient to prevent initial disease or the recurrence or spread of a disease in a subject disease, including but not limited amount tends disease. 预防有效量还可以表示在疾病预防方面提供预防效果的用量。 A prophylactically effective amount may also be expressed in an amount that provides preventive effect of disease prevention. 另外,本发明物质的预防有效量表示其单独或与其他制剂组合,在预防所述疾病方面提供了预防效果的量。 Further, a prophylactically effective amount of the substance of the present invention is represented alone or in combination with other agents, a prophylactic effect in preventing the disease. 在用于表示本发明物质的用量时,该术语可以包括能够改善总体预防或增强预防效力或与其他预防制剂的协同作用的用量。 When used to represent the amount of the substance of the present invention, the term may include an amount capable of improving overall prophylaxis or enhances the prophylactic efficacy of or synergies with another prophylaxis of formulation. 可用于包括本发明的物质的制剂中的添加剂包括,例如湿润剂,乳化剂,或pH緩沖剂。 Formulations can be used include materials of the present invention include additives such as wetting agents, emulsifying agents, or pH buffering agents. 包括本发明的物质的制剂可以包括一种或多种其他赋形剂,如糖类和多元醇。 Substance of the present invention comprises a formulation may comprise one or more other excipients, such as sugars and polyols. 优选的是,可以药用的载体本身不会诱导生理学反应,例如,免疫反应。 Preferably, the pharmaceutically acceptable carrier does not itself induce a physiological response, e.g., immune response. 最优选的是,所述可以药用的载体不会导致任何负面或不希望的副作用和/或不会导致过度的毒性。 Most preferred that the pharmaceutically acceptable carrier does not cause any adverse or unwanted side effects and / or does not result in undue toxicity. 可用于本发明的制剂中的可以药用的载体包括,但不局限于盐水,緩沖盐水,葡萄糖,水,甘油,无菌等渗緩冲水溶液,以及它们的组合。 Formulations can be used in the present invention, pharmaceutically acceptable carriers may include, but are not limited to saline, buffered saline, dextrose, water, glycerol, sterile isotonic aqueous buffer, and combinations thereof. 在以下文献中提供了可以药用的载体、稀释剂和赋形剂的其他例子:Remington's Pharmaceutical Sciences( Mack Pub, Co. , N, J. , current edition;以上文献均被完整地收作本文参考)。 Provided in the literature a pharmaceutically acceptable carrier, diluents and other excipients: Remington's Pharmaceutical Sciences (Mack Pub, Co., N, J., current edition; above documents are fully incorporated herein by reference ). 本发明的制剂可以是固体,如适合重建的冷冻干燥的粉末,液体溶液,悬浮液,片剂,药丸,胶嚢,緩释制剂,或粉末。 Formulations of the invention may be solid, as for the reconstruction of the lyophilized powder, liquid solutions, suspensions, tablets, pills, gum Nang, sustained release formulations, or powders. 含有本发明的物质的制剂可以用本领域已知的任何可以接受的制备方法制备。 It can be prepared by any acceptable method for preparing a formulation containing a substance according to the present invention may be known in the art. 具体的制备方法取决于要施用的具体物质,并且, 这些变化属于本领域普通技术人员的知识范围。 Specific methods of preparation to be administered depends on the particular substance, and the variation within the knowledge of those of ordinary skill in the art. 本发明涉及施用本发明的物质的溶液和颗粒形式和它们的混合物的方法,包括快速作用,中速作用,和长时间作用制剂,这些制剂可以用任何物质获得。 The present invention relates to a solution and method for a substance in particulate form, and mixtures thereof of the present invention administered, including fast-acting, in-action, long acting formulations and these formulations can be obtained by any substance. 用于所述方法的制剂和本发明的制剂可以是包括本发明的物质的一种或多种制剂的混合物。 Formulations and formulations of the invention may be used in the process include a mixture of a substance of the present invention, one or more agents. 所述制剂中的物质可以处在不同的物理结合状态,例如,单聚体或二聚体状态。 The formulation may be in different physical substance binding state, e.g., dimeric or monomeric status. 所述物质的化学状态可以通过标准重组DNA技术修饰,以便产生处于不同结合状态的不同化学结构式的物质。 The chemical state of matter can be modified by standard recombinant DNA techniques, in order to produce a substance different chemical structure in different binding states. 另外, 可以改变溶液参数,如pH,以便导致所述物质的制剂处在不同的结合状态。 Further, the solution may be varied parameters such as pH, so as to cause the formulation of the substance in different binding states. 本发明还涉及本发明物质的其他化学修饰。 The present invention further relates to substances other chemical modifications of the present invention. 使用本发明方法,需要较小剂量的物质就能获得与常规施用方法类似的治疗效力。 Using the method of the present invention, it requires a smaller dose of the substance can be obtained with the conventional administration methods similar therapeutic efficacy. 与通过常规方法输送相同的物质相比,按照本发明方法输送的物质具有改善了的治疗效力。 Compared with conventional methods by the same transport material, the material transfer method according to the present invention have improved therapeutic efficacy. 在施用生物学分子的情况下,所述分子可来自不同的动物物种, 包括但不局限于猪,牛,绵羊,马等。 In the case of administration of biological molecules, the molecules may be from different animal species, including but not limited to, pigs, cattle, sheep, horses and the like. 本发明涉及本发明的物质为颗粒形式,即,不是完全溶解在溶液中的制剂。 The present invention relates to formulations of the present invention is a substance in particulate form, i.e., not completely dissolved in the solution. 在某些实施方案中,至少30%,至少50%,至少75%的所述物质是颗粒形式的。 In certain embodiments, at least 30%, at least 50%, at least 75% of said substance is of particulate form. 尽管不希望受到特定作用模式的限制,所述物质呈颗粒形式的本发明的制剂至少具有一种能促进所述物质沉淀的制剂。 While not wishing to be bound by a particular mode of action, the formulation of the invention substance in particulate form having at least a material which promotes the formulation of the precipitated material. 可用于本发明的制剂中的沉淀制剂可以是蛋白类物质, 例如,鱼精蛋白,阳离子聚合物,或非蛋白类物质,例如,锌或其他金属或聚合物。 The precipitate formulations can be used in the formulations of the invention may be a protein substances, e.g., protamine, cationic polymer, or a non-protein substances, e.g., zinc or other metals or polymers. 要输送或施用的物质的形式包括存在于可以药用的稀释剂或溶剂中的它的溶液、乳液、悬浮液、凝胶、悬浮的或分散的诸如微型颗粒和纳米颗粒的颗粒,以及它们的原位形成的媒介物。 Form of a substance to be delivered, or may be present in the administration include a pharmaceutically acceptable diluent or solvent, its solutions, emulsions, suspensions, gels, suspended or dispersed particles such as microparticles and nanoparticles, as well as their vehicle formed in situ. 包括本发明的物质的制剂可以是适合接合层给药的任何形式。 Agents of the invention include a formulation may be in any form suitable for administration of the bonding layer. 在一种实施方案中,本发明的接合层制剂是可流动的、可注射的介质形式的,即, 低翻度制剂,它可以用注射器注射。 In one embodiment, the formulations of the invention the bonding layer is flowable medium in the form of an injectable, i.e., a low degree turn formulations, which can be injected with a syringe. 所述流动性可注射的介质可以是液体。 The flowable, injectable medium may be a liquid. 另外,所述流动性可注射的介质是悬浮了颗粒状材料的液体,这样所述介质保留了它的流动性,以便可以注射,例如,可以通过注射器施用。 Further, the flowability of the injectable medium is a liquid suspension of particulate material, such that the dielectric retains its fluidity, so that can be injected, for example, can be administered by syringe. 本发明的制剂能够以单位剂量形式制备。 Formulations of the invention can be prepared in unit dosage form. 每个小瓶中的单位剂量可以包括0.1-1 mL的制剂。 Each unit dose vial may comprise 0.1-1 mL of the formulation. 在某些实施方案中,本发明接合层制剂的单位剂量形式可以包括大约50jiL - 100 |iL,50pL - 200 nL, 50jaL- 500jaL或50jaL-lmL的制剂。 In certain embodiments, the unit dosage form of a layer bonded formulation of the invention may comprise from about 50jiL - 100 | iL, 50pL - 200 nL, or formulation 50jaL- 500jaL 50jaL-lmL of. 如果必要,可以向每一个小瓶中添加无菌稀释剂将所述制剂调整到需要的浓度。 If necessary, the sterile diluent may be added to adjust the concentration of the formulation required to each vial. 根据本发明方法施用的制剂的体积不是可能使接合层过载的体积,这种过窄会导致制剂被分配到一个或多个其他区室中,如皮下区室。 The volume of administration of the formulation according to the invention the bonding layer may not excessive volume overload, which leads to narrow formulation is assigned to one or more other compartments, such as subcutaneous compartment. 不过,在通过本发明的接合层施用方法施用时所述制剂的体 However, when administered by the administration method of the present invention the bonding layer of the formulation thereof

积与使用其他常规施用方法相比不太重要。 The plot is less important than with other conventional application methods. 在不受特定理论约束的前提下,据信,接合层注射对于较大体积的快速浓注来说更能够接受,这是因为接合层结締组织的弹性和高的可变形性。 Under the premise bound by a particular theory, it is believed that the bonding layer to the bolus injection of a larger volume is more able to accept, and this is high because the engagement of the elastic deformability of the layer of connective tissue. 因此,使用本发明方法,大约O. 5mL或以上,更特别的大约1. OmL或以上的注射体积可以施用到所述接合层。 Thus, using the method of the present invention, about O. 5mL or more, more particularly about 1. OmL injection volume or more may be applied to the bonding layer. 5. 3接合层输送方法在某些实施方案中,本发明涉及本文所披露的物质的接合层给药的方法,例如,输送到患者皮肤的接合层,优选通过选择性地和专一性地靼定接合层,而又不穿透它。 5.3 bonding layer transfer method] In certain embodiments, the present invention relates to a method of administering a substance joining layer disclosed herein, e.g., delivered to the patient's skin layer is bonded, preferably by selective and specific manner pedaled predetermined bonding layer, without penetrating it. 在最优选的实施方案中,直接靶定所述接合层。 In a most preferred embodiment, the bonding layer is directly targeted. 一旦制备了包括要输送的物质的制剂,典型地, 所述制剂被转移到接合层给药的注射装置,例如注射器中。 Once the substance to be delivered comprises a formulation, typically, the formulation prepared is transferred to an injection device for administration bonding layer, for example, a syringe. 本发明在某种程度上是基于发明人的发现,即将物质输送到接合层可减弱或消除不希望的免疫反应和免疫毒性作用,包括,但不局限于IgE-介导的过敏性,抗体-介导的细胞毒性过敏性,免疫复合物介导的过敏性,和细胞介导的过敏性,活性成分的免疫中和和/或抗体的免疫交叉反应性的危险和/或细胞介导的对天然物质的免疫性。 The present invention is based partly on the findings of the inventors, i.e. transport of material to the bonding layer may reduce or eliminate unwanted immune responses and immune toxic effects, including, but not limited to allergic IgE- mediated, antibody - cytotoxicity mediated hypersensitivity, immune complex mediated hypersensitivity, and cell-mediated allergic, immunological active ingredient and and / or immune antibody of the risk of cross reactivity and / or cell-mediated immune natural substances. 根据本发明方法输送本发明的制剂提供了所述物质的改善了的治疗和临床效力。 Delivery formulation of the invention provides a method according to the present invention improves the clinical efficacy and therapeutic substance. 包括本发明物质的制剂具有改善了的药物动力学,如在接合层中的改善了的吸收摄取。 Improved pharmaceutical formulations comprising a substance of the present invention has a kinetic, as in the bonding layer improves the absorption uptake. 在本文中,给药到接合层中表示将物质以这样一种方式输送到接合层中,使得所述物质能方便地到达接合层的静脉丛和毛细血管后微静脉的稠密网络,并且被迅速吸收,变得可系统性地生物利用。 Herein, is administered to the bonding layer shows a material transport in such a manner to the bonding layer, such that the material can easily reach the venous plexus of the bonding layer and a dense network of post-capillary venules, and is quickly absorption, it becomes possible to systematically bioavailable. 据信,主要以至少大约1.5mm的分布,优选至少大约2 mm,最多不超过大约3 mm,优选不超过大约2.5 mm的深度沉积的物质会导致所述物质的快速吸收和免疫反应减弱。 It is believed mainly to the distribution of at least about 1.5mm, preferably at least about 2 mm, no more than about 3 mm, preferably no more than about the depth of the deposited material will cause a 2.5 mm rapid absorption of the substance and weakened immune response. 优选的是,按照本发明方法输送的物质能进入患者皮肤的接合层,而不是穿透它。 Preferably, the substance delivery method according to the present invention can be brought into engagement with the patient's skin layer, rather than penetrate it. 将所述物质置于皮下层(例如,超过2. 5 mm的深度)不仅会导致所述物质吸收緩慢,而且还与不希望的免疫反应相关,因此,是本发明方法所不 The material was placed in the subcutaneous layer (e.g., over a depth of 2. 5 mm) not only results in slow absorption of the material, but also associated with undesirable immune response, therefore, is a method of the present invention is not

希望的。 hopefully. 将所述制剂导入接合层的实际方法并不重要,只要它能刺入受试者皮肤达到接合层中的理想的目标深度,而又不穿过它就行。 The actual preparation method of introducing the bonding layer is not critical, as long as it can achieve the desired piercing the skin of a subject target depth in the bonding layer, without it passing through the line. 在大多数情况下,所述装置会刺入皮肤,并且达到大约2-3mm的深度, 优选2.5謹的深度。 In most cases, the device will penetrate the skin and reaches a depth of about 2-3mm, preferably 2.5 wish depth. 在某些实施方案中,所述装置将刺入皮肤达到不超过2.5隨的深度。 In certain embodiments, the device will penetrate the skin to a depth of not more than 2.5 with. 根据本发明方法将物质输送到接合层的优点之一是接合层的厚度不取决于注射的部位或特定的受试者。 One advantage of the method according to the present invention delivery of a substance to the bonding layer is a bonding layer thickness does not depend on the site of injection or specific subject. 可用于本发明方法的用于接合层给药的任何注射部位包括,但不局限于, 大腿、腹部、胸肌或胸部三角肌、前臂和前臂后部的接合层。 Any injection site for administration of the bonding layer may be used in the methods of the present invention include, but are not limited to, thigh, abdomen, chest or pectoral deltoid, the bonding layer and the rear arm forearm. 施用的接合层方法包括微型操作针-型注射和输液系统或能精确靶定接合层的任何其他装置。 The method comprises a bonding layer applied micro-needle - or any other device type injection and infusion systems or precisely targeted bonding layer. 施用的接合层方法不仅包括微型装置型注射元件,而且还包括其他输送方法,如将液体或粉末经无针弹道注射递送到接合层,通过微型装置强化的离子电渗疗法,以及液体,固体,或其他剂型直接沉积到皮肤中。 The bonding layer method of administration include not only microdevice-type injection device, but also other delivery methods, such as a liquid or powder is a needle-free ballistic injection is delivered to the bonding layer, reinforced by the micro-device iontophoresis, and a liquid, solid, or other dosage forms is deposited directly into the skin. 本发明包括常规注射针形物,导管或单独或多针形物阵列使用的所有已知类型的微型操作针。 The present invention comprises a conventional injection needle, catheters or all known types of single-needle or micro-needle arrays were used. 在优选实施方案中,当向接合层中施用涉及到针形物时,针形物的前端距离皮肤表面优选2.5 mm,并且斜头跟部距离皮肤表面2 咖。 In a preferred embodiment, when the needle was directed applied to the bonding layer, the distal end of the needle-shaped material 2 from the skin surface coffee preferably 2.5 mm, and the oblique head portion with a skin surface distance. 优选的是,为了精确地和选择性地靶定接合层,将所述针形物垂直地插入皮肤表面。 Preferably, in order to accurately and selectively targeting the bonding layer, the needle was inserted perpendicular to the skin surface. 从针形物顶端到所述倾斜的跟部的倾斜部分的大小必须在0. 55 - 0.60 mm范围内,以便将物质输送到接合层。 Needle from the tip portion thereof to the size of the inclination of the inclined portion of the heel must be 0.55 - In the range of 0.60 mm to delivery of a substance to the bonding layer. 本发明的接合层施用方法导致了一种物质的改善了的药物动力学(PK)和药效学(PD)。 The method of administration of the bonding layer according to the invention leads to improved pharmacokinetics of a substance (PK) and pharmacodynamic (PD). "改善了的药物动力学",表示例如,通过标准药物动力学参数,如时间与最大血浆浓度(Tmax),最大血浆浓度的大小(Cnax)或出现最低可检测血液或血浆浓度的时间(Tlas) 测定的药物动力学特征的增强。 "Improved pharmacokinetics" represents, for example, by standard pharmacokinetic parameters such as time to maximum plasma concentration (Tmax of), the size of the maximum plasma concentration (Cnax) or the minimum detectable blood or plasma concentration (TlAs occurs ) enhanced drug kinetics assay. "增强了的吸收特征"表示通过所述药物动力学参数衡量,所述吸收增强了或更强。 "Enhances absorption characteristic" means a measure of the pharmacokinetic parameters, or the greater the absorption enhancement. 药物动力学参数测定和最低有效浓度的测定是按照本领域的常规方法进行的。 Determination of pharmacokinetic parameters and determination of the lowest effective concentration is carried out according to conventional methods in the art. 通过与标准施用途径,例如皮下施用或肌内施用比较,确定所获得的值 By standard routes of administration, such as subcutaneous administration or intramuscular administration, and determines the obtained value

提高了。 increased. 在所述比较中,尽管不是必须的,施用到接合层中以及施用到参考部位,如皮下施用,优选的是涉及相同的剂量水平,即相同量和浓度的药物,以及相同的载体媒介物,和相同的施用速度, 以单位时间的量和体积形式表示。 In the comparison, though not necessarily, applied to the bonding layer and applied to the reference site such as subcutaneous administration, it is preferable that relate to the same dose level, i.e., the same amounts and concentrations of the drug, as well as the same carrier vehicle, and the same rate of application, amount of volume per unit time and the form of FIG. 因此,例如,将特定的药用物质以100Mg/ml的浓度和每分钟lOOy 1的速度用5分钟时间施用到接合层,优选与以相同的100|LAg/ml和每分钟100 u 1的速度用5分钟时间将相同的药用物质施用到皮下空间进行比较。 Thus, for example, a specific drug substance at a rate 100Mg / ml concentration and administered lOOy 1 minute to 5 minutes with the bonding layer, preferably at the same 100 | speed LAg / ml per minute and 100 u 1 of 5 minutes of the same pharmaceutical substance into the subcutaneous space for administration of comparison. 通过精确导向接合层能最好地实现上述PK和PD效果现。 By accurately guide the bonding layer will best achieve the above current PK and PD effects. 例如, 这一目的是通过使用外径不超过大约250微米、并且具有小于5 mm, 优选小于3 mm的暴露长度的微型操作针系统实现的。 For example, this object is achieved by the use of an outer diameter of no more than about 250 micrometers, and having less than 5 mm, preferably less than micro-needle system exposed length of 3 mm to achieve. 用于本发明方法的优选的输送装置是30G、 2 mm针形物长度、组装成作为药物容器的注射器,所述系统可以用已知方法由各种材料,包括钢铁,硅, 陶瓷,和其他金属,塑料,聚合物,糖,生物学和/或生物可降解的材料,和/或它们的组合制成。 The preferred delivery device of the present invention is a method for 30G, 2 mm needle length was assembled into the syringe as a medicament container, the system may be made by known methods of various materials including steel, silicon, ceramics, and other metal, plastic, polymers, sugars, biological and / or bio-degradable material, and / or combinations thereof are made. 业已发现,接合层施用方法的某些特征提供了临床上有用的PK/PD和剂量精确性。 It has been found that certain features of the method of application layer bonded to provide clinically useful PK / PD and dose accuracy. 例如,业已发现,针形物出口在皮肤内的位置能明显影响PK/PD参数。 For example, it has been found that the position of the needle outlet within the skin significantly affect the PK / PD parameter. 本发明的另一个优点是,相对ID输送而言,将物质输送到接合层降低了反压的危险。 Another advantage of the invention that the relative delivery ID, the material will be conveyed to the bonding layer reduces the risk of backpressure. 尽管不希望受特定作用机制的限制,但这可能在某种程度上是由于接合层中缺少弹性蛋白纤维所致。 While not wishing to be bound by a particular mechanism of action, but this may be due to some extent in the bonding layer due to the lack of elastin fibers. 通常,通过ID途径以快速浓注形式输送100 - 120 pL的注射时间在8-15秒范围内,这在一定程度上是由于真皮区室的内在弹性。 Typically, conveyed by the ID route 100 in the form of bolus injection - the injection time in the range of 120 pL of 8-15 seconds, which is due to the inherent elasticity of the dermal compartment to some extent. 注射到真皮区室中的最大注射体积在5(UL - 250|^1^范围内,这取决于身体的部位。与ID输送相反,接合层给药的注射时间更快,即少于10秒钟,并且最大注射体积超过250jaL,与注射部位无关。用于实施本发明的施用方法包括将本发明的物质通过快速浓注和输液输送到人体或动物受试者体内。快速浓注剂量是以单一体积单位形式用较短的时间,通常少于大约IO分钟输送的单一剂量。输液施用包括以选定速度施用流体,该速度可以是恒定的或可变的, Injected into the dermal compartment in the maximum injection volume 5 (UL - 250 |. ^ 1 ^ the range, depending on the part of the body opposite to the transport ID, an injection time of joining layer faster administration, i.e., less than 10 seconds clock, and the maximum injection volume exceeds 250jaL, irrespective of the injection site. the method for implementing the present invention comprises administering the agent of the invention is delivered to the human or animal subject by bolus injection and infusion. bolus doses are in the form of a single volume unit with a shorter period of time, usually less than about IO minutes, a single dose delivery. infusion administration comprises administering a fluid at a selected speed, the speed may be constant or variable,

所用的时间相对更长,通常超过大约10分钟。 We used a relatively longer time, usually more than about 10 minutes. 为了输送物质,将接合层进入装置放置在受试者皮肤附近,提供直接定向进入接合层的通道,并且将所述物质输送或施用到接合层,在这里,所述物质可以局部起作用,或者被血液吸收并且系统性地分布。 In order to transport material, the bonding layer into the device is placed near the skin of the subject, direct the orientation layer is bonded into the channel, and the transport of material or applied to the bonding layer, where the substance may act locally, or blood is absorbed and systemically distributed. 所述接合层进入装置可以与容纳有要输送物质的容器连接。 The bonding layer containing access device may be connected to the transport container material. 从容器输送到接合层可以被动地进行,即不对要输送的物质施加外部压力或其他驱动方式,和/或主动地施加压力或其他驱动方式。 It can be passively delivered to the vessel from the bonding layer, i.e., external pressure or other driving system, and / or application of pressure or other actively driven manner not material to be transported. 优选的压力发生装置的例子包括泵,注射器,弹性体膜,气体压力,压电装置,电动装置,电磁泵送,或盘形弹簧或垫團或它们的组合。 Examples of preferred pressure generating means include pumps, syringes, elastomer membranes, gas pressure, piezoelectric, electric means, electromagnetic pumping, or Belleville springs or pads groups, or combinations thereof. 如果需要的话,所述物质的输送速度可以通过压力发生装置可变地控制。 If desired, the conveying speed of the substance may be variably controlled by the pressure generating means. 结果,所述物质进入接合层,并且以足以产生临床效果的量和速度吸收。 As a result, the substance enters the bonding layer and in an amount sufficient to produce clinical effects and absorption speed. 在本文中,术语"临床效果"表示临床上有用的生物学反应,包括诊断上和治疗上的有用反应,这种反应是通过施用本发明的物质产生的。 As used herein, the term "clinical effect" represents a clinically useful biological reaction, comprising the reaction of useful diagnostically and therapeutically, by administering a substance which is the reaction of the present invention is produced. 例如,诊断测定或预防,疾病或症状的控制和治疗是临床效果。 For example, diagnostic assays or prevention, control and treatment of diseases or symptoms of the clinical effect. 5.4用于接合层给药的装置本发明涉及用于精确地和选择性地靶定患者皮肤的接合层的任何装置。 5.4 The present invention relates to administration of the bonding layer for any device for accurately and selectively targeting the bonding layer of the skin of the patient. 所使用的装置的性质并不重要,只要它能刺入受试者皮肤到达接合层中的目标深度而又不穿过它就行。 Properties of the device used is not critical, as long as it reaches the target depth of piercing the subject's skin layer without engaging it through the line. 优选的是,所述装置刺入皮肤的深度为至少大约2 mm,最大深度不超过大约3 mm,最优选不超过大约2.5mm。 Preferably, the apparatus piercing the skin depth is at least about 2 mm, a maximum depth of no more than about 3 mm, most preferably no more than about 2.5mm. 本发明包括披露于以下文献中的药物输送装置和针形物组件:美国专利6, 494, 865和美国专利申请号10/357, 502和10/337, 413 (申请日分别为2003年2月4日和2003年1月7日),所有文献都以它们的整体形式收作本文参考。 The present invention is disclosed in the following documents comprising the drug delivery device and needle assembly thereof: U.S. Patent No. 6, 494, 865 and U.S. Patent Application No. 10/357, 502 and 10/337, 413 (filed February 2003, respectively and January 7, 2003) 2014, all documents are in their entirety in the form incorporated herein by reference. 本领域技术人员一旦掌握了本申请的与接合层的边界相关的知识,就可以通过常规实验改进在上述专利和专利申请中所披露的装置,以便适于接合层给药。 Those skilled in the art once mastered the present application associated with the boundary layer bonded knowledge, the device can be improved by routine experimentation in the above patents and patent applications disclosed, the bonding layer is adapted to be administered. 本发明涉及常规注射针形物,导管或所有已知类型的单独使用或用在多针形物阵列上的微型操作针,另外,本发明涉及无针形物装置,包括弹道注射装置。 The present invention relates to a micro-needle or with a conventional injection needle used in a multi-needle array of individually shaped object, catheters or all known types, in addition, the present invention relates to a needle-free device thereof, comprising a ballistic injection devices. 在本文中,术语"针形物"意在包括所有这样的针形物样结构。 As used herein, the term "needle-like substance" is intended to encompass all such needle-like structure thereof. 其例子包括,但不局限于常规注射针形物, 套管,导管或所有已知类型的微型操作针。 Examples include, but are not limited to conventional injection needle pieces, pipes, conduits or all known types of micro-needle. 在本文中,术语"微型操作针"意在包括30号和更小,通常大约31-50号的结构,这种结构是圆筒性质的。 As used herein, the term "mini-needle" is intended to include 30 and less, typically about 31-50 No. structure, this structure is cylindrical in nature. 因此,术语微型操作针所包含的非筒状结构应当具有相当的直径,并且包括锥体,矩形,八边形,楔形和其他几何形状。 Thus, the term micro-operation comprising non-needle-like tubular structure should have a comparable diameter and include pyramidal, rectangular, octagonal, wedge, and other geometric shapes. 本发明涉及使用包括至少一个针形物,优选微型操作针的装置将物质输送到接合层中。 The present invention relates to a composition comprising at least one needle, preferably a micro-needle means of delivering a substance to the bonding layer. 优选的是,所述针形物的长度足以刺入接合层,并且出口深度位于接合层中,以便所述物质被输送并且分布在接合层中。 Preferably, the length of the piercing needle has sufficient bonding layer, the bonding layer and the outlet is located in a depth so that the substance to be delivered and distributed in the bonding layer. 在某些实施方案中,针形物的长度为大约2 mm-大约5 mm,优选大约2 mm-大约3 mm。 In certain embodiments, the needle has a length of about 2 mm- about 5 mm, preferably from about about 2 mm- 3 mm. 在其他实施方案中,在插入针形物时,所述针形物的出口被放置在约2 mm-大约3 mm,优选大约2 mm-大约2. 5 mm的深度。 In other embodiments, when the needle was inserted into the outlet of the needle has been placed at about about 2 mm- 3 mm, preferably about 2 mm- depth of about 2. 5 mm. 不过,优选的是所述装置具有用于控制皮肤穿透到接合层中的理想深度的结构装置。 However, it is preferable that the depth of penetration into the structure of the device over the bonding layer has a means for controlling the skin. 最常见的是,通过以垂直于皮肤表面的角度将微型操作针插入,直到针形物向皮肤的穿刺被针形物接口所限制,或通过防止针形物更深穿透的部件来限制。 Most commonly, by the vertical angle of the micro-needle is inserted into the skin surface, until the needle-shaped material is limited to the skin puncture needle-shaped material interfaces, or to restrict the composition by preventing a deeper needle penetration member. 所述部件可以是微型操作针套管的一部分,或组装的部件。 The member may be a part of a micro-needle cannula, or assembled components. 用于接合层给药的微型操作针的长度在生产过程中可方便地改变,并且通常以小于3mm的长度生产。 Micro-needle length for the bonding layer may be administered easily changed in the production process, and is generally less than the length of the production of 3mm. 所述微型操作针可以是一次性针状体,它被组装成药物容器,如注射器,或者可以是与注射器顶端预先接合层的针形物。 The micro-needle may be disposable needles, which are assembled into a pharmaceutical container, such as a syringe, or may be a needle-shaped tip of the syringe was pre-bonded with a layer. 用于本发明方法的微型操作针还可以是非常尖锐的, 并且具有非常小的型号,如30或34G,以便在注射或输液期间进一步减少疼痛和其他感受。 Micro-needle used in the process according to the present invention may also be very sharp, and have very small models, such as 34G or 30, to further reduce pain and other feelings during injection or infusion. 它们可以作为单独的单腔微型操作针使用, 或者可以组装多个微型操作针或者以线性阵列或二维阵列形式生产,以便提高输送速度或提高特定时间内输送物质的量。 They may be used as separate single lumen micro-needle, or a plurality of micro-needle may be assembled or produced in a linear array or two-dimensional array, in order to increase the conveying speed or increasing the amount of transporting substance within a specific time. 微型操作针可以接合层在多种装置上,如固定器和外壳,它们同样可用于限 Micro-needle bonding layer may be in a variety of devices, such as fixed and the housing, they also can be used to limit

制刺入深度。 The penetration depth of the system. 本发明的接合层给药装置还可以包括在输送之前容纳所述物质的容器,或泵或其他用于在加压条件下输送药物或其他物质的装置。 The bonding layer drug delivery device of the present invention may further include a receiving container of the substance prior to delivery or pumps or other means for a drug or other substance is delivered under pressure. 或者,所述接合层给药装置可以从外部与与这些附加部件连接。 Alternatively, the bonding layer of the drug delivery device may be connected to these additional members from the outside. 在一种实施方案中,本发明用于接合层给药的装置包括以下部分:针形物,其长度足以刺入接合层,并且其出口深度在接合层内, 以便所述物质被输送并且分配到接合层中;用于加载,储存和分配所述物质的结构;和用于控制皮肤穿透到接合层中的理想深度的结构。 In one embodiment, the present invention is a device for administering the bonding layer comprises the following components: a needle-shaped objects, of sufficient length to pierce the bonding layer, and the depth of the outlet within the bonding layer, so that the substance to be delivered and assigned the bonding layer; for loading, storing and dispensing the material structure; and means for controlling skin penetration to the desired depth of the structure of the bonding layer. 在一种实施方案中,所述用于加载,储存和分配所述物质的结构是注射器。 Structure In one embodiment, the means for loading, storing and dispensing said substance is a syringe. 在另一种实施方案中,所述结构是自动化注射器,例如,但不局限于笔式,枪式或自动注射器。 In another embodiment, the structure is automated syringes, such as, but not limited to, a pen, syringe or automatic gun. 用于控制皮肤穿透深度的结构可以起着允许将针形物垂直插入受试者皮肤的作用。 Structure for controlling the depth of penetration of the skin can function allows the needle was inserted perpendicular to the skin of a subject effect. 在一种实施方案中,本发明的装置具有用于加载,储存和/或分配含有本发明物质的制剂的结构装置,即容器。 In one embodiment, the device according to the present invention has for loading, storing and / or dispensing structure containing the device materials of the present invention formulations, i.e. the container. 从所述容器到接合层的递送可以是被动进行的,即不对要输送的物质应用外部压力或其他驱动方式,和/或是主动地应用压力或其他驱动方式。 Delivery layer from the container to be engaged may be passive, i.e., not a substance to be delivered, or other external pressure application driving mode and / or pressure application or other actively driven manner. 优选的压力发生装置的例子包括泵,注射器,弹性体膜,气体压力,压电装置,电动装置,电磁泵送,或盘形装置或垫圏或它们的组合。 Examples of preferred pressure generating means include pumps, syringes, elastomer membranes, gas pressure, piezoelectric, electric means, electromagnetic pumping, or rings of a disc-shaped device or mat or a combination thereof. 具体地讲,注射器或自动化注射器,例如,但不局限于笔式,枪式或自动注射器可有利地用于本发明中。 In particular, automated syringe or syringes, such as, but not limited to, a pen, a gun or automatic injector may advantageously be used in the present invention. 如果需要的话,所述物质的输送速度可以通过压力发生装置进行可变的控制。 If desired, the conveying speed of the material can be variably controlled by the pressure generating means. 结果,所述物质进入接合层,并且以足以产生临床效果的量和速度吸收。 As a result, the substance enters the bonding layer and in an amount sufficient to produce clinical effects and absorption speed. 在某些实施方案中,所述输送的速度和体积可以采用具有逻辑元件的程序自动化控制。 In certain embodiments, the transport velocity and volume can be employed to automate the control has a logic element. 所述程序的例子包括, 但不局限于生理学模型,基于模型的规格或运动平均方法,治疗药物动力学模型,监测信号处理程序,预测控制模型和它们的组合。 Examples of such programs include, but are not limited to physiological model, the average size or model-based motion, therapeutic pharmacokinetic model, monitor signal processing program, model predictive control, and combinations thereof. 在一种实施方案中,所述装置具有用于控制皮肤穿刺到接合层中的理想深度的结构装置。 In one embodiment, the device has configuration means for puncturing the skin to a desired depth to control bonding layer. 这一目的最常见的是通过与接合层进入装置的轴相连的变宽的部分或接口实现的,所述接合层进入装置可 This object is most common widened portion or the interface bonding layer by a shaft connected to the access device implemented, the access device may bonding layer

以采用支撑结构或平台的形式,将针形物连接在它上面。 In the form of a support structure or platform, the needle was attached thereon. 在生产过程中,可以方便地改变作为接合层进入装置的针形物的长度,并且通常其长度小于5 mm,优选小于3 mm。 In the production process, you can easily change the length of the bonding layer as the needle-shaped object into the apparatus, and is generally less than the length 5 mm, preferably less than 3 mm. 针形物还是非常尖锐的并且具有非常小的型号,以便进一步减少在注射或输液期间的疼痛或其他感觉。 It was still very sharp needle-shaped and has a very small model, to further reduce pain and other sensation during the injection or infusion. 它们在本发明中可以作为单个针形物使用,或者将多个针形物组装或加工成线性阵列或二维阵列,以便提高输送速度或在特定时间内输送物质的量。 In the present invention, they can be used as a single needle-shaped objects, or assembled from a plurality of needle-shaped or processed into a linear array or a two-dimensional array, in order to increase the conveying speed or amount of material conveyed within a certain time. 可以将针形物接合层在多种装置上,如固定器和外壳,它们可用于限制刺入深度。 Needle bonding layer may be in a variety of devices, such as fixed and the housing, which may be used to limit the penetration depth. 容纳所述接合层进入装置的装置可以在外部与其他部件连接,如容器和用于控制施用体积和速度的控制装置。 Means for receiving said bonding layer access device may be connected to other member on the outside, such as containers and administration control means for controlling the volume and speed. 本发明方法还包括弹道流体注射装置,粉末喷射输送装置,压电,电动,电磁辅助的输送装置,气体辅助的输送装置,它能直接刺入皮肤,以便提供输送或直接将物质输送到接合层内的目标部位的通道。 The method of the present invention further includes a ballistic fluid injection devices, apparatus, piezoelectric, electric, electromagnetic assisted delivery devices, gas-assisted injection conveying powder delivery device, it can directly penetrate the skin to provide a delivery or directly deliver substances to the bonding layer target site within the channel. 5. 5治疗效力的测定含有本发明物质的制剂的治疗效力可以使用本领域技术人员所公知或本文所披露的任何标准方法测定。 Determination of the therapeutic efficacy of the formulation containing the therapeutic efficacy 5.5 substances may be used according to the present invention the skilled artisan or assay known to any standard method disclosed herein. 用于测定本发明的制剂的治疗效力的测定方法可以是基于体内或体外的测定方法,包括基于动物的测定。 A method for the determination of therapeutic efficacy of the formulations of the invention may be measured in vitro or in vivo assays based, including animal-based assay. 优选的是,本发明的制剂的治疗效力是在临床设施中测定的。 Preferably, the therapeutic efficacy of the formulations of the present invention is measured in the clinical facility. 在某些实施方案中,优选使用本领域技术人员所公知的标准方法定量测定本发明物质的输送的药物动力学和药效学参数。 In certain embodiments, it preferred quantitative determination of pharmacokinetic and pharmacodynamic parameters transporting material of the present invention using standard methods known to those skilled in the art. 在优选实施方案中,将用本发明方法输送的本发明的物质的药效学和药物动力学特性与通过其他常规施用模式,例如皮下或肌内输送所输送的物质的特性进行比较,以便确定根据本发明方法施用的物质的治疗效力。 In a preferred embodiment, the dynamic characteristics of the substance of the present invention, the method of the present invention and drug delivery and pharmacodynamic, property of a substance e.g. subcutaneous or intramuscular delivery delivered by comparison to other conventional modes of administration, in order to determine the present method of treatment efficacy administered substance. 可以根据本发明方法测定的药物动力学参数包括,但不局限于T吣,Cma" Tlag, AUC等。可以按照本发明方法测定的其他药物动力学参数包括,例如,半衰期(tm)、清除速度常数和部分AUC值。 The pharmacokinetic parameters may include a method of assay of the present invention, but are not limited to T Qin, Cma "Tlag, AUC, etc. Other pharmacokinetic parameters can be determined according to the method of the present invention include, for example, the half-life ((TM)), clearance rate AUC values ​​and constant part.

公知的标准统计学测验对所获得的药物动力学和药效学参数进行统计学分析。 Standard statistical tests known to pharmacokinetic and pharmacodynamic parameters obtained were analyzed statistically. 在具体实施方案中,本发明涉及测定按照本发明方法施用的物质的治疗效力,包括将它的药物动力学特征与例如,皮下或肌内输送荻得的特征进行比较。 In a specific embodiment, the present invention relates to determining the therapeutic efficacy of the substance administered according to the method of the present invention, including its pharmacokinetic characteristics with e.g., subcutaneous, or intramuscular delivery Di obtained feature compared. 用于测定物质的治疗效力的典型测定方法可以包括以下步骤:用30G, 1.5mm的针形物,或用34G, 2mm的针形物,用34G, 3mm的针形物施用本发明的物质,或皮下或肌内注射到人体内。 A typical assay method for determining the efficacy of the treatment substance may include the following steps of: 30G, 1.5mm needle-shaped material, with or 34G, 2mm needle-shaped object, with a 34G, 3mm needle-shaped material of the present invention was applied, or subcutaneous or intramuscular injection into the human body. 优选将5/8英寸25G针形物用于肌内注射。 Preferably 5/8 inch 25G needle was used for intramuscular injection. 将O. 2mL的注射体积用于接合层和皮下输送,并且将0. 5mL的体积用于肌内输送。 The injection volume for engaging O. 2mL layer and delivered subcutaneously, 0. 5mL and the volume for intramuscular delivery. 对于疫苗来说,在第0, 7和21天进行强化注射。 For the vaccine, in the 0, 7 and 21 days booster shots. 采集血样, 并且优选在样品釆集之后1小时内在2-8'C下以3000rpm的速度离心至少15分钟。 Blood samples were collected, and centrifuged at 3000rpm preferably at 2-8'C within one hour after the sample collector preclude at least 15 minutes. 转移来自采血管的血清用于血清水平分析。 Analysis of serum levels of serum for transferring from the blood collection tube. 通过以下非限定性实施例可以进一步说明本发明。 The present invention is further illustrated by the following non-limiting examples. 6.实施例6. 1依诺肝素@的接合层输送将2000或4000aXa IU的依诺肝素@制剂注射到受试者的接合层。 6. EXAMPLES 6.1 enoxaparin bonding layer will transport @ 2000 4000aXa IU or enoxaparin @ formulation is injected into the bonding layer of the subject. 依诺肝素⑧的接合层注射获得了1. 5-2. 3小时的Tmax,这一时间比皮下注射的速度更快,表明了依诺肝素⑧在接合层输送时更快地起作用。 Enoxaparin injected ⑧ bonding layer is obtained 1. 5-2. Tmax of 3 hours, this time faster than a subcutaneous injection, enoxaparin ⑧ indicates act faster delivery during the bonding layer. C固值(0. 2 - 0. 6 aXa IU/mL)和总的AUC ( 2 - 4. 5 aXa IU/mL/ 小时)对于接合层和皮下注射来说是相同的。 Solid value C (0. 2 - 0. 6 aXa IU / mL) and total AUC (2 - 4. 5 aXa IU / mL / hr) and injected subcutaneously for the bonding layer is the same. 6. 2 FONDAPARINUX⑧的接合层给药将Fondaparinux⑧注射到受试者的接合层。 The bonding layer 6. 2 FONDAPARINUX⑧ administration will Fondaparinux⑧ subject injected into the bonding layer. Fondaparinux⑧的接合层注射获得了1. 5-2. 3小时的乙x,表明了与皮下注射相比,在接合层注射时依诺肝素@能更快起作用。 Fondaparinux⑧ bonding layer obtained injection 1. 5-2. 3 hours B x, show that compared to subcutaneous injection, enoxaparin @ can function faster injection time of the bonding layer. 对于接合层和皮下注射来说, C值(0. 3- 0. 45 fflg/mL)和总的AUC大体上相同。 For the bonding layer and for subcutaneous, C value (0. 3- 0. 45 fflg / mL), and the total AUC is substantially the same. 6.3在健康的人类志愿者体内进行狂犬病病毒疫苗的开放随机 6.3 open random rabies virus vaccine in healthy human volunteers

化研究本研究的主要目的是研究输送深度对狂犬病疫苗的免疫反应的影响,包括评估对狂犬病抗原的抗体反应。 The main purpose of this research study was to investigate the influence of the depth of the immune response to the rabies vaccine delivery, including an assessment of antibody response to the rabies antigen. 将狂犬病疫苗输送到血清阴性人类志愿者体内,并且使用不同长度的针形物改变输送深度。 The rabies vaccine delivered to seronegative human volunteers, and the different lengths of the needle depth was changed delivery. 实验设计是开放式、平行组随机化的研究。 The experimental design was open-label study, parallel-group randomized. 受试者:每组招募10个受试者,包括男性和女性,年龄在18-40 岁之间。 Participants: Each group recruited 10 subjects, male and female, between the ages of 18-40 years old. 在下面的表1和2中提供了入选的和非入选的指标。 Providing the non-selected and selected indicators in Tables 1 and 2 below. 表l :受试者的入选标准•健康的男性和女性白种人受试者,年龄在18-40岁之间, .受试者的主要器官功能必须在可接受的医学极限范围内,该极限是通过临床病史和身体检查确定的,-初筛访视时,在标准条件下测定:在仰卧休息至少5分钟之后,受试者必须具有正常的血压和心跳速度:SBP在90 - 140 mmHg范围内, DBP在40 - 85 mmHg范围内,并且HR为40 - 85 bpm,.初筛访视时,在休息至少5分钟之后记录的受试者12-导联心电图必须正常:PR在120 — 200 ms范围内,QRS<120ms,而QTc < 440 ms。 Table l:. Subjects inclusion criteria • healthy male and female Caucasian subjects, between the ages of 18-40 years, the main organ of the subject must be within the acceptable medical limits, the limit is determined by the clinical history and physical examination, - when the screening visit, measured under standard conditions: after supine rest of at least 5 minutes, the subject must have a normal blood pressure and heart rate: the SBP at 90 - 140 mmHg in the range of, DBP 40 - in the range of 85 mmHg, and HR is 40 - 85 bpm ,. when the screening visit, at least 5 minutes after the break of the recording must be subject to normal 12-lead ECG: PR in 120-- within 200 ms range, QRS <120ms, and QTc <440 ms. 不完全的右束支阻滞是可以接受的-受试者必须具有正常范围内的实验结果,或者被研究者认为在临床上不相关,•受试者针对狂犬病疫苗抗原必须是血清阴性的, -受试者必须同意不施用任何药物,这些药物可能影响在免疫之后在体内产生的狂犬病抗体,女性受试者必须采取适当的生育控制方法(激素处理或子宫内装置) 以避免在本研究的免疫之前和之后至少3个月时间怀孕,并且在筛查时尿妊娠试验必须是阴性的。 Incomplete right bundle branch block is acceptable - a subject must have results within the normal range, or by researchers considered not clinically relevant, • subjects against rabies vaccine antigen must be seronegative, - subjects must agree not to administration of any drugs that may affect the rabies antibodies following immunization in vivo, female subjects must take appropriate method of birth control (hormone treatments or intrauterine device) in the present study to avoid before and after the immunization for at least 3 months of pregnancy, and at screening urine pregnancy test must be negative. 表2:受试者的非入选指标•受试者具有对狂犬病疫苗的任何成分(白蛋白,新霉素)过敏或 Table 2: Selected indicators of non-subject • subject of any component of the rabies vaccine (albumin, neomycin) or allergies

超敏的已知病史,•受试者具有已知的免疫缺陷,系统性癌症,或使用了免疫抑制治疗,包括癌症化疗和系统性类固醇,,受试者具有活动性皮肤病,•受试者具有I型糖尿病或其他重病,•受试者具有轻微的上呼吸道和下呼吸道疾病,ENT局部感染,胃肠道疾病或其他发热事件,这些病症是预见到的和记录到要解决的, 这样的受试者被暂时排除在外,•在筛查时具有有症状的或无症状的直立性低血压的受试者,以在仰卧和站立状态之间SDP或DDP降低超过20 mmHg来界定, .在尿液药物篩查时呈阳性的受试者(大麻素,苯二氮萆类), •怀孕或哺乳的受试者,'在筛查期间,血液中针对狂犬病抗原的抗体水平在0. 5UI/mL以上的受试者,.具有乙肝或丙肝病史的受试者和/或来自肝炎血清学的阳性结果,它表明了存在急性或慢性乙型或丙型肝炎, •具有阳性HIV血清 Known history of hypersensitivity, • subjects with known immunodeficiency, systemic cancer, or the use of immunosuppressive therapy, including cancer chemotherapy and systemic steroids ,, subjects with active skin disease, • test who has type I diabetes or other serious illness, • subjects with mild upper respiratory tract and lower respiratory tract, ENT localized infections, gastrointestinal disease or other febrile episodes, these conditions are foreseen and recorded to be solved, so the subject is temporarily excluded, • having asymptomatic or symptomatic orthostatic hypotension subject at screening, or to reduce the SDP DDP between supine and standing defined state for more than 20 mmHg. when urine drug screen was positive subjects (cannabinoids, benzodiazepines castor type), • pregnant or lactating subject, 'during the screening, the blood levels of antibodies against the rabies antigen is 0. 5UI / mL or more subjects. subjects with a history of hepatitis B or C and / or positive results from the hepatitis serology which indicate the presence of acute or chronic hepatitis B or C, • having a positive HIV serum 学的受试者, '在最近3个月内提供了超过400mL血液的受试者, ,在参与本研究期间的30天之内参加了另一项临床研究的受试者, •在上肢具有过多体毛的受试者。 School subjects, 'offers more than 400mL blood of the subject in the last three months, he participated in another clinical study within the period of the study involved 30 days of subjects, • have the upper limbs excessive body hair of a subject. 研究的药物:在本研究中使用了纯化的Vero细胞狂犬病疫苗(PVRV)。 Drug research: using purified Vero cell rabies vaccine (PVRV) in this study. 该疫苗是由Aventis Pasteur (法国)用Vero细胞生产的,并且业已证实在用于人类狂犬病预防和治疗是安全和有效的。 The vaccine is composed of Aventis Pasteur (France) with Vero cell production, and has been confirmed in a human rabies prevention and treatment is safe and effective. 业已报道了有关肌内输送TVRV的安全性和效力的多项研究。 It has been reported that a number of studies on intramuscular delivery TVRV safety and effectiveness. 另外, 还在人体上对真皮内输送狂犬病疫苗进行了全面研究,进行了专家分组评议。 In addition, also on human rabies vaccine for intradermal delivery of a comprehensive study, we carried out an expert review group. 狂犬病疫苗的真皮内输送途径被认为与前期和后期暴露免疫的肌内途径一样有效和安全。 Intradermal delivery route of rabies vaccine is considered safe and as effective as intramuscular and pre- and post-exposure immunization. 真皮内途径的主要优点是抗原剂量节省,例如,1/10的肌内剂量,这意味着对于狂犬病仍然是公共 The main advantage is that intradermal antigen dose savings, for example, intramuscular dose of 1/10, which means that rabies is still common

卫生问题的发展中国家来说能节省大量的成本。 Health issues in developing countries who can save a lot of costs. 由于PVRV狂犬病抗原的高抗原效果,所有年轻的健康志愿者都是该疫苗的效应者,在临床实验中在免疫之后记录的资料中没有任何严重负面事件的危险。 Due to the high antigen effect PVRV rabies antigen, and all the young volunteers who are the effects of the vaccine, information on clinical trials after immunization records in no danger of any serious adverse events. 因此,PVRV狂犬病疫苗被认为在临床研究中是安全可靠的免疫药理学模型。 Therefore, PVRV rabies vaccines are considered in clinical studies to be safe and reliable immune pharmacological models. 除了该疫苗的安全性特征之外, 还存在选择PVRV狂犬病疫苗作为志愿者的临床研究模型的其他优点,包括它在成年人体内的强抗原效果,对所述疫苗具有大约100% 的应答。 In addition to the security features of the vaccine, there are other advantages as the selection PVRV rabies vaccine clinical study volunteers model, including its effect in the adult body is highly antigenic, having about 100% of the response to the vaccine. 另外,由于狂犬病免疫在法国不是强制免疫接种的,大部分法国民众对PVRV抗原是血清阴性的。 In addition, because rabies vaccination is not mandatory vaccination in France, most French people to PVRV antigen is seronegative. 研究装置:在本研究中使用了四种不同的研究装置: 作为阳性对照,使用了长度为16 mm的针形物进行肌内注射(IM)。 Study: The use of four different research means in this study: As a positive control, a length to 16 mm needle was injected intramuscularly (IM). 在这种情况下,每次注射的疫苗输送的剂量为0.5 mL。 In this case, each injection of vaccine delivered dose of 0.5 mL. 对于真皮内注射(ID)来说使用了30G, 1.5 mm的针形物,其中,每次注射的疫苗剂量为0.2 mL。 For injection (ID) used for intradermal 30G, 1.5 mm needle-shaped objects, wherein each injection of vaccine dose is 0.2 mL. 对于接合层注射(n)来说,使用了34G长度为2 mm和3 mm的针形物,并且每次注射的输送剂量与使用ID输送的相同。 For injection bonding layer (n), using a 34G of 2 mm and a length of 3 mm and a needle-shaped objects, and the same for each injection using the delivered dose delivered ID. 研究设计:每个处理组包括IO个成年健康的志愿者,在处理组中包括女性和男性;第I组:使用1.5mm的针形物进行真皮内注射; 第II组:使用2mm的针形物进行接合层注射;第III组:使用3 mm 的针形物进行接合层注射;第IV组:使用16 mm的针形物进行IM 注射。 Study Design: IO for each treatment group including adult healthy volunteers, including men and women in the treated group; Group I: use of needle-shaped 1.5mm was injected intradermally; Group II: a needle-shaped using 2mm the bonding layer was injected; group III: use of 3 mm needle was injected bonding layer; group IV: to 16 mm needle used was IM injection. 本研究的目的是研究免疫反应之间的差异,这种差异是通过在免疫反应诱导阶段的循环抗原效价衡量的。 Purpose of this study was to investigate the difference between the immune response, this difference by circulating antigen titer immune response as measured by the induction phase. 因此,比较了使用单一剂量的狂犬病疫苗所产生的从DO到D14天的抗体效价。 Thus, comparing the antibody titers from DO to D14 day using a single dose of rabies vaccine produced. 所述抗狂犬病免疫方案包括在DO, D14和D21进行的三次连续的注射。 The anti-rabies immunization scheme comprises three successive injections at DO, D14, and D21. 抗体效价的测定是在免疫之后DO, D7, D14, D21和D49天进行的。 Determination of antibody titer after the immunization is DO, D7, D14, D21 and D49 days. 结果: result:

图3和表3表示在单次注射狂犬病疫苗之后抗体的几何平均效价(GMT)。 Figure 3 and Table 3 shows the geometric mean titer (GMT) after a single injection of rabies vaccine antibodies. 用2 mm长的针形物进行接合层注射与其他输送途径相比得到了较低的GMT。 Long by 2 mm was bonded needle injection layer as compared to other delivery routes has been lower GMT. 通过接合层注射在D7天产生的较低的GMT有可能是由于在将抗原输送到深度为2 mm的接合层时推迟了的免疫反应。 Lower GMT by injection layer bonded generated D7 days may be due to delayed delivery of an antigen when the bonding layer to a depth of 2 mm immune response. 考虑到狂犬病疫苗是非常有效的抗原,在2腿深度进行接合层给药在D7和D14天的较低的GMT表明了接合层与真皮和肌肉相比, 接合层在诱导对狂犬病病毒疫苗的免疫反应方面的反应性较弱。 Considering the very effective rabies vaccine antigen administered bonding layer 2 and the lower leg depth D7 of GMT D14 day indicated as compared to the bonding layer dermis and muscle, to induce an immune bonding layer rabies virus vaccine reactivity of the reactive aspects of the weak. 不过,以3 mm的深度输送在所产生的免疫反应强度方面与真皮内输送相同。 However, the transport depth of 3 mm in the immune response generated with strength intradermally deliver the same. 在进行2-3次随后的注射之后,免疫反应没有受到输送途径的显著影响(图4)。 2-3 after performing a subsequent injection, the immune response is not significantly affected by the delivery pathway (FIG. 4). 表3:在单次注射狂犬病疫苗之后抗体的几何平均效价(GMT)<table>table see original document page 30</column></row> <table>尽管业已结合具体实施方案对本发明进行了说明,对本领域技术人员来说,显而易见的是,在不超出所附权利要求书限定的本发明的构思和范围的前提下,可以作出各种改变和改进。 Table 3: Geometric mean titers (GMT) after a single injection of rabies vaccine antibodies <table> table see original document page 30 </ column> </ row> <table> While it has been in conjunction with the specific embodiments of the present invention has been described , the skilled person, it is apparent, on the premise of the spirit and scope of the present invention without departing from the appended claims, various changes and modifications may be made.

Claims (19)

  1. 1. 选自低分子量肝素,五糖,p干扰素,促红细胞生成素,抗体, 蛋白,多肽激素,生长激素,抗-血栓形成药和白介素的物质用于生产用于将物质输送到人类受试者体内的方法中所用药品的用途,所述方法包括通过插入接合层的小号针形物将所述物质输送到人类患者皮肤的接合层,所述针形物的长度和出口深度足以穿透接合层。 1. selected from low molecular weight heparin, pentasaccharide, P interferons, erythropoietin, antibodies, proteins, polypeptides, growth hormone, anti - thrombotic drug substances and for the production of interleukins for delivering substance to the human subject a method as in test's body by the use of drugs, said method comprising inserting through a small needle bonding layer material was conveyed to the bonding layer of the skin of a human patient, the length and depth of the outlet of the needle has sufficient wear through the bonding layer.
  2. 2. 选自低分子量肝素,五糖,p干扰素,促红细胞生成素,抗体, 蛋白,多肽激素,生长激素,抗-血栓形成药,和白介素的物质生产用于将物质输送到人类受试者体内的方法中所用药品的用途,所述方法包括通过插入接合层的小号针形物将所述物质输送到人类患者皮肤的接合层,所述针形物具有足以穿透接合层的长度和深度在接合层内的出口,以便所述物质沉积在接合层内。 2. selected from low molecular weight heparin, pentasaccharide, P interferons, erythropoietin, antibodies, proteins, polypeptides, growth hormone, anti - thrombotic drugs, and the production of interleukins for delivering a substance to a human subject substance a method of in vivo by the use of pharmaceuticals, said method comprising the bonding layer by insertion of the small needle-shaped material was conveyed to the bonding layer of the skin of a human patient, said needle having a length sufficient to penetrate the bonding layer and the depth of the outlet within the bonding layer, so that said substance is deposited in the bonding layer.
  3. 3. 如权利要求1或2的用途,其中,所述针形物是垂直插入患者皮肤的接合层的。 Or 3. The use as claimed in claim 2, wherein said vertical needle was inserted into the bonding layer of the skin of the patient.
  4. 4. 如权利要求1或2的用途,其中,所述物质能方便地到达接合层的静脉丛和毛细血管后微静脉的稠密网络,并且能快速吸收和系统性地分布。 4. The use as claimed in claim 1 or 2, wherein the substance can easily reach the dense after joining the network layer and the venous plexus capillary venules, and can be rapidly absorbed and systemically distributed.
  5. 5. 如权利要求1或2的用途,其中,所述物质不会导致不希望的免疫反应。 5. The use as claimed in claim 1 or 2, wherein said substance does not cause undesired immune reactions.
  6. 6. 如权利要求1或2的用途,其中,所述针形物的长度为2mm 一5 mm。 6. The use as claimed in claim 1 or 2, wherein said needle has a length of 2mm is a 5 mm.
  7. 7. 如权利要求1或2的用途,其中,所述针形物的长度为2mm —3 mm。 7. Use as claimed in claim 1 or 2, wherein said needle has a length of 2mm -3 mm.
  8. 8. 如权利要求1或2的用途,其中,所述针形物为30 - 34 G。 8. The use as claimed in claim 1 or 2, wherein said needle-shaped object of 30 - 34 G.
  9. 9. 如权利要求1或2的用途,其中使用一个针形物。 Or The use according to claim 2, wherein a needle-shaped object.
  10. 10. 如权利要求1或2的用途,其中,所述针形物选自下列一组:微型操作针,导管针形物和注射针形物。 10. The use as claimed in claim 1 or 2, wherein said needle is selected from the group consisting of: a micro-needle, a catheter needle and needle-shaped objects thereof.
  11. 11. 如权利要求1或2的用途,其中,在插入所述针形物时所述出口深度为大约2 mm — 2. 5 mm。 11. The use as claimed in claim 1 or 2, wherein, upon insertion of the needle has a depth of the outlet is from about 2 mm - 2. 5 mm.
  12. 12. 如权利要求1或2的用途,其中,所述物质是以0. 5 mL或以上的体积输送的。 12. Use as claimed in claim 1 or 2, wherein said substance is 0. 5 mL or more in volume delivery.
  13. 13. 如权利要求1或2的用途,其中,所述物质是以1. 0 mL或以上的体积输送的。 13. Use as claimed in claim 1 or 2, wherein said substance is 1. 0 mL or more of the volume delivered.
  14. 14. 如权利要求1或2的用途,其中,所述物质是低分子量肝素或五糖。 14. The use as claimed in claim 1 or 2, wherein said substance is a low molecular weight heparin or pentasaccharide.
  15. 15. 如权利要求1或2的用途,其中,所述物质是依诺肝素。 15. The use as claimed in claim 1 or 2, wherein said substance is enoxaparin.
  16. 16. 如权利要求1或2的用途,其中,所述物质是Fondaparinux。 16. Use as claimed in claim 1 or 2, wherein said substance is Fondaparinux.
  17. 17. 如权利要求1或2的用途,其中,所述物质是胰岛素。 17. Use as claimed in claim 1 or 2, wherein the substance is insulin.
  18. 18. —种用于对患者皮肤进行物质的接合层给药的针形物,包括用于限制针形物刺入皮肤的深度的装置,并且具有相对所述穿透限制装置定位的出口,以便在将所述针形物插入皮肤至由所述穿透限制装置决定的深度时,所述出口的深度在所述接合层内,使得所述物质沉积在接合层中。 18. - a kind of patient skin layer bonded needle was administered substance, including means for limiting the depth of the needle for piercing the skin material, and relative to the penetration limiting means having an outlet positioned to when the needle is inserted into the skin by the penetration depth determination means limits the depth of the outlet in the engaged inner layer, such that the substance is deposited in the bonding layer.
  19. 19. 一种用于对患者皮肤进行物质的接合层给药的装置,包括如权利要求18的针形物,和用于加载,保存和分配所述物质的装置。 19. An apparatus for administering to the patient's skin engaging layer of material, comprising a needle-shaped material as claimed in claim 18, and for loading, storage and dispensing device of the substance.
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