CN104546669B - Nanochannel device and correlation technique - Google Patents

Abstract

A nanochannel delivery device and methods of making and using the same. The nanochannel delivery device comprises an inlet, an outlet and a nanochannel. The nanochannels may be oriented parallel to a major plane of the nanochannel delivery device. The inlet and outlet can be in direct fluid communication with the nanochannel.

Description

Nanochannel devices and related methods

This application is a divisional application with an application date of November 13, 2009, an application number of 200980154070X, and an invention title of "nano-channel device and related method".

Cross references to related applications

This application claims U.S. Provisional Patent Application Serial 61/114,687, filed November 14, 2008, entitled "Nanochanneled Device and Method of Use" and U.S. Provisional Patent Application Serial No. 61/114,687, filed April 13, 2009, entitled "Nanochanneled Device and Method of Use Priority of Patent Application Serial No. 61/168,844, the entire contents of which are expressly incorporated herein by reference.

Background Information

This invention was made with Government support under contract NNJ06HE06A awarded by NASA. The government has certain rights in this invention.

Over the past 30 years, considerable progress has been made in the field of therapeutic agent (eg, drug) delivery technology, resulting in many breakthroughs in clinical medicine. Fabricating therapeutic agent delivery devices that can deliver therapeutic agents in a controlled manner remains a challenge. One of the major requirements for implantable drug delivery devices is the controlled release of therapeutic agents from small drug molecules to larger biological molecules. It is particularly desirable to achieve a continuous passive drug release profile that conforms to zero order kinetics so that the concentration of the drug in the bloodstream remains constant throughout the extended delivery period.

These devices can improve therapeutic efficacy, eliminate potentially life-threatening side effects, improve patient compliance, reduce health care provider intervention, reduce hospital stays and reduce shifts from regular dosing to substance abuse.

Nanochannel delivery devices can be used in drug delivery products to efficiently administer drugs. In addition, nanochannel delivery devices can be used in other applications requiring controlled release of drugs over time.

brief description

Embodiments of the present invention include a nanochannel delivery device having nanochannels within the structure configured for higher mechanical strength and higher flow rates. Various fabrication schemes can be used to form the nanochannel delivery device. Embodiments of fabricated devices are characterized by horizontal nanochannel designs (e.g., nanochannels parallel to the main plane of the device), high molecular transport rates, high mechanical strength, optional multilayer design, ability to select Layer material and optional clear top cover. Based on silicon microfabrication techniques, the dimensions of the nanochannel regions and the accompanying microchannel regions can be precisely controlled, thus providing predictable, reliable, constant release rates of drug (or other) molecules over extended periods of time. In some embodiments, the nanochannel delivery device can be used to create multilayered nanochannel structures. The multilayer nanochannel structure can break through the limitation of single-layer nanochannel delivery devices or systems on the range of release rates, allowing a wider range of predetermined porosity to achieve arbitrary release rates using any preferred nanochannel size.

In some embodiments, the nanochannel delivery device is fabricated from a "sandwich" of materials, including a thinner top layer, horizontal nanochannels, and a thicker bottom wafer. The thinner top layer can accommodate arrays of microchannels that provide inlets or outlets for molecular diffusion. It can also be used as the cap or upper top of the nanochannel by providing the top surface of the channel. Thicker bottom wafers can accommodate arrays of microchannels, providing indirect egress or ingress. It should be noted that in the following, the inlet refers to the bottom wafer, and the outlet refers to the top layer, but the present invention is not limited thereto. In some embodiments, the nanochannels are fabricated by sacrificial layer techniques that provide smooth surfaces and precisely controllable dimensions. This nanochannel can be formed between these two layers, which connects the outlet microchannels to the array of inlet microchannels formed in the bottom wafer, additionally allowing a thinner surface layer to be used independently for the top and top surfaces, with the purpose of Optimize channel properties such as surface charge, hydrophobicity, wettability, and conductivity. Each inlet and outlet microchannel can be connected to one, two or more nanochannels. The height, width and length of the nanochannels can be used to maintain constant (zero order) delivery. With the help of nanoscale fabrication methods, nanochannel lengths of 10 nm or less are feasible.

In some embodiments, the nanochannel delivery device is designed for higher strength. This can be achieved with supportive structures obtained on the bottom side of the thicker wafer. The structure may consist of a regular mesh of micrometric walls creating larger side surfaces of the inlet macrochannel. Furthermore, the top of the bottom wafer (in or on which nanochannels can be fabricated) can be engineered to provide good mechanical stability.

The thickness of the support layer below the nanochannels can be optimized by controlling the depth of the inlet microchannels and outlet macrochannels or by selecting an SOI wafer with a buried oxide layer of appropriate thickness. The material and thickness of the top layer can also be optimized for the properties described above.

Some embodiments include a nanochannel delivery device comprising: an inlet microchannel; a nanochannel; and an outlet microchannel, wherein the inlet microchannel and the outlet microchannel are in direct fluid communication with the nanochannel. In specific embodiments, said nanochannels are oriented parallel to a major plane of said nanochannel delivery device. In specific embodiments, the flow path from the inlet microchannel through the nanochannel to the outlet microchannel requires up to two changes in direction.

In specific embodiments, the inlet microchannel has a length, width, and depth; the outlet microchannel has a length, width, and depth; and the nanochannel has a length, width, and depth. In some embodiments, the ratio of nanochannel length to inlet microchannel length is 0.01-10.0, and the ratio of nanochannel length to outlet microchannel length is 0.01-10.0. In specific embodiments, the nanochannel length is greater than the inlet microchannel length, and the nanochannel length is greater than the outlet microchannel length. In specific embodiments, the ratio of nanochannel length to inlet microchannel length or outlet microchannel length is 0.2-5.0, 0.3-3.0, 0.4-2.0, or 0.5-1.0. In some embodiments, the nanochannel length is greater than the length, width and depth of the outlet microchannel. In specific embodiments, the inlet microchannel is in direct fluid communication with said outlet microchannel through a single nanochannel.

Some embodiments include a nanochannel delivery device comprising: an inlet microchannel; a nanochannel; an outlet microchannel; and a fluid flow path from the inlet microchannel to the outlet microchannel, wherein the fluid flow path needs to have a maximum Two changes. In specific embodiments, said nanochannels are oriented parallel to a major plane of said nanochannel delivery device. In specific embodiments, the inlet and outlet microchannels are in direct fluid communication with the nanochannels.

Some embodiments include a nanochannel delivery comprising: a substantially planar body comprising a first surface and a second surface opposite the first surface; a nanochannel within the substantially planar body; an inlet microchannel in fluid communication with the nanochannel; and an outlet microchannel in fluid communication with the nanochannel. In specific embodiments, the inlet microchannel extends from the nanochannel to the first surface, wherein the outlet microchannel extends from the nanochannel to the second surface.

Some embodiments include a nanochannel delivery device comprising a plurality of inlet microchannels; a plurality of nanochannels; and a plurality of outlet microchannels, wherein each inlet microchannel is in direct fluid communication with the outlet microchannel through a single nanochannel. In specific embodiments, the nanochannels are oriented parallel to the major plane of the nanochannel delivery device, and/or the inlet and outlet microchannels are in direct fluid communication with a common nanochannel. In specific embodiments, each inlet and outlet microchannel is arranged perpendicular to the main plane of the nanochannel delivery device; a plurality of inlet microchannels form a first array; a plurality of outlet microchannels form a second array; the The first array and the second array overlap each other such that the individual inlet microchannels are distributed between the individual outlet microchannels when viewed along a section taken perpendicular to the principal plane.

Some embodiments include a nanochannel delivery device comprising: a substantially planar body comprising a length, a width, and a thickness, wherein the length and width are greater than the thickness; an inlet surface, wherein the inlet surface is bounded by the length and width of the substantially planar body; and an outlet surface on the second side of the substantially planar body. In specific embodiments, said outlet surface is bounded by the length and width of said substantially planar body, and wherein the inlet surface is substantially parallel to said outlet surface. Particular embodiments include a nanochannel within said substantially planar body, wherein said nanochannel includes an inlet port and an outlet port; an inlet microchannel in fluid communication with said nanochannel; and a nanochannel in fluid communication with said nanochannel. An outlet microchannel in fluid communication, wherein the inlet microchannel and the nanochannel are configured such that a first linear axis can extend between the inlet surface and the inlet end of the nanochannel. In specific embodiments, the outlet microchannels and nanochannels are configured such that the second linear axis can extend between the outlet surface and the outlet end of the nanochannels. In some embodiments, the major axis of the inlet microchannel is perpendicular to a plane parallel to the substantially planar body. Particular embodiments include an inlet macrochannel between the inlet surface and the inlet microchannel, wherein the inlet macrochannel comprises bounding walls generally perpendicular to the inlet surface. In a specific embodiment, the inlet macrochannel is formed by deep reactive ion etching. In a specific embodiment, the major axis of the outlet microchannel is perpendicular to a plane parallel to said substantially planar body.

Some embodiments include a device comprising a first nanochannel delivery device inserted into an enclosure. In a specific embodiment, said first nanochannel delivery device is mounted perpendicular to the main axis of said enclosure. In specific embodiments, the enclosure comprises a spacer. In some embodiments, the spacer comprises a self-sealing substance. In a specific embodiment, the spacer comprises silicone rubber. In some embodiments, the septum is configured to receive an injection of a therapeutic agent.

Particular embodiments include a cap covering the septum. In some embodiments, the cap comprises an aperture adapted to guide the injection needle towards the septum. In specific embodiments, the enclosure comprises a lid extending over the first nanochannel device. In specific embodiments, the cover comprises one or more apertures. In some embodiments, the one or more orifices are sized such that they do not limit diffusion of a therapeutic agent from the capsule during use. In some embodiments, the cover is configured to protect the first nanochannel delivery device from mechanical damage. In specific embodiments, said cover is configured to protect said first nanochannel delivery device from intrusion by biological tissue structures after said capsule is implanted in a living organism. In some embodiments, the enclosure comprises a first inner reservoir. In specific embodiments, said first nanochannel delivery device is in fluid communication with said first inner reservoir.

In specific embodiments, the enclosure comprises a second inner reservoir in fluid communication with the second nanochannel delivery device. In some embodiments, the first and second inner reservoirs are not in fluid communication with each other. In a specific embodiment, said first and second inner reservoirs are separated by a wall. In specific embodiments, said first inner reservoir comprises a first therapeutic agent and said second inner reservoir comprises a second therapeutic agent. In specific embodiments, said first nanochannel delivery device is configured to diffuse a first therapeutic agent at a first diffusion rate, and said second nanochannel delivery device is configured to diffuse a first therapeutic agent at a second diffusion rate. Two therapeutic agents.

In some embodiments, the volume of the first inner reservoir can be changed by replacing the first removable component of the capsule with a larger removable component. In specific embodiments, said first inner reservoir comprises a coating compatible with the therapeutic substance. In specific embodiments, the capsule comprises an outer coating configured to prevent unwanted tissue encapsulation. In specific embodiments, said capsule comprises a cylindrical shape. In some embodiments, the capsule comprises a disk shape. In some implementations, the enclosure includes rectangular surfaces and arcuate surfaces. In specific embodiments, the capsule has a uniform cross-section.

In some embodiments, the capsule comprises one or more of the following: stainless steel, titanium, polyether ether ketone, polysulfone, epoxy, silicone rubber, polyether ketone ketone, and thermoplastic polyurethane . In a specific embodiment, the capsule comprises an anchoring component. In some embodiments, the anchoring member is configured to accept sutures. In specific embodiments, the capsule comprises a color code to indicate the nature of the capsule or nanochannel delivery device. In specific embodiments, the color code indicates the nature of the therapeutic agent contained within the capsule. In specific embodiments, the enclosure comprises a translucent or transparent cover extending over the first nanochannel delivery device.

Some embodiments include methods of making nanochannel delivery devices. In specific embodiments, the method includes: providing a first substrate; forming a plurality of nanochannels in the first substrate; forming a plurality of inlet microchannels in the nanochannels of the first substrate; providing a second forming a plurality of outlet microchannels in the second substrate; and bonding the second substrate to the first substrate, wherein each inlet microchannel is in direct fluid communication with a nanochannel.

In a particular embodiment of the method, said first substrate comprises a silicon-on-insulator wafer. In some embodiments, the height of each nanochannel is about 1-10 nanometers. In specific embodiments, the height of each nanochannel is about 10-20 nanometers, about 20-30 nanometers, about 30-50 nanometers, about 50-100 nanometers, or about 100-200 nanometers. In some embodiments, the second substrate comprises a sacrificial release layer of indium tin oxide film on silicon. Particular embodiments also include depositing a glass film on the second substrate prior to forming the plurality of inlet microchannels in the second substrate. In specific embodiments, the second substrate comprises a glass wafer; and the glass wafer is bonded to the first substrate, and the glass wafer is ground to reduce thickness prior to forming the plurality of outlet microchannels.

Some embodiments include a method of making a nanochannel delivery device, wherein the method comprises: providing a first substrate; forming a plurality of nanochannels on the first substrate; filling the plurality of nanochannels with a first sacrificial material ; forming a plurality of inlet microchannels in the first substrate; filling the second sacrificial material into the plurality of inlet microchannels; forming a cap layer covering the plurality of nanochannels; forming a plurality of outlet microchannels in the cap layer channels; removing a first sacrificial material from the plurality of nanochannels; and removing a second sacrificial material from the plurality of inlet microchannels.

In a particular embodiment of the method, the inlet microchannels are arranged perpendicular to the main plane of said first substrate. In a specific embodiment, the outlet microchannels are arranged perpendicular to the main plane of said first substrate. In some embodiments of the method, the inlet microchannel is in direct fluid communication with the nanochannel. In specific embodiments, the outlet microchannel is in direct fluid communication with the nanochannel.

In some embodiments of the method, the first substrate comprises a silicon-on-insulator wafer, the wafer comprising an inner oxide layer. In a specific embodiment, a photolithographic process is used to construct the inlet and outlet microchannels. In some embodiments, forming a plurality of inlet microchannels includes etching material from the first substrate, wherein the etching ends at an inner oxide layer. In a particular embodiment of the method, forming the plurality of inlet macrochannels comprises etching material from the backside of said first substrate, wherein said etching ends at an inner oxide layer.

In some embodiments, removing the inner oxide layer after etching the material to form the inlet microchannels and inlet macrochannels opens the path between the inlet microchannels and the inlet macrochannels. In specific embodiments of the method, each nanochannel is about 1-10 nanometers deep, about 10-20 nanometers deep, about 20-30 nanometers deep, about 30-40 nanometers deep, or about 40-200 nanometers deep.

In some embodiments of the method, the first sacrificial material can then be removed by selective etching. In a specific embodiment, the first sacrificial material is tungsten. In particular embodiments, the second sacrificial material may subsequently be removed by selective etching. In some embodiments of the method, the second sacrificial material is selected from the group consisting of: tungsten, copper, doped glass, and undoped glass. In a specific embodiment, the second sacrificial material is filled into a plurality of inlet microchannels, so that the second sacrificial material extends at the top of the inlet microchannels, and is made by chemical-mechanical planarization (CMP). It becomes flat.

In a particular embodiment of the method, said capping layer is selected from silicon nitride, silicon oxide, silicon carbonitride, silicon carbide and silicon. In some embodiments, the cap layer comprises multiple deposits of material comprising tensile stress and compressive stress such that the net stress of the cap layer is tensile. In some embodiments of the method, the capping layer is about 0.5-1.0 microns thick, about 1.0-2.0 microns thick, about 2.0-4.0 microns thick, or about 4.0-10.0 microns thick. In specific embodiments, the capping layer is greater than 10.0 microns thick.

Particular embodiments include a method of making a nanochannel delivery device, wherein the method comprises: providing a first substrate; forming a plurality of nanochannels on a first side of the first substrate; filling the plurality of nanochannels with a sacrificial material. in the channel; bonding an initial cap layer to the first side of the first substrate; forming a plurality of inlet microchannels in the cap layer; preparing a second substrate with an adhesive layer; bonding the second substrate onto the second side of the first substrate; removing a first portion of the second substrate; providing an additional capping layer to the second substrate; forming a plurality of outlet microchannels in the second substrate; and removing The sacrificial material opens multiple nanochannels.

In some embodiments of the method, the second substrate comprises a release layer, wherein the release layer can be selectively removed to separate the second substrate from the first substrate. In a specific embodiment of the method, the outlet microchannel is in direct fluid communication with said nanochannel. In a particular embodiment of the method, the first substance comprises a silicon-on-insulator type wafer comprising an inner oxide layer. In some embodiments, forming the plurality of inlet microchannels includes etching species from the cap layer, wherein the etching ends at an inner oxide layer.

In some embodiments, forming the plurality of inlet macrochannels includes etching species from the backside of the first substrate, wherein the etching ends at an inner oxide layer. In specific embodiments, removing the inner oxide layer after etching the material to form the inlet microchannels and inlet macrochannels opens the path between the inlet microchannels and the inlet macrochannels.

In some embodiments, each nanochannel formed is about 1-10 nanometers deep, about 10-20 nanometers deep, about 20-30 nanometers deep, about 30-40 nanometers deep, or about 40-200 nanometers deep.

In particular embodiments, the sacrificial material may subsequently be removed by selective etching. In a specific embodiment, wherein said sacrificial material is tungsten. In some embodiments, the initial cap layer is silicon nitride deposited by plasma enhanced chemical vapor deposition. In some embodiments of the method, the initial cap layer is about 0.01-0.5 microns thick, about 0.5-1.0 microns thick, about 1.0-2.0 microns thick, about 2.0-4.0 microns thick, or about 4.0-10.0 microns thick . In specific embodiments of the method, said initial cap layer is greater than 10.0 microns thick. In some embodiments of the method, the initial cap layer is selected from silicon nitride, silicon oxide, silicon carbonitride, silicon carbide, and silicon. In specific embodiments, the initial cap comprises multiple deposits of material comprising tensile and compressive stresses such that the net stress of the cap is tensile. In some embodiments of the method, the adhesive layer is selected from the group consisting of benzocyclobutene, silicon oxide, copper, doped glass, gold and gold alloys.

In some embodiments, the method of bonding the second substrate to the first substrate is selected from the group consisting of: anodic bonding, fusion bonding, and thermocompression bonding.

Particular embodiments include nanochannel delivery devices comprising: a plurality of inlet microchannels, wherein each inlet microchannel has a length, width, and depth, and wherein the length of the inlet microchannel is greater than the width and depth of the inlet microchannel; a plurality of outlet microchannels a channel, wherein each outlet microchannel has a length, width and depth; a plurality of nanochannels in fluid communication with the plurality of inlet and outlet microchannels. In a specific implementation, the plurality of inlet microchannels are arranged such that the width and depth of the inlet microchannels define a first surface parallel to the major plane of the nanochannel delivery device; and the plurality of outlet microchannels are arranged, Such that the width and depth of the outlet microchannel define a second surface parallel to the major plane of the nanochannel delivery device.

Particular embodiments include a method of treating a disease in a human, the method comprising: providing a nanochannel delivery device described herein; providing a reservoir in fluid communication with the nanochannel delivery device; providing a material in the reservoir, wherein the substance is configured to treat the disease; and the substance is administered to a human via the nanochannel delivery device. In a particular embodiment of the method, said substance is selected from the group consisting of: leuprolide acetate, letrozole, lapatinib, buprenorphine, interferon and zidovudine. In some embodiments, the disease is selected from the group consisting of: prostate cancer, breast cancer, opioid dependence, giant cell hemangioblastoma, and HIV. In specific embodiments of the method, administering said substance to a human via said nanochannel delivery device comprises subcutaneously inserting said nanochannel delivery device into a human.

Hereinafter, the term "coupled" is defined as connected, although not necessarily direct, and not necessarily mechanically.

The use of the word "a" or "an" when used in conjunction with the term "comprising" in the claims and/or specification may mean "one", but it is also consistent with "one or more" or "at least one" " meaning. The term "about" generally means plus or minus 5% of the stated value. The use of the term "or" in the claims is used to mean "and/or" unless otherwise stated to mean only one alternative or alternatives are mutually exclusive, although the content of this text supports only one alternative and "and/ or" definition.

The terms "comprise" ("comprise", and any form of comprise, such as "comprises" and "comprising"), "have" ("have", and any form of have, such as "has" and "having"), " "include" ("include", and any form of include, such as "includes" and "including") and "contain" ("contain", and any form of contain, such as "contains" and "containing") are open-end Copula. Therefore, a method or apparatus that "comprises", "has", "includes" or "contains" one or more steps or components has said one or more steps or components, but is not limited to only having said One or more components. In addition, a step of a method or a component of a device that "comprises", "has", "includes" or "contains" one or more features has the one or more features, but is not limited to having the one or more features multiple features. Furthermore, a device or a configuration configured in a certain way is configured in at least the manner described, but may also be configured in a manner not listed.

The term "entrance microchannel" is defined as a microchannel through which molecules are transported prior to entering the nanochannel of the nanochannel delivery device.

The term "exit microchannel" is defined as a microchannel through which molecules are finally transported before leaving the nanochannel delivery device.

The term "nanochannel" is defined as a channel having a cross-section having at least one dimension (eg, height, width, diameter, etc.) of less than 200 nm.

The term "macrochannel" is defined as a channel having a cross-section that has its largest dimension (eg, height, width, diameter, etc.) greater than about 10 μm.

Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and specific examples, while indicating particular embodiments of the invention, are given by way of illustration only, since the detailed description and specific examples will be understood to be within the spirit and scope of the invention. Such changes and modifications will be apparent to those skilled in the art.

Brief description of the drawings

1A-1J are schematic diagrams of a manufacturing method according to an exemplary embodiment.

2A-2E are perspective views of a first portion of a nanochannel delivery device during fabrication.

3A-3F are perspective views of a second portion of a nanochannel delivery device during fabrication.

Figure 3G is a partial perspective view of a nanochannel delivery device with representative dimensions marked.

4A-4L are schematic diagrams of a manufacturing method according to an exemplary embodiment.

5A-5H are schematic cross-sectional views of a nanochannel delivery device during fabrication, according to an exemplary embodiment.

6A-6J are schematic diagrams of a manufacturing method according to an exemplary embodiment.

Figure 7 is a schematic cross-sectional side view of an exemplary embodiment of a nanochannel delivery device.

8A-8I are schematic diagrams of a manufacturing method according to an exemplary embodiment.

8J-8P are front and perspective views of an exemplary embodiment at various stages of the manufacturing process.

Figure 9 is a perspective view of a nanochannel delivery device according to an exemplary embodiment.

Figure 10 is a schematic cross-sectional side view of an exemplary embodiment of a nanochannel delivery device.

Figure 11 is a scanning electron microscope image of a portion of a nanochannel delivery device according to an exemplary embodiment.

12 is an optical image of a bonded wafer of a nanochannel delivery device according to an exemplary embodiment.

13 is an optical image of the front surface of a nanochannel delivery device according to an exemplary embodiment after polishing.

Figure 14 is a scanning electron microscope image of a portion of a nanochannel delivery device according to an exemplary embodiment.

15 is an optical image of a portion of a nanochannel delivery device according to an exemplary embodiment after polishing.

Figure 16 is a scanning electron microscope image of a portion of a nanochannel delivery device according to an exemplary embodiment.

Figure 17 is a scanning electron microscope image of a portion of a nanochannel delivery device according to an exemplary embodiment.

Figure 18 is a list of materials used in the fabrication method in an exemplary embodiment.

Figure 19 is an exploded perspective view of a capsule and nanochannel delivery device according to an exemplary embodiment.

FIG. 20 is an assembled perspective view of the embodiment of FIG. 19 .

FIG. 21 is an assembled perspective view of a capsule according to an exemplary embodiment.

FIG. 22 is an exploded perspective view of the embodiment of FIG. 21 .

23 is an exploded perspective view of a capsule and nanochannel delivery device according to an exemplary embodiment.

24 is an exploded perspective view of a capsule and nanochannel delivery device according to an exemplary embodiment.

FIG. 25 is an assembled perspective view of a capsule according to an exemplary embodiment.

FIG. 26 is an exploded perspective view of the embodiment of FIG. 25 .

FIG. 27 is an assembled perspective view of a capsule according to an exemplary embodiment.

FIG. 28 is an exploded perspective view of the embodiment of FIG. 27. FIG.

29 is a perspective view of a capsule according to an exemplary embodiment.

30 is a perspective view of an enclosure in an installed position according to an exemplary embodiment.

FIG. 31 is a perspective view and a cutaway view of a capsule according to an exemplary embodiment.

Detailed Description of Illustrative Embodiments

Option 1: Combined cap layers

Figures 1a-1j, 2A-2E, and 3A-3G provide illustrations of steps performed in an exemplary first method of making a nanochannel delivery device. Specific dimensions are provided for illustrative purposes only, it being understood that other exemplary embodiments may contain different dimensions.

In an exemplary embodiment fabricated according to this protocol, the top layer was a lid with a 5 μm thick evaporated glass layer, and the bottom wafer was a 4 inch SOI wafer with a 30 μm device layer and a 500 μm bulk layer to enable the The support layer under the nanochannel has a thickness of 30 μm. In this exemplary structure, the inlet and outlet microchannels are 5 μm x 5 μm, and the in-plane dimensions of each nanochannel are 5 μm x 5 μm. The distance between adjacent openings (eg, the distance between adjacent nanochannels) is 2 μm. The inlet macrochannel below the support mesh is approximately 200 μm x 200 μm above the 500 μm thick bulk layer.

A general overview of the fabrication method is first given, followed by a more detailed discussion of the features included in the nanochannel delivery device. In this embodiment, the nanochannel delivery device is fabricated without chemical mechanical polishing (CMP), and the microfabrication protocol includes the following steps. Starting with SOI (silicon-on-insulator) wafers (see FIG. 2A ), a hard mask layer protecting the underlying silicon, such as a silicon nitride film or a LTO (low temperature oxidation) film, is deposited during thermal oxidation. If silicon nitride is used, a silicon dioxide underlayer can be deposited prior to the nitride deposition. Alternatively, if the rate of the etch process can be well characterized, the base substrate can also be a silicon wafer instead of SOI. In this case, the etch depth is controlled by timing.

Nanochannel regions can then be constructed on the masking layer using photolithographic processes. (See Figures 1(a) and 2B) and selectively remove the masking material over the nanochannel region without affecting the underlying silicon. A combination of dry etching and short wet etching can be used for this purpose. A silicon dioxide film (of appropriately controlled thickness) can then be deposited on the exposed silicon regions by thermal oxidation. In this embodiment, the thickness of the oxide layer is used to define the height of the nanochannels and strip the masking layer.

A masking layer suitable for deep silicon etching can then be deposited. The masking layer should be able to be structured and be highly selective to silicon during deep silicon etch. Depending on the technique of deep silicon etching, a silicon oxide layer, a photoresist layer or a metal film layer can be used.

In this embodiment, as shown in Figure 1(b) and 2C, the entrance microchannel is constructed on the masking layer, and the entrance microchannel is etched down by deep RIE (reactive ion etching) or ICP (inductively coupled plasma) technique to the oxide layer of the SOI wafer. If a silicon wafer is used, the etch depth is determined by the etch rate and time.

As shown in Figure 1(c) and 2D, the entrance large channel (large opening on the back) is laid and etched to the oxide layer of the SOI wafer, and the exposed oxide area is cleaned by HF solution. (See Figures 1(d) and 2E). To build the cap of the nanochannel delivery device, in this embodiment, starting from a supporting wafer (eg, a silicon wafer), a sacrificial layer is deposited. (See Figures 1(e), 1(f) and 3A). The sacrificial layer (eg, indium tin oxide (ITO)) is chosen so that it can be removed in a solution that is safe for silicon and cap materials.

The cap of the nanochannel delivery device was deposited on the sacrificial layer (see Figures 1(g) and 3B), and the outlet was constructed on this structure, as shown in Figures 1(h) and 3C). Alternatively, lift-off techniques can be used for sputtered glass or e-beam evaporated glass. These materials can be any suitable material, for example, spin-on glass, sputtered glass, e-beam evaporated glass, ITO-laminated glass, silicon, polymers, etc. These materials may include glasses and glass materials known in the art to be bonded to silicon by specific means such as anodic bonding or fusion bonding. These materials should be able to bond with silicon in some way. For glass, for example, anodic bonding can be used. Spin-on-glass layers may also be suitable. Depending on the nature of the surface, a planarization method may be required.

As shown in Figures 1(c), 3D, and 3E, the structural wafer and cap can be bonded together by techniques such as anodic bonding or Si-Si direct bonding or interlayer-assisted bonding, and the supporting wafer for the cap can be removed (as shown in Figures 1(j) and 3F). Finally, individual nanochannel delivery devices were obtained by dicing the wafer and washing it.

In another exemplary embodiment fabricated according to this scheme, while keeping the bottom silicon substrate the same 4 inch SOI wafer with a 30 μm device layer and a 500 μm bulk layer as described in the above embodiment, the top layer is 10 μm thick glass membrane. The 10 μm thick glass film was fabricated by thinning a thicker glass layer. To prepare the thin films, glass wafers with a thickness of 100 μm to 500 μm are bonded to structured silicon substrates. A planarization technique such as backgrinding, or lapping, or CMP, or chemical etching, or dry etching is then used to thin the glass layer until a set thickness of 10 μm is reached. An outlet is then built into this thinned glass membrane and etched down to the underlying silicon surface to open up the outlet. In this exemplary structure, the inlet and outlet microchannels are 5 μm x 5 μm, and the in-plane dimensions of each nanochannel are 5 μm x 5 μm. The distance between adjacent openings (eg, the distance between adjacent nanochannels) is 2 μm. The inlet macrochannel below the support mesh is approximately 200 μm x 200 μm above the 500 μm thick bulk layer.

FIGS. 2A-2E and 3A-3F are now described in detail, providing a more detailed view of the features of nanochannel delivery device 100 . Referring first to FIG. 2A , SOI wafer 10 includes top layer 15 on substrate 20 separated by oxide layer 35 . A series of nanochannels 25 are formed in the top layer 15 using an image mask as shown in FIG. 2B . One or more inlet microchannels 30 are formed using an image mask in each nanochannel 25 as shown in FIG. 2C , exposing the oxide layer 35 between the substrate 20 and the top layer 15 . For purposes of clarity, not all features, such as inlet microchannel 30, are labeled in the figures.

As shown in FIG. 2D , a portion of substrate 20 is removed from beneath oxide layer 35 using an image mask. The oxide layer 35 is then removed (as shown in FIG. 2E ), forming inlet microchannels 30 to allow material transport through the substrate 20 and top layer 15 . At this stage, the lower portion 40 of the nanochannel delivery device 100 is complete.

Referring now to FIGS. 3A-3F , upper portion 45 of nanochannel delivery device 100 is fabricated starting from sacrificial layer 50 deposited on supportive substrate 55 . Also as shown in FIG. 3B, additional layers 60 (eg, spin-on-glass, sputtered glass, e-beam evaporated glass, ITO-laminated glass, silicon, polymer, etc.) can be used in the process using lift-off techniques. As shown in Figure 3C, outlet microchannels 70 are formed in the sacrificial layer (and additional layer 60, if used).

At this stage, the upper part 45 and lower part 40 of the nanochannel delivery device 100 are ready to be joined. It should be understood that the designations "upper" and "lower" are for the purpose of clearly describing the drawings only, and do not indicate the interrelationship between the components during use of the device. As shown in Figures 3D and 3E, upper part 45 and lower part 40 are bonded together (by, for example, anodic bonding or Si-Si direct bonding or interlayer assisted bonding). As shown in FIGS. 3F and 3G , the supportive substrate 55 is removed from the upper portion 45 , completing the nanochannel delivery device 100 . The embodiment shown in FIG. 3G includes optional tapered surfaces in the transitions between outlet microchannel 70 and nanochannel 25 and between nanochannel 25 and inlet microchannel 30 .

As shown in Figure 3G, the nanochannel 25 lies in a plane parallel to the major plane of the nanochannel delivery device 100 (e.g., the plane defined by the larger dimensions [in this example, L and W] of the nanochannel delivery device 100) middle. This configuration allows the nanochannel 25 to vary in length (e.g., approximately the distance between adjacent outlets 70 and inlets 30), as well as the height and width of the nanochannel, without changing the length L, width W, and width of the nanochannel delivery device 100. Thickness T. Thus the thickness T of the nanochannel delivery device 100 may be based on other criteria (eg, mechanical integrity) without the need to control the flow of the substance delivered through the nanochannel delivery device 100 .

The embodiment shown in FIGS. 3A-3G is also used for each outlet 70 in fluid communication with any inlet 30 through a single nanochannel 25 . This configuration can be used to more robustly control the diffusion of substances delivered through the nanochannel delivery device 100 . For example, the rate of diffusion through the nanochannel delivery device 100 is more dependent on the size of the nanochannel 25 than in configurations having multiple nanochannels in fluid communication with a single extended inlet. In these configurations, the inlet (rather than the nanochannel) can become a restriction on flow, limiting the ability to control flow by changing the size of the nanochannel.

As shown in the detailed view (not to scale) of Figure 3G, the nanochannel 25 comprises a length nL, a width nW and a height nH. The outlet microchannel 70 comprises a length oL, a width oW and a height oH. Furthermore, the inlet microchannel 30 comprises a length iL, a width iW and a height iH. As shown in FIG. 3G , the "length" of each channel is a measure along the path along which molecules move from the inlet microchannel 30 , through the nanochannel 25 , and out through the outlet microchannel 70 . In some embodiments, oL=4 μm, oW=5 μm, oH=5 μm when nH=50 nm, nW=4 um, nL=5 um; and oL=30 μm, oW=5 μm, oH=5 um.

In some embodiments, the oL/nL or iL/nL ratio can be 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8 , 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3 , 4.4, 4.5, 4.6, 4.7, 4.9, 5.0, 5.1., 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 20, 30, 4050, 60, 70, 80, 90 or 100.

Scheme 2: Multilayer structure with bonded cap layer

In a second embodiment, a multilayer nanochannel structure can be fabricated by modifying the above scheme 1. This embodiment includes the following steps. Starting from a SOI (silicon-on-insulator) silicon wafer, a silicon dioxide layer (with a controlled thickness) is deposited by thermal oxidation, the thickness of the oxide layer can be used to determine the height of the nanochannels. Alternatively, the bottom substrate can also be a silicon wafer instead of SOI if the etch process rate is well characterized. Nanochannel regions can be built on the oxide layer using photolithographic processes.

Silicon oxide on non-nanochannel regions can be selectively removed without affecting the oxide on nanochannel regions (see Figure 4(a)). A polymeric silicon structural layer can be deposited on top of the oxide nanochannel spacer layer. (See Figure 4(b)). An oxide layer of a second defined thickness can be deposited again, and nanochannel regions can be built on the oxide layer using a photolithographic process. The silicon oxide on the non-nanochannel regions can be selectively removed without affecting the oxide on the nanochannel regions (see Figure 4(c)). This approach completes the second layer of nanochannels. The previous two steps can be repeated to complete the desired number of layers.

As an alternative to the foregoing steps, other materials can also be used for the silicon oxide nanochannel spacer layer and the multilayer structure layer. For example, aluminum films are used as nanochannel spacers, and evaporated glass films are used as layers in multilayer structures.

A first masking layer suitable for deep silicon etch can be deposited. It should be possible to build this masking layer and be highly selective to silicon during deep silicon etch. Depending on the technique of deep silicon etching, a silicon oxide layer, a photoresist layer or a metal film layer can be used optionally.

An inlet microchannel is constructed on the first masking layer, and a second masking layer is deposited on top of the first masking layer. Inlet microchannels are constructed on both the first and second masking layers. The outlet microchannel is etched down to a depth close to the oxide layer of the SOI wafer, and the second masking layer is stripped to expose the first masking layer. Outlet microchannels are etched through multiple layers of nanochannel spacer and structural layers. A combination of wet etching and DRIE can be used. This also etches the entry down to the insulator layer of the SOI wafer. (See Figure 4(d)). If a silicon wafer is used, the etch depth is determined by the etch rate and time. The backside entry macrochannel is then laid and etched down to the oxide layer of the SOI wafer (see Figure 4(e)), and the oxide on the exposed areas is cleaned. (See Figure 4(f)).

To fabricate the cap of the nanochannel delivery device, starting from a supporting wafer (eg, a silicon wafer), a sacrificial layer is deposited (see Figure 4(h)). The sacrificial layer is chosen so that it can be removed in a solution that is safe for silicon and capping materials. The cap of the nanochannel delivery device is deposited on a supporting wafer, and the inlet microchannels are etched. Lift-off techniques can be used in some cases (see Fig. 4(i,j)). These materials may include, for example, spin-on glass, sputtered glass, e-beam evaporated glass, ITO-laminated glass, silicon, and the like. These materials should be able to bond with silicon in some way. For example, transparent glass layers can be deposited by e-beam evaporation. Spin-on-glass layers can also be used. Depending on the nature of the surface, planarization may be required. The structural wafer and cap of the previous steps can be bonded together by some technique such as anodic bonding, Si-Si direct bonding or interlayer assisted bonding. (See Figure 4(k)). The supporting wafer with the top cover can be removed (see Fig. 4(l)) and the device obtained by dicing the wafer and cleaning.

Solution 3: Cap layer of integral manufacturing

As a third embodiment, nanochannel structures can be fabricated integrally (eg, without bonding) and optionally use CMP in the process. This exemplary microfabrication scheme includes the steps shown in Figures 5A-5H.

Specific dimensions are provided for purposes of illustration only, and it is understood that other exemplary embodiments may include different dimensions. In this embodiment, the top layer is about 2 μm of deposited silicon nitride. This embodiment also includes a bottom wafer that is an 8 inch SOI wafer with a 30 μm device layer such that the support layer under the nanochannels is 30 μm thick and a 725 μm bulk layer. In this exemplary structure, the openings of the inlet and outlet microchannels are 3 μm x 5 μm, and the in-plane dimensions of each nanochannel are 3 μm x 5 μm. The spacing between adjacent microchannel openings is 2 μm. As in the previous embodiment, the inlet macrochannel below the support mesh is about 200 μm x 200 μm above the 725 μm thick bulk layer.

Starting from a SOI (silicon on insulator) wafer 210, a nanochannel spacer layer 220 is deposited (with a controlled thickness, eg ±5% of the relevant portion of the SOI wafer 210). The thickness of the spacer layer 220 can be used to define the height of the nanochannel. This spacer layer 220 is a sacrificial layer, the material is removed in a subsequent step so that the underlying silicon surface directly becomes the "floor" of the final nanochannel. The spacer material should have high wet etch selectivity to other materials in the nanochannel delivery device (nDD). For example, tungsten, germanium, or silicon oxide may be used for the nanochannel spacer 220 .

As shown in FIG. 5A , capping layer 230 is deposited on nanochannel spacer layer 220 . The cap layer 230 will eventually become the "ceiling" of the nanochannel. Silicon nitride, silicon oxide, silicon carbide, or other materials that are highly etch-selective to the material of the spacer layer 220 may be used for the cap layer 230 .

A masking layer (not shown) suitable for deep reactive-ion etching (DRIE) is deposited, and an inlet microchannel 240 is formed on the masking layer by photolithography. As shown in FIG. 5B , the DRIE method etches microchannels 240 through capping layer 230 , spacer layer 220 and silicon down to buried oxide layer 250 of SOI wafer 210 . The masking layer can then be removed.

As shown in Figure 5C, the inlet microchannel 240 is filled with a fill material 260 that may be polished or etched by CMP. Non-limiting examples of fill material 260 include copper, tungsten, polysilicon, or phosphosilicate glass, respectively deposited by techniques known in the art. The fill material 260 should be capable of wet etching, which is highly selective to silicon and the material of the cap layer 230 . In this exemplary embodiment, the fill material 260 only needs to fill the top of the inlet microchannel 240 . CMP or etch back can be used to remove excess fill material 260 that diffuses onto or out of inlet microchannel 240 . The surface of the remaining filling material 260 should be above the level of the spacer layer 220 .

Referring now to FIG. 5D , other materials may be deposited over the cap layer 230 . The regions of cap layer 230 and spacer layer 220 above and between inlet microchannels 240 may be constructed using photolithographic processes. Spacer layer 220 and cap layer 230 outside of entrance nanochannel 240 (eg, regions 221 and 231 ) can be etched to, or slightly below, the silicon surface.

Referring now to FIG. 5E , a final capping layer 270 is deposited over the entire surface of the wafer 210 to provide structural rigidity and seal off the sidewalls of the nanochannel region. Using a photolithographic process, the outlet microchannel 280 can be constructed and etched through the cap layers 230, 270 and optionally through the spacer layer 220 into the silicon 210 of the range for other methods. A protective layer 275 is deposited over the cap layer 270 and the outlet microchannel 280 as shown in FIG. 5F .

Now describing FIG. 5G , the wafer 210 can then be inverted and the large openings of the entry macrochannels 245 on the backside of the wafer 210 formed by DRIE down to the buried oxide layer 250 of the wafer 210 . As shown in FIG. 5H , the sacrificial and protective layers used in this process (eg, spacer layer 220 , filling material 260 , cap layer 270 and portions of oxide layer 250 ) are removed by suitable methods known in the art. As shown in FIG. 5H, when the spacer layer 220 is removed, nanochannels 205 are formed. The wafer is then diced to obtain individual nanochannel delivery devices.

As described in this embodiment, nanochannel 205 is in direct fluid communication with inlet microchannel 240 and outlet microchannel 280 . Specifically, inlet microchannel 240 and nanochannel 205 are directly connected such that fluid entering from the inlet microchannel directly enters the nanochannel without passing through an intermediate object.

As a variation of this solution, and similar to solution 2 above, a multi-layer structure can be constructed by reusing the monolithic top-level approach. Multiple cap layer 230 and spacer layer 220 pairs may be deposited. The inlet microchannels can be etched through all layers down to the buried oxide, filled with fill material 260 and polished as described above. A final cap layer 270 may be used and outlet microchannels 280 etched, as described above.

Scheme 4: Changing the length of nanochannels

In some embodiments, Protocol 1 can be modified to fabricate nanochannel delivery devices with different nanochannel lengths while keeping other features unchanged. An exemplary microfabrication protocol includes the following steps.

Starting from a SOI (silicon on insulator) wafer, a hard masking layer such as a silicon nitride film or an LTO (low temperature oxidation) film that protects the underlying silicon during thermal oxidation is deposited. If silicon nitride is used, a silicon dioxide underlayer can be deposited prior to deposition of the nitride. Alternatively, the underlying substrate can also be a silicon wafer instead of SOI if the rate of the etching process can be well characterized.

Nanochannel regions can be built on the masking layer using photolithographic processes. (See Figure 6(a)), the masking material over the nanochannel region is selectively removed without affecting the underlying silicon. A combination of dry etching and short wet etching can be used for this purpose. A silicon dioxide film (of controlled thickness) is deposited on the exposed silicon areas by thermal oxidation. A silicon dioxide film (of appropriately controlled thickness) can then be deposited on the exposed silicon regions by thermal oxidation. In this embodiment, the thickness of the oxide layer is used to define the height of the nanochannels and strip the masking layer and oxide.

Deposit a masking layer suitable for a potassium hydroxide (KOH) wet etch, such as silicon nitride. A new masking material is designed for the layout of the inlet and outlet microchannels on the same layer, and the nanochannel length is defined by the spacing between adjacent inlet and outlet microchannels. The new masking material is used to build up the masking layer by standard photolithographic processes. The masking material over the open area is selectively removed. A KOH wet etch is then applied to form an opening with sloped walls, and the masking layer is stripped. (See Figure 6(b)).

Masking layers suitable for deep silicon etch can be deposited. This masking layer should be able to be structured and be highly selective to silicon during deep silicon etch. Depending on the technique used for the deep silicon etch, silicon oxide layers, photoresist layers, metal film layers, or other suitable materials may be used.

Outlet microchannels are built on the masking layer and etched down to the oxide layer of the SOI wafer by a suitable technique such as deep RIE or ICP techniques. (See Figure 6(c)). If using a silicon wafer, the etch depth can be determined by the etch rate and time.

The entrance channel is laid from the back and etched to the oxide layer of the SOI wafer, and the exposed oxide area is cleaned by HF solution. (See Figure 6(d)). To build the cap of the nanochannel delivery device, starting from a supporting wafer (eg, a silicon wafer), a sacrificial layer is deposited. (See Figure 6(e,f)). The sacrificial layer (eg, ITO) is chosen so that it can be removed in a solution that is safe for silicon and cap materials.

A cap of the nanochannel delivery device is deposited on the sacrificial layer. (See Figure 6(g)), an outlet is built on this structure. (See Figure 6(h)). Alternatively, lift-off techniques can be used in the case of sputtered glass or e-beam evaporated glass. In some embodiments, these materials may be spin-on glass, sputtered glass, e-beam evaporated glass, ITO-laminated glass, silicon, polymers, and the like. These materials should be able to bond with silicon in some way. For glass, for example, anodic bonding can be used. Spin-on-glass layers may also be suitable. Depending on the nature of the surface, a planarization method may be required

The structural wafer and cap of step (6) can be bonded together by techniques such as anodic bonding, Si-Si direct bonding, or interlayer assisted bonding. (See Figure 6(i)). The supporting wafer with the top cap removed (see Figure 6(j)), the device is obtained by dicing the wafer and cleaning.

If the preferred length of the nanochannel is less than 500 nm, nanofabrication techniques such as e-beam or nanoimprinting can be used. Isotropic silicon etching techniques can also be used. Figure 7 is a schematic block diagram of a shorter nanochannel delivery device. As shown in FIG. 7 , the inlet microchannel 340 has a flared or tapered portion 341 adjacent to the nanochannel 305 . Similarly, outlet microchannel 380 has a flared or tapered portion 381 adjacent nanochannel 305 . Nanochannel 305 is thus shortened due to portions 341 and 381 .

Option 5: Hybrid Integral Combined Cap Layer

As a fifth embodiment, instead of using the CMP method, nanochannel structures can be fabricated using bonding as a non-critical step in the fabrication of the cap layer. This exemplary microfabrication scheme includes the following steps as shown in Figures 8A-8P.

Referring first to FIG. 8A , starting from an SOI (silicon-on-insulator) base wafer 410 , a nanochannel spacer layer 420 is deposited (with a controllable thickness, eg, ±5% of the relevant portion of the SOI base wafer 410 ). The thickness of the spacer layer 420 can be used to define the height of the nanochannel. This spacer layer 420 is a sacrificial layer and the material is removed in a subsequent step so that the underlying silicon surface directly becomes the "floor" of the final nanochannel. The spacer material should have a high wet etch selectivity to all other species in the nanochannel delivery device. For example, a thin film of tungsten, germanium, or silicon oxide may be used for the nanochannel spacer layer 420 .

A cap layer 430 is deposited on the nanochannel spacer layer 420 . The cap layer 430 will eventually become the "ceiling" of the nanochannel. Silicon nitride, silicon oxide, silicon carbide, or other materials that are highly etch-selective to the material of the spacer layer 420 may be used for the cap layer 430 . A nanochannel region is constructed on the spacer layer 420 and the cap layer 430 using a photolithography process. As shown in FIG. 8B , spacer layer 420 and cap layer 430 on non-nanochannel regions 432 and 433 may be etched to the silicon surface of silicon wafer 410 , or slightly below the silicon surface.

Referring now to Figure 8C, further cap material 431 is deposited and optionally planarized by CMP to provide a flat surface. The inlet microchannel 440 is constructed on the masking layer (not shown) by photolithography. The DRIE method etches inlet microchannel 440 through cap layer 430 , spacer layer 420 , and silicon, etch down to buried oxide layer 450 of SOI wafer 410 . The masking layer is removed and, if desired, an additional suitable surface layer for bonding can be deposited on the surface.

Referring now to FIG. 8D , on another silicon substrate (eg, cap wafer 411 ), a layer 421 (comprising, eg, silicon nitride or silicon oxide) may be deposited. On top of layer 421, an adhesive layer 441 is deposited. The material of adhesive layer 441 may be selected to adhere well to materials on the surface of wafer 410 (eg, lid 431 ). The material of the adhesive layer 441 can also be designed such that any surface particles can be absorbed into the adhesive layer 441 to prevent any delamination between the cover wafer 410 and the base wafer 411 after bonding. Alternatively, high-level cleaning methods can be used before and during bonding when there is no such requirement. Exemplary materials for the adhesion layer 441 include polymeric materials, silicon oxide, and copper. A "release layer" 421 may also be used with an additional silicon nitride or silicon oxide layer (not labeled) on top of the adhesion layer 441 and optionally a material with a very high etch rate, before the application of the adhesion layer 441 . Layer 421 may contain substances that are highly selective to other materials of the nanochannel delivery device.

Now describing FIG. 8E , the cap wafer 411 and the base wafer 410 are bonded to each other. In some embodiments, the bond may be a polymer-silicon nitride bond, such as benzocyclobutene (BCB)-silicon nitride, copper-copper thermocompression bond, or oxide-oxide fusion bond, respectively using Suitable pre- and post-binding treatments known to those skilled in the art.

Now describing FIG. 8F , the silicon portion of the cap wafer 411 is then removed by suitable methods such as mechanical thinning, chemical etching, or a combination thereof. With the optional addition of a "release layer" 421 , this release layer can be selectively removed to cause separation of the silicon cap wafer 411 from the base wafer 410 .

Referring now to FIG. 8G , using a photolithographic process, an outlet microchannel 480 can be constructed and etched through an optional release layer 421, adhesive layer 441, lid 431, cap layer 430, and optionally through a spacer layer 420 for use in other methods. range of silicon.

Referring now to FIG. 8H , a protective cap layer 470 is deposited on the surface of the base wafer 410 . Wafer 410 is then inverted (with layer 421 and adhesion layer 441 of wafer 411 ) and access macrochannel 445 down to buried oxide layer 450 of wafer 410 may be formed by DRIE.

Referring now to FIG. 8I , the sacrificial layers (eg, spacer layer 420 , cap layer 470 and portions of oxide layer 450 ) are removed by suitable methods known in the art. As shown in FIG. 81 , when the spacer layer 420 is removed, nanochannels 405 are formed. As shown in this embodiment, nanochannel 405 is in direct fluid communication with inlet microchannel 440 and outlet microchannel 480 .

Referring now to FIG. 8J , a top view of the entire wafer 410 is shown. As shown in this figure, wafer 410 (before dicing) contains several nanochannel delivery devices 400 (only one of which is labeled in this figure). Wafer 410 may be diced to separate individual nanochannel delivery devices 400 from each other. Shown in FIG. 8K is a detailed view of a single nanochannel delivery device 400 with exemplary dimensions. In this figure, a plurality of inlet macrochannels 445 can be seen on one side of the nanochannel delivery device 400 . This exemplary embodiment of the nanochannel delivery device 400 is about 6.0 mm ² , with the inlet macrochannel generally forming a ring with a diameter of about 3.6 mm. It should be understood that while the wafer 410 of Scheme 5 is illustrated in Figure 8J, other schemes would result in a wafer containing multiple nanochannel delivery devices, which could be diced or separated into individual devices. It should also be understood that other exemplary embodiments may include different dimensions than those shown in FIG. 8K. In some embodiments, wafer 410 may remain intact to effectively form nanochannel delivery devices of similar dimensions to silicon wafers, eg, about 500-750 microns thick and 100, 150, 200, 300, 450 or 675 mm in diameter.

For example, referring to Figures 8L and 8M, a nanochannel delivery device 500 is shown comprising a body 501 that is substantially flat and rectangular having a thickness "T", a length "L" of 4 mm, and a width "W" of 3 mm . Thickness "T" can vary, but in some embodiments is about 550-700 μm, less than length L or width W. The length L and width W define the main plane of the nanochannel delivery device 500 . As shown in these figures, the body 501 has an inlet surface 502 on one side and an outlet surface 503 on the opposite side. The inlet surface 502 and outlet surface 503 are generally parallel to each other and to the main plane of the nanochannel delivery device 500 . Multiple inlet megachannels 545 can be seen in FIG. 8M (only one is shown in the figure). Figure 8N provides a partial cross-sectional perspective view of nanochannel delivery device 500 along line 8N-8N in Figure 8M. The section shown in FIG. 8N contains an inlet macrochannel 545 and a plurality of inlet microchannels 540 and outlet microchannels 580 . As shown in FIGS. 8L-8N , inlet microchannels 540 and outlet microchannels 580 are formed such that each inlet and outlet microchannel is perpendicular to the major plane of the nanochannel delivery device 500 (e.g., along a direction perpendicular to the major plane of the device). line to measure the length of the microchannel). In addition, the plurality of inlet microchannels 540 and outlet microchannels 580 form an overlapping array such that each inlet microchannel 580 is distributed between each outlet microchannel 580 and vice versa. Figure 8 is now described. As shown in the detailed view of FIG. 80 , each nanochannel 505 is in direct fluid communication with an inlet microchannel 540 and an outlet microchannel 580 .

Referring now to FIG. 8P , a detailed cutaway view of one section of nanochannel delivery device 500 is shown. In this view, three inlet nanochannels 540 can be seen, along with a pair of outlet microchannels 580 and a pair of nanochannels 505 . As shown, nanochannel 505 includes an inlet end 506 and an outlet end 507 . In this embodiment, a first linear axis 508 extends between inlet end 506 and inlet surface 502 . It can also be seen in FIG. 8P that the second linear axis 509 extends between the outlet end 507 and the outlet surface 503 .

Meanwhile, as shown in FIG. 8P , the inlet microchannel 540 includes a main axis 512 , and the outlet microchannel 580 includes a main axis 511 . As shown in this embodiment, major axis 511 and major axis 512 are perpendicular to plane 513 , which is parallel to substantially planar body 550 of nanochannel delivery device 500 . In Fig. 8P, only a portion of the substantially planar body is shown. A complete view of the substantially planar body 550 can be seen in Figures 8L and 8M.

Referring now to Figure 9, specific dimensions are provided for an exemplary embodiment of a nanochannel delivery device fabricated according to the protocol described above. It should be understood that these dimensions are illustrative only of the particular embodiment shown and that other embodiments may incorporate different dimensions.

Referring now to FIG. 10 , a partial cross-section of a nanochannel delivery device 500 showing a diffusion path 575 of molecules passing through the nanochannel delivery device 500 . It should be understood that the nanochannel delivery device 500 may be oriented in any direction during use. As shown in FIG. 10 , flow path 105 requires a maximum of two changes in direction between the point at which molecules enter nanochannel delivery device 500 and the point at which molecules exit nanochannel delivery device 500 . For example, molecules entering nanochannel delivery device 500 are initially located within inlet macrochannel 545 . The molecule then enters the inlet microchannel 540. In the illustrated embodiment, flow path 575 turns right at a 90 degree angle as the molecule enters nanochannel 505 in direct fluid communication with inlet microchannel 540 . After the molecule exits the nanochannel 505, the flow path changes again (this time a 90 degree turn to the left) as it enters the outlet microchannel 580, which is also in direct fluid communication with the nanochannel 505. Thus, as the molecule diffuses through the nanochannel delivery device 500, the flow path 575 requires a maximum of two changes in direction. Although a molecule can change orientation more than 2 times while it passes through the nanochannel delivery device 500, it only needs to change orientation 2 times.

Example - Protocol 1: Bonded capping layer

The following example is provided merely as an illustration of one non-limiting embodiment of a method of making a nanochannel delivery device according to Scheme 1 (described above). This example is for illustrative purposes only and is not intended to limit the scope of the invention described herein.

Processing starts with a double-sided polished 4" SOI wafer (available from Silicon Quest). The wafer contains the device layer, which is 30 μm thick, <100> oriented P-type, doped with boron, and has a 1-10 Ohm-cm Surface resistivity; 0.4 μm thick buried oxide layer; and handle layer, which is 500 μm thick, P-type, boron doped, and has 1-10 Ohm-cm surface resistivity. In fresh Piranha solution (3: 198% sulfuric acid: 30% hydrogen peroxide, more than 100 ℃) to clean the wafer for 10 minutes, and spin dry. Then thermally grow a 50nm pad oxide layer on its surface. Then by low pressure chemical vapor deposition (LPCVD ) deposit 100nm low stress nitride on this pad oxide layer. By standard photolithography process, using EVG 620 collimator, transfer the 5μm wide nanochannel structure from the photographic masking material to the silicon nitride layer. Remove the exposed by CF4RIE the nitride region.

After stripping the photoresist, the pad oxide was cleaned by soaking in a 1:10 HF aqueous solution. The wafer is then placed in a thermal oxide reactor to create a sacrificial oxide. The thickness of the sacrificial oxide determines the height of the nanochannel, ie the height of the nanochannel=0.46*oxide thickness. In this example, a 39nm oxide was produced for an 18nm nanochannel. Nitrides and oxides are then removed in dilute HF solution. A 3 μm layer of low temperature oxide (LTO) is then deposited on its surface by LPCVD. The backside of the wafer was then protected by 3 μm spin-on Futurrex negative photoresist. The front LTO is removed in a buffered oxide etch (BOE) solution and the wafer is cleaned in a piranha solution.

A 500 nm LTO film was deposited on the wafer using LPCVD. The 5 μm x 5 μm inlet microchannel structure was transferred to the LTO film on the device side of the wafer using a standard photolithography process on an EVG 620 aligner, and the LTO was etched using CF4RIE. The 200 μm x 200 μm entry macrochannel structure was then transferred to the backside of the wafer for RIE.

After cleaning away the photoresist, a deep silicon etch of the inlet microchannels was performed using an Oerlikon DSE etcher. The etch stops at the buried oxide layer. The wafer was flipped over and attached to the handle wafer with thermal grease (AI Technology). The 190µm x 190µm entry macrochannel was then etched on an Oerlikon DSE etcher, stopping at the oxide layer. Figure 11 shows the SEM image of the deeply etched 190 μm opening. The wafer is separated from the handle wafer and cleaned. The wafer was soaked in BOE for 5 minutes to open the buried oxide layer and spun dry. The masked LTO films on both sides of the wafer are then diced in aqueous HF.

A 500 μm thick double-sided polished 7740 glass wafer was anodically bonded to a silicon substrate as a cap for the nanochannels using an EVG 520 bonder. The anodic bonding was performed at 800 volts and 325C for 10 minutes. Figure 12 shows a view of the bonded wafers. The bonded wafer pair was attached to a wafer holder using wax, the glass was thinned to 30 μm using back grinding, and then CMP polished to a final thickness of 5-10 μm (Valley Design Corp).

Figure 13 shows a view of the front surface after polishing. Illumination shows that the nanochannels are open. A 5 μm x 5 μm outlet microchannel was formed by CF4/Ar RIE using the Ni film as a masking layer. To accomplish this, a copper seed layer is first deposited onto the glass surface. The 5 μm x 5 μm outlet microchannel structure was transferred onto the copper film using standard photolithographic processes on an EVG 620 etalon and wet etched. Ni was then electroplated onto the constructed copper film. Inlet microchannels were etched into the glass membrane using CF4/Ar RIE to reach the silicon surface. After stripping the masking layer, the wafer was cleaned and diced with a DAD321 Dicing Saw (Disco). The overall dimensions of the fabricated device were 6mmx6mm. A total of 161 openings of 190 μm x 190 μm are arranged in a 3.6 mm diameter ring. Each such opening was connected to a total of 501 5 μm x 5 μm inlet channels connected to nanochannels and outlet channels.

Example - Option 3: Integral fabricated cap layer

The following example is provided merely as an illustration of one non-limiting embodiment of a method of making a nanochannel delivery device according to Scheme 3 (described above). This example is for illustrative purposes only and is not intended to limit the scope of the invention described herein

The process started with a double-sided polished silicon-on-insulator (SOI) wafer, using a post-690 μm base wafer with a 30 μm thick top silicon layer and a 2 μm thick buried oxide. The wafer was cleaned with piranha solution (3: 198% sulfuric acid: 30% hydrogen peroxide, over 100°C) to remove organic and metal contamination. A smooth (typically <5 A rms), uniform (typically <2% non-uniformity) layer of tungsten metal was sputtered onto the wafer using physical vapor deposition (PVD) at a temperature of 100°C. The thickness of the tungsten layer is selected as the height of the nanochannel layer, eg 5 nm.

This nanochannel spacer layer is then covered by low-stress (380°C, appropriate stoichiometry) plasma-enhanced chemical vapor deposition (PECVD) silicon nitride ("SiN1") with a target thickness of 500nm and non-uniformity <2% . Then spray positive photoresist to a thickness of 2 μm. If desired, inlet microchannels are exposed in the photoresist, ranging in size from 1 μm to over 5 μm. Using this photoresist and tungsten, the silicon nitride used is etched using conventional C4F8 etch chemistry with appropriate plasma powders, other reactive and inert gases.

The etch in this method is timed to allow a depth to go completely through the tungsten layer, which takes several minutes. Another etch is performed, still using the photoresist as a mask, to pass through the silicon to a depth sufficient to access the buried oxide. A Bosch etch with 5dep/5 etch per cycle is used in this step because this etch automatically terminates at the buried oxide and is highly selective to the buried oxide. A slight overetch of 10-20% of the most critical structures is provided to compensate for the non-uniformity of the method. Oxygen plasma is then used to remove the remaining photoresist, and the wafer is further cleaned of polymer residue using appropriate wet chemistry. Fig. 14 shows an example of the apparatus in the processing at this stage.

The next module consists of filling or capping these inlet microchannels. This can be achieved by plugging the inlet with copper. A TiN barrier layer with a thickness of 300A was deposited by sputtering. A copper seed layer with a nominal thickness of about 4000 Å was deposited by PVD sputtering. Low current (2A, 1015 minutes) electroplating was used to fill or plug the inlet microchannels. Excess copper loading is then removed by polishing using a pad/slurry combination at appropriate pressure/velocity (2-4psi, 30-90rpm). In this same method, the TiN in the non-microchannel regions (fields) can also be completely removed. Finally, a short bake anneal at 150-250° C. for about 30 minutes to harden the inlet microchannel and clean the surface. Figure 15 shows a top view of the device after filling with copper.

A thin layer of silicon nitride ("SiN2") of about 50 nm was deposited by PECVD to cap the copper. The silicon nitride (SiN1 and SiN2) layers are then etched using a photolithographic process together with the tungsten nanochannel material, exposing the nanochannel lines (1.3 μm) in the photoresist, and etching tens of nanometers into the silicon.

A thicker tensile silicon nitride ("SiN3") is then deposited to a thickness of about 1-1.5 [mu]m. The tensile stress of this layer is chosen so that all dielectric buildup layers can be slightly stretched by about 20 MPa. The outlet microchannels are then exposed on the photoresist layer (nominal thickness 2 μm), and all the silicon nitride layers (SiN1, SiN2, SiN3) are further etched together with the W nanochannel layer so that the bottom of the outlet microchannels are at the bottom of the device. Silicon ends. The photoresist is stripped after this stage. Figure 16 shows a cross-section of the device at this stage of processing.

Apply a suitable protective layer to this surface - Ti/TiN (250/300A), Tungsten (5000A), then use phosphosilicate glass (PSG) with a thickness of 1 μm, which can be used as HF protector and surface Protective agent. The wafer was then flipped over and a thick photoresist (10 μm) was sprayed. Using the anterior alignment marks, expose the large channel on the dorsal side. The large channels were etched all the way through the wafer (about 700 μm) using the Bosch DRIE method. This process reaches the buried oxide, forming an effective etch stop. Figure 17 shows a cross-section of the device at this stage of processing. The buried oxide is then removed by plasma etching.

A series of wet etches are performed to remove all sacrificial material. A short buffered HF etch, eg 5 minutes, is performed to remove any residual oxide (in the buried oxide) and remove the PSG layer. The wafer was then wet etched in SC-1 solution (hot ammonium hydroxide-hydrogen peroxide mixture) for 10 minutes to remove the TiN barrier on the top surface and bottom of the inlet microchannel. The wafer was subjected to a piranha etch for about 20 minutes to remove copper in the inlet microchannels. All TiN was then removed from the sidewalls of the inlet microchannel by another SC-1 etch. Finally, the tungsten in the nanochannels was removed by placing the wafer in wafer hydrogen peroxide for 2 hours, followed by rinsing with DI water. The wafer was then rinsed with isopropanol (IPA), which replaced the water, and the wafer was allowed to dry.

material selection

Regardless of the protocol used to fabricate the nanochannel delivery device, the materials used in the fabrication process should be selected to successfully remove sacrificial material while preserving non-sacrificial material. As shown in Figure 18, the choice of nanochannel "site supports" (e.g., sacrificial materials used to fill the nanochannel space) and nanochannel "ceiling" and "floor" materials (e.g., substrate and cap layers) or etchant selection. Examples of suitable solvents and etchants that can be used to remove the sacrificial material while preserving the base and cap layers are shown in FIG. 18 . It should be understood that other combinations of materials may also be used.

post-wafer processing

In post-wafer processing, the individual wafers are taped to the belt ring. UV release tape is preferred because it is more adhesive. Since both surfaces of the wafer have critical device structures, UV tape is bonded to the top and bottom surfaces. The wafer is then diced into individual molds and cleaned. The wafer frame is then exposed to a UV light source to reduce the adhesion between the tape and the surface. Each cutout is picked individually using the automated pick and place picker and placed in an empty mold holder. The tape on the top surface of the mold was then removed by hand. The cuts were then placed separately in final wash containers, rinsed with acetone, and finally rinsed with IPA to facilitate channel drying. The mold is mated to the package bonding surface by epoxy or other fixing methods.

Encapsulation configuration

Referring now to Figures 19 and 20, the nanochannel delivery device 500 may form part of a larger assembly, eg, an enclosure 600 that may be used to administer a drug or other therapeutic agent to a human. FIG. 19 shows a detailed view of one end of enclosure 600 in a partially exploded view, while FIG. 20 shows an assembled view of enclosure 600 . It should be understood that in other embodiments, the nanochannel delivery device 500 may be used for other applications requiring precise control of the diffusion or transport of small quantities of any substance.

In the embodiment shown in FIGS. 19 and 20 , enclosure 600 comprises a generally cylindrical body 620 configured with an end portion 630 to receive first cap 610 and second cap 625 . In this embodiment, nanochannel delivery device 500 is mounted to a plane perpendicular to the major axis of enclosure 600 (eg, parallel to the long axis of cylinder 620 and concentric with cylinder 620). The end portion 630 also includes a recessed portion 640 configured to receive the nanochannel delivery device 500 . In some embodiments, glue or other adhesives may be used to secure the nanochannel delivery device 500 in the recessed portion 640 . When assembled, nanochannel delivery device 500 may be inserted into recessed portion 640 and first cap 610 may be mounted to end portion 630 .

During use, a drug (or any other substance that can be administered through the capsule 600 ) can be delivered from the cylinder 620 to the nanochannel delivery device via the inner volume 650 contained within the cylinder 620 . After diffusing through nanochannel delivery device 500 and into first cover 610 , the administered substance may exit cap 610 through outlet 615 . In an exemplary embodiment, the dimensions of outlet 615 (and other aspects of enclosure 600 , such as inner volume 650 and cap 610 ) are sufficiently large such that these features do not limit diffusion of the administered substance from enclosure 600 . As a result, the diffusion of the administered substance can be more precisely controlled by selecting the dimensions of the nanochannel delivery device 500 , and in particular the dimensions of the nanochannel 505 . Cap 610 can also provide dimensional precision and protect nanochannel delivery device 500 from mechanical damage and intrusion of post-implantation biological tissue structures.

In some embodiments, the inner volume 650 is configured to minimize trapping points for air bubbles. For example, inner volume 650 may contain radiused corners and (when enclosure 600 is installed) surfaces that are not angled in such a way that air bubbles can be trapped.

Referring now to FIGS. 21 and 22 , enclosure 700 is similar to enclosure 600 previously described. However, in this embodiment, the capsule 700 is fitted with a spacer 760 at the end of the cylindrical body 720 remote from the end portion 630 . The septum 760 comprises a self-sealing material (eg, silicone rubber) that allows injection of therapeutic agents into the inner volume 750 of the cylindrical body 720 . In some embodiments, the therapeutic agent may be injected with a hypodermic needle immediately prior to implantation of capsule 700 .

Referring now to FIG. 23 , enclosure 800 contains components equivalent to those of the previous embodiments. However, this embodiment includes a cap 825 covering the septum 860 . Cap 825 may contain a port (not visible in the perspective view of FIG. 21 ) configured for guiding a needle or other means for penetrating through septum 860 and injecting a therapeutic agent into the inner volume of cylinder 820 850 in.

Referring now to FIG. 24 , a capsule 900 comprises a cylindrical body 922 mated to a separate tip assembly 935 and cap 925 . In this embodiment, cylinder 922 may be replaced with another cylinder having a different length to vary the internal volume of capsule 900 (and the amount of therapeutic agent that capsule 900 may contain). Similar to the previous embodiments, tip assembly 935 includes tip portion 930 configured to receive cap 910 . Tip assembly 935 also includes a recessed portion 940 configured to receive nanochannel delivery device 500 .

Referring now to FIGS. 25 and 26 , the enclosure 1000 comprises a disc-shaped body 1020 with a cap 1010 containing a series of outlets 1015 . In this embodiment, the disc-shaped body 1020 contains a septum 1060 through which the therapeutic agent can be injected. As shown in the partially exploded view of FIG. 26 , support 1050 may be used to hold nanochannel delivery device 500 near outlet 1015 . In this way, the therapeutic agent contained within the capsule 1000 is forced through the nanochannel delivery device 500 just before exiting the capsule 1000 .

In the embodiment shown in FIGS. 27 and 28 , the enclosure 1100 includes a rectangular planar surface 1121 and an arcuate surface 1120 . Enclosure 1100 also includes a closed end 1125 and a septum 1160 that can be inserted into open end 1161 . In the illustrated embodiment, the spacer 1160 covers the entire open end 1161 . In other embodiments, the spacer can cover the open end of the section and the cap can cover the remaining section. Similar to the previous embodiments, septum 1160 is self-sealing and can be pierced with a needle to insert a therapeutic agent. Enclosure 1100 also includes a first recessed portion 1140 configured to receive nanochannel delivery device 500 and a second recessed portion 1130 configured to receive cap 1110 containing outlet 1115 . Orifice 1135 extends through recessed portion 1140 into inner volume 1150 bounded by rectangular planar surface 1121 , arcuate surface 1120 , closed end 1125 and septum 1160 . In this embodiment, a therapeutic agent can be contained within inner volume 1150 and dispensed through orifice 1135 , nanochannel delivery device 500 and outlet 1115 .

Referring now to FIG. 29, another embodiment of enclosure 1200 is generally equivalent to enclosure 1100, but includes features to house two nanochannel delivery devices (not labeled). In this embodiment, enclosure 1200 includes a rectangular planar surface 1221 , an arcuate surface 1220 , a closed end 1225 and a spacer 1260 . Capsule 1200 also includes a pair of first recessed portions 1240 each configured to receive a nanochannel delivery device (not labeled) and a second pair of recessed portions 1230 each configured to accept a cap having an outlet (not labeled). Each recessed portion 1240 includes an orifice 1235 to allow fluid communication between the inner volume 1250 and the environment surrounding the enclosure 1200 .

In some embodiments, inner volume 1250 comprises separate inner reservoirs, wherein each reservoir is in fluid communication with orifice 1235 . The inner reservoir may be separated by an inner wall within the aperture 1235 . In these embodiments, each reservoir can be filled with a different therapeutic agent. Each nanochannel device can be configured to provide preferred doses of various therapeutic agents.

Referring now to FIG. 30 , another embodiment of a capsule 1300 is shown in an installed position such that it extends partially below the epidermal surface 1301 of a patient into which the capsule 1300 has been inserted. Enclosure 1300 includes a plurality of covers 1310 with outlets 1315 . Beneath each cap 1310, the nanochannel delivery device is inserted onto an orifice in fluid communication with the inner volume of the enclosure 1300 (similar to the embodiment described with respect to Figures 27-29). The inner volume of enclosure 1300 can be divided into different compartments so that each nanochannel delivery device can be used to administer specific and different therapeutic agents. The enclosure 1300 also includes an anchor member 1305 configured to serve as a point at which sutures (not labeled) attach to the enclosure 1300 when the enclosure 1300 is installed. The anchor member 1305 may also be connected to a string or other means (not shown) for removing or retrieving the capsule 1300 .

Referring now to FIG. 31 , another embodiment of an enclosure 1400 is shown. The capsule is a minimal cover on the back and sides of the nanochannel device to define the "reservoir" for containing the drug as the volume of the large channel on the back of the chip (e.g., nanochannel delivery device), shown in Figure 8K In embodiments said volume is about 4.5 mm ³ . This embodiment can be made extremely small, eg 2mm x 2mm x 0.5mm, and is therefore particularly suitable for implanting very effective drugs in sensitive locations, such as glaucoma drugs inside the eye.

Exemplary embodiments of the capsule described above may be sized such that the capsule can be implanted subcutaneously. In specific embodiments, the diameter of the capsule may be 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3 , 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8 , 4.9, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0, 11.0, 12.0, 13.0, 14.0, 15.0, 16.0, 17.0, 18.0, 19.0 or 20.0mm. In other embodiments, the capsule may have a diameter greater than 20.0 mm.

In some embodiments, the thickness of the capsule can be 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7., 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4 , 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0mm. In other embodiments, the thickness of the capsule may be greater than 10.0 mm.

In specific embodiments, the width of the enclosure may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 , 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44 , 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69 , 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94 , 95, 96, 97, 98, 99, 100mm. In other embodiments, the width of the enclosure may be greater than 100 mm.

In specific embodiments, the length of the capsule can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 , 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44 , 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69 , 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94 , 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119 , 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144 , 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169 , 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194 , 195, 196, 197, 198, 199 or 200mm. In other embodiments, the length of the enclosure may be greater than 200mm.

It should be noted that various embodiments of the enclosure described herein comprise a cross-section that is nominally invariant along the length of the enclosure. This optional configuration can facilitate sliding removal from the surgical site in the body without damaging surrounding tissue.

In an exemplary embodiment, the capsule may comprise suitable materials such as stainless steel, titanium, polyether ether ketone, polysulfone, and other plastics and metals. In some embodiments, the capsule may comprise a coating on the inside to provide an optimal environment for the therapeutic substance; and/or a coating on the outside to prevent unwanted tissue encapsulation. In particular embodiments, the capsule may contain a color code to indicate the form or particular properties of the capsule (eg, therapeutic agent, rate of drug administration, capacity of the capsule, etc.). In some embodiments, the capsule may contain a translucent or transparent portion or component (eg, a cap) to facilitate viewing the amount of therapeutic agent contained within the capsule. For example, a translucent or transparent cap covering the nanochannel delivery device may allow a person to confirm that it is full by orienting the capsule such that the nanochannel delivery device is facing towards the top of the capsule. A needle (or other loading device) can then pass through the septum and the therapeutic agent can be injected into the capsule. When fluid appears at the top of the nanochannel delivery device (as viewed through the cap), the person filling the capsule is notified that the capsule is full.

In an exemplary embodiment, the capsule may be used to administer one or more of the following: adrenocorticosteroids; adrenocortical inhibitors; aldosterone; alkylating agents; antagonists; amino acids; anabolic agents; Analgesic; Narcotic; Anorexogenic; Antiacne; Antiepinephrine; Antiallergic; Antialopecia; ; Anti-asthma agent; Anti-atherosclerotic agent; Antibacterial agent; Antibiotic; Anticancer agent; Anticholinergic agent; Anticoagulant agent; Anticonvulsant agent; Antidepressant agent; Antidyskinesia agent; antiemetic agent; antiepileptic agent; antifibrinolytic agent; antifungal agent; hemostatic agent; antihistamine agent; antihypercalcemic agent, antihyperlipidemic agent; antihypertensive agent Triglyceridemia agent; antihypertensive agent; antiinfective agent; antiinflammatory agent; antiischemic agent; antimicrobial agent; antimigraine agent; antimitotic agent; antimycotic agent; antinausea agent; antineoplastic agent; Antineutropenic Agent; Antiobesity Agent; Antiosteoporotic Agent, Antiparasitic Agent; Antiproliferative Agent; Antipsychotic Agent; Antiretroviral Agent; Antiresorptives; Antirheumatic Agent; Antiseborrheic Agent; Suppressant Secretory Agent; Antispasmodic Agent; Antiscorbutic Agent; Antithrombotic Agent; Antineoplastic Agent; Antiulcer Agent; Antiviral Agent; Anorectic Agent; Bisphosphonate; Blood Glucose Regulator; Bronchodilator; Cardiovascular Agent; Central nervous system drugs; contraceptives; cholinergic drugs; concentration aids; sedatives; diagnostic aids; diuretics; DNA-containing drugs, dopamine agents; estrogen receptor agonists; fertility agents; plasmin; fluorescent agents ; Oxygen free radical scavenger; Gastric acid inhibitor; Gastrointestinal motility effect agent; Glucocorticoid; Glutamatergic agent; Hair growth stimulator; Hemostatic agent; Histamine H2 receptor antagonist; Hormone; Cholesterol-lowering agent; Hypoglycemia agent; hypolipidemic agent; hypotensive agent; imaging agent; immune agent; immunomodulator; immunostimulator; Pupil Agent; Nasal Decongestant; Neuromuscular Blocking Agent; Neuroprotective Agent; NMDA Antagonist; Nonhormonal Steroid Derivative; Nootropic Agent; Parasympathomimetic Agent; Plasminogen Activator; Platelet Activating Factor Antagonist ; platelet aggregation inhibitors; platinum-containing agents, psychotropic agents; radioactive reagents; raf antagonists, RNA-containing agents, scabicides; sclerosing agents; sedatives; sedative-hypnotics; selective adenosine Al antagonists; selective estrogens Receptor Modulator, Serotonin Antagonist; Serotonin Inhibitor; Serotonin Receptor Antagonist; Steroid, Stimulant; Thrombin Agent; Thyroid Hormone; Thyroid Inhibitor; Thyromimetic Drug; Sedative; Vasoconstrictor agent; vasodilator; wound healing agent; xanthine oxidase inhibitor, etc.; abacavir, abacavir sulfate, abacavir, acarbose, paracetamol, acyclovir, adalimumab , adapalene, alendronic acid, alendronate sodium, alfuzosin, aliskiren, allopurinol, alvimopan, an Risentan, aminocaproic acid, amitriptyline hydrochloride, amlodipine, amlodipine besylate, amoxicillin, amoxicilline, amphetamine, anastrozole, aripiprazole, amofenib , Atazanavir, Atenolol, Atomoxetine, Atorvastatin Calcium, Atorvastatin, Atropine Sulfate, Azelastine, Azithromycin, Balsalazide, Benazepril, Bendamole Hydrochloride Stine, Benzepril Hydrochloride, Bevacizumab, Bicalutamide, Bimatoprost, Bisoprolol, Bisoprolol Fumarate, Bosentan, Botulinum Toxin, Budesonide, Buformin, Buproxil Norphine, bupropion, bupropion hydrobromide, bupropion hydrochloride, cabergoline, calcipotriol, calcitriol, candesartan cilexetil, capecitabine, captopril carbidopa, carisoprodol, carvedilol, caspofungin, cefdinir, cefoperazone, cefotiam, cefprozil, cefuroxime, celecoxib, cephalexin, cerizumab, cetirizine, cetrizine hydrochloride, cetuximab, chlorpromazine hydrochloride, chlorpheniramine maleate, ciclesonide, cilastatin, cimetidine , Calcimimetic Drugs, Ciprofloxacin, Citalopram Hydrobromide, Clarithromycin, Clindamycin, Clindamycin, Clindamycin Hydrochloride, Clomipramine Hydrochloride, Clonidine Hydrochloride, Clopix Gray, clopidogrel bisulfate, clopidogrel sodium, amoxicillin clavulanate potassium mixture, codeine phosphate, colchicine, colesevelam, cyclobenzaprine hydrochloride, cyclophosphamide, cyclosporine, erythropoietin alfa, darfenacin, DCRM 197 protein, desloratadine, desloratadine, desmopressin sulfate, desloratasone, dexamethasone, diclofenac, diethylcarbamate citrate, Difluprednate, diphenhydramine, dipyridamole, DL-methionine, docetaxel, donepezil, doripenem, dorzolamide, doxazosin, doxazosin mesylate, doxycydine, drospirenone , duloxetine, dutasteride, eculizumab, efavirenz, emtricitabine, enalapril, enalapril maleate, enoxaparin sodium, eprosartan, Rotinib, erythromycin, hematopoietin, escitalopram, esomeprazole, estradiol, estrogen, eszopiclone, etanercept, Ethembutol hydrochloride, ethosuximide , ethinyl estradiol, etonogestrel, etoricoxib, etravirine, exenatide, ezetimibe, ezetimibe, factor VII, famotidine, famotidine , fenofibrate, fenofibrate, fentanyl, fentanyl citrate, ferrous sulfate, fexofenadine, fexofenadine hydrochloride, filgrastim, finasteride, fluconate oxazole, fluoxetine hydrochloride, fluticasone, fluvastatin, folic acid, follicle-stimulating hormone alpha, follicle-stimulating hormone beta, formoterol, fosinopril sodium, gabapentin, gabapentin, gemcitabine, insulin glargine, glatiramer, glimepiride, Goserelin, histrelin acetate, human growth hormone, hydralazine hydrochloride, hydrocodone, hydroxyurea, hydroxyzine hydrochloride, ibandronate, imatinib, imiglucerase , imipenem, imiquimod, indinavir sulfate, infliximab, interferon beta-1a, ipratropium , irbesartan, irinotecan, isoniazid, isosorbide moninitrate, ixabepilone, ketamine, ketoconazole, ketorolac, lactobionic acid, lamivudine, lamivudine, lamivudine Triazine, Lanreotide Acetate, Lansoprazole, Lapatinib, Laropiran, Latanoprost, Letrozole, Leuprolide Acetate, Levosalbutamol, Levamisole Hydrochloride, Levetiracetam , levocetirizine dihydrochloride, levodopa, levofloxacin, levonorgestrel, levothyroxine, levothyroxine sodium, lidocaine, linezolid, dexamphetamine dimesylate, lisinopril , rapid-acting insulin, lopinavir, loratadine, lorazepam, losartan potassium, maraviroc, dronabinol, meclizine hydrochloride, meloxicam, memantine, meropenem , metaxalone, metformin, metformin hydrochloride, methadone, methoxypolyethylene glycol erythropoietin beta, methylphenidate, methylphenidate hydrochloride, metoprolol, metoprolol tartrate, metronidazole, formazan Nitazole, miglitol, minocycline, minocycline hydrochloride, mirtazepine, modafinil, mometasone, montelukast, montelukast sodium, morphine, moxifloxacin, mycophenolate mofetil , Naloxone, Naloxone Sodium, Natalizumab, Neostigmine Bromide, Niacin, Niacinamide, Nifedipine, Nifurtimox, Nilotinib Hydrochloride Monohydrate, Nitrofurantoin, Dexime Hydrochloride Parmin, Nystatin, Olanzapine, Olanzepine, Olmesartan, Olmesartan Medoxomil, Olopatadine Hydrochloride, Omalizumab, Omeprazole, Ondansetron , Orlistat, Oseltamivir, Oxaliplatin, Oxcarbazepine, Oxybytynin chloride, Oxycodone Hydrochloride, Paclitaxel, Palivizumab, Pantoprazole, Paracetamol, Paroxetine, Paroxetine Hydrochloride, Peginterferon alfa-2a, pemetrexed, penicillamine, penicillin V potassium, phenformin, phenytoin, pioglitazone, piperacillin, potassium chloride, pramipexole, pravastatin, pravastatin Statin Sodium, Prednisolone, Quetiapine Fumarate, Pregabalin, Primaquine Phosphate, Progesterone, Promethazine, Promethazine Hydrochloride, Proponolol Hydrochloride, Propoxyphene Hydrochloride, Pseudoephedrine, Pseudoephedrine Hydrochloride, Bromine Pyridostigmine, vitamin B6 hydrochloride, quetiapine, quetiapine fumarate, quinapril hydrochloride, rabeprazole, raloxifene, raltegravir, ramipril, ranitidine , ranitidine hydrochloride, recombinant factor VIII, retapamulin, rimonabant, risedronate, risedronate sodium, risperidone, ritonavir, rituximab, rivans rivastigmine tartrate, rizatriptan, ropinirole, rosiglitazone, rosiglitazone maleate, rosuvastatin, rotavirus vaccine, rotigotine, albuterol, sulfate albuterol, salmeterol, sapropterin dihydrochloride, sertraline, sertraline hydrochloride, sevelamer, sevoflurane, sildenafil, sildenafil citrate, simvastatin, simvastatin , Sitagliptin, Sodium Valproate, Solifenacin, Somatostatin, Somatotropin, Stavudine, Sulfomethoxazole, Sumatriptan, Suma Succinate Protan, tacrolimus, tadalafil, tamoxifen citrate, tamsulosin, tamsulosin hydrochloride, tegaserod, telmisartan, temazepam, temozolomide, tamsulosin Division, tenofovir, terazosin hydrochloride, terbinafine, teriparatide, testosterone, tetracycline hydrochloride, thalidomide, thymopentin, timolol maleate, tiotropium bromide, Tipranavir, tolterodine, tolterodine tartrate, topiramate, topotecan, tramadol, tramadol hydrochloride, trastuzumab, trazodone hydrochloride, trimethoprim, valacyclo Wei, valaciclovir hydrochloride, valproate semi-sodium, valsartan, vancomycin, vardenafil, varenicline, venlafaxine, venlafaxine hydrochloride, verapamil hydrochloride, vitamin Gliptin, voglibose, voriconazole, acetylsalicylate sodium, warfarin sodium, zaleplon, zidovudine, ziprasidone, zoledronate, zolpidem, or its pharmaceutically Acceptable salts; 16-alpha fluoroestradiol, 17-alpha dihydroequilenone, 17-alpha estradiol, 17-beta estradiol, 17-hydroxyprogesterone, 1-dodecapyrrolidone, 22 - Oxalcitriol, 3-isobutyl-gamma butyric acid, 6-fluoroursodeoxycholic acid, 7-methoxytacrine, abacavir, abacavir sulfate, abamectin , abanoquine, abatacept, abacal, abiraterone, arusast, arusast sodium, acaldesine, acamprosate, acarbose, acebutolol, hydrochloride Acetanilide, aceclofenae, acetaminophen, acetaminophen, aluminum acetylglutamine, acemannan, acetaminophen, acetazolamide, hexylurea acetate, acetohydroxamic acid, acetomepregenol, acetyl maleate Perphenazine, Dapsone Sodium, Acetylcholine Chloride, Acetylcysteine, Acetyl-L-Carnitine, Acemethadol, Acyclovir, Acifuran, Acipimox, Acixitinib Esters, acithate, acevectin, arubicin, escalactin, naphthalene disulfonate, alcodazole hydrochloride, aconiazid, acridinium, arvastatin, ac Ronine, axoamide, atodigin, acyclovir, acylfulvene, adaserin hydrochloride, adamantyl, adalimumab, adapalene, adaserin, adecypenol, adecypenol, adecypenol Fovir, Ademitra, Adenosylmethionine, Vidarabine, Aldizolam, Adipheinine Hydrochloride, Adiposin, Adorexine, Atrafenib, Epinephrine, Aiclometasone Dipropionate, Airbutamine, Alapril , alemycin, alanine, alapropyl ester, alaptide, albendazole, albuterol, albuterol, Alclofenae, alcloxa, aldecalmycin, aldesleukin, aluminum allantoin, allylbenzene hydrochloride Ethylamine, Alendronate, Alendronate Sodium, Alendronate, Alendimox, Alendimox Hydrochloride, Alcuronium Chloride, Alexidine, Alpha-calciferol, Alpha-Bone Alcohol, alfuzosin, alconide, alglucosidase, aleflurane, alinastine, acemethadol, alipamide, aliskiren, allantoin, dipenylbarbe sure, Allopurinol, Alomidone, Alosetron, Alosetron Hydrochloride, Alovudine, Alpentine, α-idosone, Alpitant, Alprazolam, Propranolol Hydrochloride, Arpratine Hydrochloride Nuoxin, Alprostadil, Alastatin Sodium, Altanserin Tartrate, Alteplase, Althiazine, Hexamethylmelamine, Atomycin B, Alverinc Citrate, Alvimopan, Avesu Torto, amadene acetate, amantadine hydrochloride, amamustine, ambermycin, ambrisentan, ambrucin, ambuphylline, ambucet, amceval, amcinonide, nitrogen Zhuocillin, azedacillin ester, ammetadine hydrochloride, alomethasone, acetrol, anergide, amethraquinone acetate, methylthioametrimonium, bupropion, amfenac sodium, amflutezole, Amicycline, Amidephrine Mesylate, Amidox, Amfloxacin, Amifostine, Amilcacin, Amiloride Hydrochloride, Amidephrine Hydrochloride, Potassium Aminobenzoate, Sodium Aminobenzoate, Aminocaproic Acid, Aminoglutamine Special, sodium aminohippurate, aminolevulinic acid, aminophylline, amirex, sodium aminosalicylate, aminosalicylic acid, amiodarone, ampritose hydrochloride, amiquinine hydrochloride, amisulpride , amitraz, amitriptyline hydrochloride, amlexanol, amlodipine, amlodipine mesylate, amobarbital sodium, amodiaquine, amodiaquine hydrochloride, amorolfine, Amoxapine, amoxicillin, chloral, amphetamine, amphetamine sulfate, amphomycin, amphoterin B, ampicillin, ampiroxieam, methcarbazine sulfate, aminoquinate, amrinone, amrubicin , amsacridine, amylase, amylin, amythiamicin, anargesterone acetate, anagrelide, anakinra, ananain, anaritide, anaritide acetate, anastrozole, anazol Lin Sodium, Ancrolase, Andrographolide, Androstenedione, Angiotensinamide, Anidoxil, Anilidine, Anilopam Hydrochloride, Aniracetam, Aniroic Acid, Mebroxine Tropine, Anistreplase, Anordrinase, Anordrin, Antagonist D, Antagonist G, Anrelix, Antazoline Phosphate, Demectin, Anthralin, Antramycin , antiandrogen, antiestrogens, antineoplastic, antipyrine, antisense oligonucleotides, apadoline, apapan, apacillin sodium, apafylline, azapropanol, glycine Aphidicolin, Apixifylline, Apomorphine Hydrochloride, Apexifylline, Apexifylline Hydrochloride, Apex, Aplindine, Aplindine Hydrochloride, Apixifylline Sodium, Aprotinin, Aplotin Maleate Azapine, altiganel, purine acid, purine acid, areredipine, alanotine, abatoprost, arbekicin, arbidol, abuthamine hydrochloride, alclobenine, adeparin sodium, arga Troban, Arginine, Arginopressin Tannin, Alerone, Aripiprazole, Amorfenib, Arololol, Arpinocid, Atifrin, Attilide Fumarate, Aci Madolin, aspalatone, asparaginase, aspartate, aspartate, asperfuran, aspirin, apoxicillin, Asprel in, astemizole, asemicin sulfate, asulacrine, atamestane, atazanavir, aceteolol, ateviridine, atipamezole, atiprozine maleate, atorilide , atomoxetine, atorvastatin, atorvastatin calcium, atosiban, atovaquone, atpenin B, atracurium besylate, amomustine, atroinositol, atropine, sulfate Atropine, Auranofin, Aureobasidin A, Aurothioglucose, Avelamycin, Avopacin, Avridine, Axi, Axinastatin 1, Axinastatin 2, Axinastatin 3, Azaaniline, Azacitidinie, Hydrochloride Nichlorzine, Azaconazole, Azadirachtine, Azalanstat Dihydrochloride, Azaxan Fumarate, Azanatop Maleate, Azanidazole, Azapirone, Azalipine, Heavy Azaacetylserine, Azasetron, Azatadine Maleate, Azathioprine, Azathioprine Sodium, Azathioprine, Diazotyrosine, Azelaic Acid, Azelastine, Azedipine, Nitrogen Zopindole, Azathepa, Azimilide, Azithromycin, Azlocillin, Azolimine, Azosemide, Azomycin, Aztreonam, Azumolin Sodium, Bamcillin Hydrochloride, BacatineⅢ , bacitracin, baclofen, bacoside A, bacoside B, bactobolamine, balanol, balazipone, balhimycin, baloxacin, balsalazide, bambemycin, ban Buterol, balmexan sulfate, bamiphylline hydrochloride, banidazole, baohuoside 1, palmastine, barnidipine, bismuth subsalicylate, brazifenging, batapride hydrochloride, babus Special, Baterapine Maleate, Baimastat, Beauveria, Methioxanthone Hydrochloride, Becaplermin, Beconazole, Befloxatonate, Beinserazide, Belfodil, belladonna, belomide, bimisetron, bemitridine, bemostatan, benalizine hydrochloride, benazepril, benazepril hydrochloride, benazeprilat, Bendalolol plus sulfonate, bendamustine hydrochloride, bendaxacid, bendrofluthiazide, benzefantrine, benidipine, benotestosterone, benzoxaprofen, phenoxaprofen, orbuxa hydrochloride Caine, Benoperidol, Bentazepam, Bentyramide, Beninostat, Benzbromarone, Benzepril Hydrochloride, Benzethonium Chloride, Bentilimide Hydrochloride, Benzallodinium Bromide, Benzydryl Hydrochloride Lin, benzisoxazole, benzocaine, benzoridine, benzotamine hydrochloride, benzotepa, benzoidazoxan, benzonatate, benzoyl peroxide, benzoylstaurosporine, benzquilamine, benzthiazine , benztropine, benztropine mesylate, benzydamine hydrochloride, penicillium thiazolyl polylysine benzoate, bepridil, bepridil hydrochloride, belaquentan, beraprost, berapodil Reeveline, prafilnon, bertoxamil, deoxyerythromycin, besipirdine, beta alethine, beta clamycin B, betamethasone, betamipron, betaxolol, betaxolol hydrochloride , Choline chloride, Bethanidine sulfate, Betulinic acid, bevacizumab, bevanolol, bevanolol hydrochloride, bezafibrate, bilamicol hydrochloride, biapenem, bicalutamide, bicifadine hydrochloride, diclodine hydrochloride Er, bidesolamide, diphenylmeran, bifonazole, bicarin, bimatoprost, bimithil, bindali, binimycin, bispirone, bioxalomycin, bipenasol hydrochloride, bispirulina Periden, benzalamide hydrochloride, biriperone, bisantrene, bisaremide, bisaziridinylspermine, bisabenzimidazole A, bisabenzimidazole B, dinaphrad, bisopridine lactate, bisoprolol , bisoprolol fumarate, magnesium pyrithione sulfate, bistramide D, bistramide K, bistratene A, bisdichlorophenate sodium, nortestosterone undecylenate, diethrenol, bomanatene, Bopinolol, bosentan, botulinum toxin, boxidine, brefeldin, breflate, buquina sodium, brotacicil, bromobenzylamine tosylate, bufentanil hydrochloride, Brimonidine, Fibrozyme, Brocrisin, Bromoclina, Bromoxazinone, Brodoline Maleate, Bromazepam, Bromocloxazolone, Bromelain, Bromfenac, Brominidione, Bromocriptine , bromophenanolamine hydrochloride, bromosanide, bromoperidol, bromoperidol decanoate, brompheniramine maleate, bromopimole, brompirimine, bromotezolam, bucainide maleate , Buxinolol, Bucrizine Hydrochloride, Buxorone, Budesonide, Budipin, Budotitanium, Dingformin, Bumetanide, Bunalast, Bunazosin, Bunorolol Hydrochloride, Bupicomide, Bupivacaine Hydrochloride, Buprenorphine, Buprenorphine Hydrochloride, Bupropion, Bupropion Hydrobromide, Bupropion Hydrochloride, Brabamate, Buserel Acetate Lin, buspirone hydrochloride, busulfan, sec-butabarbital, butacetin, butalamole hydrochloride, butalbital, butamben, butamidate citrate, butaprazine , butaprost, butidronic acid tetrasodium, butenafine, butirizine, buthioninc sulfoximine, butificacin, butphenine, butirocin sulfate, butixirer, buthioninc sulfoximine Kete, Conazole Nitrate, Butoxate, Butopamine, Butopridine Hydrochloride, Butorphanol, Butoxamine Hydrochloride, Buttiline Hydrochloride, Cabergoline, Actinomycin C, Cardiac Dim, iodine, caffeine, pachycarp extract A, calcidiol, calcipotriol, calcipotriol, calcitonin, calcitriol, calcium undecylenate, calcphosphoprotein C, Captestosterone, Canbendazole, CammonamSodium, Camogrel, Canarypox IL-2, Candesartan, Candesartan Medoxil, Candesartan, Cansatra, Cansatralat, Caniglibose, canrenoate potassium, canrenone, capecitabine, crocoronate sodium, crocoronate, capreomycin sulfate, caloxumab, capsaicin, captopril, caprolactone, carbomethazine Tan, carbamide, carbachol, carbadox, carbamazepine, urea hydrogen peroxide, chlorphenamine lauryl sulfate, carbapirin calcium, carbazoline, carbazomycin C, carboxylate Benzyl Penicillin potassium, sodium carbenate, carbetim, carbetocin, carbidopa, carbidopa, levodopa, carbinoxamine maleate, carbifen hydrochloride, carbochloral, Carbolic Acid, Magenta, Carboplatin, Carpreg, Carbopol, Carboxamide-Amino-Triazole, Carboxyaminotriazole, Carboxymethyl Beta-1,3-Glucan, Carbuterol Hydrochloride, CaRest M3, Carfentanil Citrate, Carisoprodol, Carmanganate, Carmustine, CARN 700, Carnidazole, Caroxadone, Capecritide, Propionylphenazine Maleate, Carprofen, Caxatran succinate, catazolate [, carteolol, carteolol hydrochloride, carrubicin hydrochloride, carvedilol, cabotraline, cabotraline hydrochloride, cabozolexin, Caspofungin, castanospermine, caurumonam, cebasitam, antimicrobial peptide B, cedifenagore, cefaclor, cefadroxil, cefamandole, cefparole, ceftriaxone, cefazolin sodium, Cefazolin, cefcapene pivoxil, cefotaxime tosylate, cefdinir, cefditoren pivoxil, cefepime, cefetamet, cefetecol, cefixime, cephrenam, cefmexime hydrochloride oxime, cefmetazole, cefminox, cefodizime, cefoperazone sodium, cefoperazone, cefoperazone sodium, cefereide, cefotaxime, cefotaxime sodium, cefotetan, cefotiam, cefoxitin, Ceftizolam, Cefamizole, Cefpiramide, Cefpirome, Cefpodoxime Proxetil, Cefprozil, Cefoxadine, Cefsulodin, Ceftazidime, Cefditoren, Ceftibuten, Ceftizoxime Sodium, Ceftriaxooe, Cefuroxime Xin, tripterine, celecoxib, celikalim, celiprolol, cepacidiineA, cefacetonitrile sodium, cephalexin, cephalosporin, cefotaxime, cefalotin sodium, cefapirin sodium, cephradine, cevanchloramine , cerivastatin, bombesin, cilopril, cerizumab, certoparin sodium, cetaben sodium, cetaxel ammonium chloride, cetalol hydrochloride, cethuperazone, cetidil, Cetirizine, Acetomycin, Cetraxate Hydrochloride, Cetirizine Hydrochloride, Cetrorelix, Cetuximab, Cetylpyridinium Chloride, Chenodeoxycholic Acid, Chlorpheniridine Hydrochloride Alcohol, chloral betaine, chlorambucil, chloramphenicol, chlorhydantoin, chlordiazepoxide, chlorhexidine gluconate, chlorin, chlormadinone acetate, chloroorienticin A, chloroproca hydrochloride Chloroquine, Chloropropamide, Chloroquine, Chloroquinoxalinesulfonamide, Chlorothiazide, Chloroestradiol, Chloroquine, Chloroxylenol, Chlorpheniramine Maleate, Chlorpheniramine Maleate, Chlorpheniramine Maleate, Chlorpheniramine Promethazine, chlorpromazine hydrochloride, chlorpropamide, chlorprothixene, chlortetracycline sulfate, chlorthalidone, chlorzoxazone, cholestyramine resin, carbomer hydrochloride, sibenzoline, west Carboprost, cyclaphrine hydrochloride, phenazimindole, ciclesonide, ciclobutanine, ciclopirox, cycloprofen, ciprorolol, cidofovir, cidoxepin hydrochloride, Oxazoline, ciglitazone, ceradopa hydrochloride, cilansetron, Cilastatin, cilastatin sodium, cilazapril, cilnidipine, cilopramine mesylate, ciloridine, cilofungin, cilostazol, cimaterol, sime Tidine, citropium bromide, calcium mimetic drugs, cinalast, cinnaserin hydrochloride, cinnaphate maleate, cinnaflunamide, engestrol, cinapride, cinapride, cinnamon Lizine, cinoxepam, cinoxacin, cinoperine, cinnamonium bromide, simpentazone, octyremide, ceorone, cipantylline, ciprofadol succinate, cyprotonide , ciprofibrate, ciprofloxacin, ciprostene, cilamadol, siromycin, cisplatin, cisapride, besylate cis atracurium, ciconazole, cis porphyrin, citrate Kexin, citalopram, citalopram hydrobromide, cetamide, citicoline, citreamicin α, cladribine, ketamine hydrochloride, clarithromycin, citamide, potassium clavulanate, Clarazolam, clobendazolamide, clobopride, clemastine, clentiazem maleate, criclidinium bromide, clinfloxacin, clindamycin, clindamycin hydrochloride, clioquinol, cliodine Shani, Criprofen, Clobazam, Clobetasol Propionate, Clobetasol Butyrate, Clocotorone Acetate, Llordanolline, Chlordadone Hydrochloride, Clodronic Acid, Clofazimine, Clomiphene, Chlorfeinium Phosphate, Chlorprogesterone Acetate, Chlormacolen Phosphate, Chlormegestone Acetate, Chlormedrol, Chlormethiazole, Clomiphene Analogues, Clomiphene, Clomiphene, Hydrochloric Acid Clomipramine, Clonazepam, Clonidine, Clonidine Hydrochloride, Clonidine Hydrochloride, Cloniseril, Clonixin, Cloperamide, Clopenthixol, Clopiquantone Hydrochloride, Clopidogrel, Sulfate Clopidogrel Hydrochloride, Clopimozil, Cloperazine Mesylate, Clopyrac, Cloprednisol, Cloprostenol Sodium, Dipotassium Chlordiazepine, Chlorxolone, Cloperacine Hydrochloride Long, clopronaline hydrochloride, closulon, chlorteramine hydrochloride, closantamide, chlorxilamine acetylglycine, clothiapine, chlorthioxanthane maleate, chlorthiocasone propionate, clotrimazole , benzathine o-cloxacillin, o-cloxacillin sodium, clozapine, clozapine, amoxicillin clavulanate potassium mixture, cocaine, coccidiostatin, codeine, codeine phosphate, codoxine, autumn Narcissin, Colesevelam, Polymer of 2-Methylimidazole and 1-Chloro-2,3-Cyclopropane, Colestipol Hydrochloride, Colestone, Corfusin, Cofocillin Palmitate, Slime Mold Sodium mesylate, colistin sulfate, collismycin A, collismycin B, corterol mesylate, combretastatin A4, complestatin, conagenin, Conorphone hydrochloride, coteterol, contortrostatin, comethasone acetate, corbrestatin Lin Ovine Tnflutate, corticotropin, cortisone, cortisazole acetate, cortisone, cosalane, costatolide, synthetic corticosteroids, cotinine, coumadin, coumadin, crambescidin, kava Statin, Clinato, Clominitrile Sodium, Cromoglycate Sodium, Clotamiton, Cryptophycin, Cucumariosid, Pistocolistin Copper, curacin A, curdlan sulfate, curiosin, cyclopenicillin, cyclazocine, cyclazosin, aminocarbazole, celilaramine maleate, cyclizine, cyclobendazole, cyclobenzaprine, hydrochloric acid Cyclobenzaprine, cyclobut A, cyclobut G, cyclocapron, pamoate, cycloheximide, cycloheximide, cyclopentanthraquinones, cyclopentathiazine, cyclopentolate hydrochloride, cyprophenazine hydrochloride, cyclophosphamide, cycloplatam, cyclopropane, cycloserine, cyclosin, cyclosporine, cyclothialidine, cyclothiazine, cyclothiazomycin, cycloheptamide, cypemycin, Cyponamine hydrochloride, ciproazepam, cyproheptadine hydrochloride, cipropridol hydrochloride, cyprotera Ketone, cipromide, cysteamine, cysteine hydrochloride, cystine, cytarabine, cytarabine hydrochloride, cytarabine ocfosfate, cytochalasin B, hexestrol phosphate, da Carbazine, dalcimab, datimicin, dactinomycin, daidzein, daredarine besylate, dalfopristin, dalteparin sodium, daltroban, dalvastatin, danaparin , danazol, dantrolene, daphlnodorin A, dapiprazole, dapitant, dapoxetine hydrochloride, dapsone, daptomycin, erythropoietin alpha, dapaglitazone sodium, darfina New, darlucin A, darrodipine, darcydomin, daunorubicin hydrochloride, dazolol maleate, azazenil hydrochloride, damegrel, dazopride fumarate, daazopride hydrochloride , DCRM197 protein, isoquine sulfate, decitabine, deferiprone, deflazacort, deoxycholic acid, dehydrodidemnin B, dehydroepiandrosterone, delapril, delapril hydrochloride, mesylate Delavirdine, delequamin, difapiperazine, demagestrol acetate, delmopinol, delphinium aglycone, demethonium bromide, demeclocycline, norcycline, demethonium Zepam, dinomycin, deoxypyridinoline, divalproex sodium, deprorone, deprostil, depsidomycin, derencyclane, dermatan sulfate, deciclovir, desinonide, desflurane Ether, desipramine hydrochloride, desirudine, deacetyl lanatoside, desloratadine, deslorelin, desmopressin, desmopressin sulfate, desogestrel, desonide , deoxymethasone, desoxoamiodarone, deoxycorticosterone acetate, detajmium tartrate, detelenol hydrochloride, detiderelide acetate, devazepi, dexamethasone, dexamizole, dexchlorpheniramine maleate, Dexchlorpheniramine maleate, ciproquil hydrochloride, dexbentimide, dexfenfluramine hydrochloride, dexifosfamide, benbimidazole, dexketoprofen, dexcloglutamine, medetomidine, Dexomaplatin, Dexoxadryl Hydrochloride, Dexpanthenol, Dexpemetic Acid, Dexpropranolol Hydrochloride, Dexrazoxane, Dexsotalol, Dextrin 2-sulfate, Dexamphetamine, Dextromethorphan, Dextrorphan hydrochloride, right Sodium thyroxine, dexverapamil, dezaguanine, diazinamine, dezocine, diacetolol hydrochloride, cyclamate, closulfonamide, diatrizoate, pan Acid, Dihydroveratridine, Diazepam, Diacrine, Diazoxide, Dibenzepine Hydrochloride, Dibenzothiophene, Dibucaine, Dichliorvos, Chloralpyrine, Dichlorosulfonamide, Disirenone , diclofenac, diclofenac sodium, diclofenac, dicranin, dicoumarol, dicyclomine hydrochloride, didanosine, daidaining B, didox, diethylstilbestrol, dienogest, diethylcarbamate citrate, Diethylhomospermine, diethylnorspermine, diethylhomospermine hydrochloride, diethylstilbestrol, fenphenamide hydrochloride, difenoxine, diflurasone diacetate, difloxacin hydrochloride, difluanine hydrochloride, diflucolone, diflumidone sodium, Diflunisal, difluprednate, defutadone, digitalis, digitoxin, digoxin, dihevirine hydrochloride, D1 receptor agonist, dihydro-5-azacytidine, bis Hydrogen Tartaric Acid, Dihydroergotamine Mesylate, Dihydroestosterone, Dihydrostreptomycin Sulfate, Dihydrotachysterol, Phenytoin Sodium, Delerolol Hydrochloride, Diltiazem Hydrochloride, Dimethfadden, Dimephrine Hydrochloride, Halo Haining, dimercaprol, dimethyldiketone, dimethylindene maleate, demethynone, dimethyl sulfoxide, dimethylhomospermine, dimethylhomospermine, aluminum dimethyl prostaglandin, dilatin racetam, dimoxamine hydrochloride, dinoprost, dinoprostone, dioxadril hydrochloride, dioxamycin, diphenhydramine, diphenhydramine citrate, difenidol, diphenoxylate hydrochloride, diphenylspiromustine, hydrochloric acid Dipiephrine, Dipiephrine, Dipliencyprone, Dipropanone, Dipropylnorspermine, Dipyridamole, Dipyrithione, Metamizol, Dirithromycin, Discodermolide, Desobutamide, Dexofenine, Disopyramide , Dioxalide, Disulfiram, Ditigiren, Divalproex Sodium Sodium, Dizocipine Maleate, DL-Methionine, Dobutamine, Docarbamine, Doxylquinone, Multi Cetaxel, Doconazole, Docosanol, Dofetilide, Dolasetron, Donepezil, Donipenem, Dorzolamide, Doxazosin, Doxazosin Mesylate, Doxycydine, Droxetine spirone, duloxetine, dutasteride, ebastine, ibiratide, ebrotidine, ebselen, ecampide, ecabet, ecatril, ecdisteron, echicetin , Saw scale (viper) blood inhibitor (cyclic) peptide, iodocolate, echloranamine maleate, etzolast, ecomustine, econazole, echinidin 722, eculizumab anti, edaravone, edatrexate, edifoxine, edifrolone acetate, ebalizumab, eduridine, edrecolumab, edrofenonium chloride, edroxyprogesteone acetate, efavirenz , Ifika Qun, eflornithine, efodipine, egualcen, ylang-ylang, eleatonin, elemene, eletriptan, ergodipine, elirodi, elsamitrucin, eltenae, elocaine, emailcalim , Emedastine, Emetine Hydrochloride, Egglitamate, Emilium Tosylate, Etifluridine, Emoteukin, Emtricitabine, Enadoline Hydrochloride, Enailciren, Enalapril, Malay Enalapril Acid, Enazatran, Encycloproxate, Endralizine Mesylate, Medexone, Enflurane, Emglitazone, Enconazole, Eniprost, Emmotumab, Enloplatin, Enolast, Enoxaparin Sodium, Enoxacin, Enoxaparin Sodium, Enoxaparin Sodium, Enoxaparin Sodium, Enoxaparin Sodium, Enoxaparin, Empiroline Phosphate, Enprofylline, Enprobamate, Entacapone, Enterostatin, Enviraden, Enviroxime, Ephedrine, Epicillin, Epimestral, Epinephrine, Epinephryl Borate, Epiperidine, Ipirazole, Epi Doxorubicin, tetracycline hydrochloride, epithiazine, erythropoietin alpha, erythropoietin beta, epoprostenol, epoprostenol sodium, epoxymexrenone, apretide, eprosartan, esprostone Desmin, dehydroequilenone, equilin, erbrozole, erdosteine, ergot mesylate, ergonovine maleate, ergotamine tartrate, erlotinib, axoril Tetra, ersofumin, erythritol, erythritol tetranitrate, erythromycin, hematopoietic hormone, escitalopram, esmolol hydrochloride, esomeprazole, essol hydrochloride Bixing, Ethioproquine Hydrochloride, Suloazepam, Estradiol, Estramustine, Estradiol Hydrobromide, Estriol, Estfurate, Estrogen, Estrone, Piperazine Estrone Thioester , Esulpron, Eszopiclone, Efedirine Hydrochloride, Etanercept, Etalonidazole, Etantrole, Etalotine, Etazolate Hydrochloride, Etrabital, Ethalox Xylazine, Sodium Diureticate, Diuretic Acid, Ethambutol Hydrochloride, Vanilla Diethylamine, Ethanolamine Oleic Acid, Ethehlorvynol, Ethembutol Hydrochloride, Ethinyl Estradiol, Ethiodol, Ethionamide, Etonam Nitrate, Proper Hydrochloride Phenylamine, Ethosuximide, Ethosuximide, Ethphenytoin, Ethoxydiazobenzene Hydrochloride, Ethyltropine, Ethyl Chloride, Ethyl Dibutate, Ethrenol, Ethyndiol, Noreth Ketone, Ethinyl Estradiol, Diacetinol, Ebendazole, Eticaine, Etidronate Disodium, Etidronic Acid, Etifinine, Etintidine Hydrochloride, Etizolam , Etodolac, Etofenamate, Etoformin Hydrochloride, Etomidate, Etonogestrel, Etoperone Hydrochloride, Etoposide, Pyrimidine, Etoricoxib, Ethyloxidine Hydrochloride, Etoposide Azoline, etribamine, etravirine, etretinate, ethyl tryptamine acetate, eucatropine hydrochloride, eugenol, euproxin hydrochloride, eveminomicin, examexime, exarelin, hexamethylene hydrochloride Proprolol, exemestane, exenatide, ezetimibe, ezetimibe, factor VII, fadrozole, faeriefungin, famciclovir, famotidine, fampril Pyridine, pantophalon, pantrexone hydrochloride, faropenem, facidotril, fasudil, fazarabine, fedotozine, felbamate, felbamate, felbinac, felodipine , phenylenepressin, finaratamide, phenamox, fenbendazole, fenbufen, fensibutol, fenclonic acid, fenclonine, benzoic acid, fentosal, feminestrazine Acid, Amphetamine Ethylline Hydrochloride, Fenfluramine Hydrochloride, Phenogabine, Phenimeth, Phenerex, Chlorfenoxazole Hydrochloride, Phenymorphone, Fenorban, Phenoxetamine Sulfate, Fenofibrate, fenoldopam, fenoprofen, fenoterol, fenoxadione, phenirast hydrochloride, fenprostaline, fenquinazole, fenretinide, fenspiride, Fentanyl, fentanyl citrate, fentic acid, fenticrol, fenticonazole, phenidinol hydrochloride, fepridol, ferpifosate sodium, ferristene, ferrixan, ferrous sulfate, superparamagnetic Iron oxide, superparamagnetic iron oxide, tetraphenoxy hydrochloride, fexofenadine, fexofenadine hydrochloride, fezolamine fumarate, fecitabine, fealuridine, fibmoxef, fibrin Raw, filgrastim, felipin, finasteride, fiorfenicol, fiorifenine, fiosatidil, fiumecinol, flunarizine, fiuparoxan, fiupirtine, fiurithromycin, fiutrimazole, fiuvastatin, fiuvoxamine, flavonedilol maleate, flavopiridol, Flavoxate HCl, Frazadone, Flecainide, Fludintrol, Fleroxacin, Fluoxinoxan, Fluxolol Sulfate, Fluethazepam, Fludlastine, Flobufen, Flofenine, Fludipine , flusquinam, flucloxacillin, fluoxuridine, fluasterone, fluzacot, flubarvinate hydrochloride, flubendazole, fluocindole, fluocindole, fluconazole, flucytosine, fluoride Deuterium alanine, fludarabine phosphate, clofluridazole, fluoro[18F]deoxyglucose, fludorex, fludrocortisone acetate, flufenamic acid, flufensal, flumazenil, Flumequine, flumeridone, flumetasone, flumemorphone, flumetazapine, fluramine, flumidazole, flumonide, flunidazole, flunisolide, flunitrazepam, flu Nisin, fluorocalcitriol, fluocinolone acetone, fluocinolone acetate, flucobutinate, fluocorolone, fluorescein, fluorodaunorunicin hydrochloride, fluorodopa, fluorometholone, uracil, flutraxine hydrochloride, fluoxetine, fluoxetine hydrochloride Cetine, Fluoxymesterone, Haloperidolamine, Fluperolone Acetate, Fluphenazine Decanoate, Fluprednisolone, Fluproquinezone, Fluprostenol Sodium, Fluoquinone, Fludoline Hydrochloride, Fluoxetine Susone, fluazepam hydrochloride, flurbiprofen, fluretofen, flucitabine, flufamide, fluprogesterone acetate, trifluoroethyl ether, fluorovinyl ether, flusperone, fluspirin, Fluticasone, Fluticasone Propionate, Flutraline, Fluvastatin, Fluvastatin Sodium, Fluazemide, Folic Acid, Follicle Regulatory Protein, Follitropin, Ovum Stimulator Follicle hormone alpha, follicle stimulating hormone beta, fomepizole, dimethylazine mesylate, folasartan, forfenex, forfenirmex, formestane, formocta, formoterol, phospholipids , fosazepam, foscarnet sodium, fosfomycin, fosinocetate sodium, fosinopril, fosinopril sodium, fosinoprilat, fosphenytoin, fosquinone, forsdil, fostrixin, formol Stine, magenta, furamoxicillin, mycomycin, furaprofen, furazolidone, furazolium chloride, furogranate sodium, furobufen, furodazole, furosemide, fusidate sodium , Fusidic acid, Gabapentin, Gadobetic acid dimeglumine, Gadoberic acid, Gadobutrol, Gadodiamide, Gadolinium texaphyrin, Magnevist solution Dimegiumine, Gadoteric acid, Gadoteridol, Gadoverselamide, Gaga Lantamine, gadansetron, gadansetron hydrochloride, golarium iodide, gallium nitrate, golopamil, galocitabine, ganirexin, gamocenic acid, ganciclovir, ganirel Gram, tetramethyldecanediol, gemcitabine, gemeprost, gemfibrozil, gentamicin sulfate, gentian violet, gepirone, progesterone, gestodene, progesterone caproate, pregnant three Enone, Gevotriline Hydrochloride, Gilisopam, Insulin Glargine, Glacimod, Glacimer, Glaucocalyxin A, Glycerin, Glitaminamide, Glibouride, Grittanide Sodium, Glycerin Liflunomide, glimepiride, glipizide, glumonam, glucagon, glutapyrone, glutimide, glyburide, glycopine, glycopril, glycopyrrolate, glibenclamide, glyburide Propyrimidine Sodium, Glipizide, Glypamide, Gold Au-198, Gonadoctrinins, Gonadorelin, Gonadotropins, Goserelin, Gramicidin, Granisetron, Gepafloxacin, Sallow Guaiphenix, Guaiphenidine, Guaiphenylline, Guanabenz, Guanabenzyl Acetate, Guanadil Sulfate, Guanidine, Guanethidine Monosulfate, Guanfacine Hydrochloride, Guanidine Sulfate, Guanidine Sulfate Chlorophen, guanoxetine hydrochloride, guanoxabenz, guanidine sulfate, guanoxifene sulfate, guarilimus trihydrochloride, halazepam, halcinonide, halichondrin B, Halobetasol propionate, chlorfluphene Alcohol, chlorfluphenhydramine hydrochloride, lipid-lowering amide, bromoclopiperquinone hydrobromide, halomon, haloperamide, haloperidol, haloprednisone, haloprogesterone, haloprogesterone, halothane, Halo Quinole, harmycin, hatomamicin, hatomarubigin A, hatomarubigin B, hatomarubigin C, hatomarubigin D, heparin sodium, hepsulfam, nerve growth factor, hetacillin, Heterooium Bromide, hexachlorophene: hydrogen peroxide, hexafluorene bromide , Methylenediacetamide, Hexidine, Hexobendine, Hexonaline Sulfate, Hexoracin, Histamine Phosphate, Histidine, Histoplasmin, Histrelin, Acetic Acid Group Amrelin, homatropine hydrobromide, xanthanine hydrochloride, human chorionic gonadotropin, human growth hormone Hydroxyzine, Hynone, Hydralazine Hydrochloride, Hyalalazine Polistirex, Hydrochlorothiazide, Hydrogen Tartaric Acid, Hydrocortisone, Hydrofluorothiazide, Hydromorphone Hydrochloride, Hydroxyamphetamine Hydrobromide, Hydroxychloroquine Sulfate, Ovenbamate , Hydroxycaproic acid, Hydroxyurea, Hydroxydroxyhydrochloride, Hydroxymethylcoumarol, Hyoscyamine, Hypericin, Ibafloxacin, Sodium Ibandronate, Ibogaine, Ibopam, Ibudilast, Ibudilast Fenac, ibuprofen, ibutilide fumarate, icatibant acetate, ichthyol, ectedine, daunorubicin, edoxifene, herpesnet, idemonone, idoxifene Fitroban, Ifosfamide, Ilepeimide, Illimaquinone, Imofosine, Ilomastat, Ilodap, Iloperidone, Iloprost, Bendimidazole HCl, Imatinib, HCl Imazodane, imidapril, imidazenil, imidazoacridone, midodec iodine, midocaine hydrochloride, midoline hydrochloride, midazolide, imiglucerase, miloxan hydrochloride, imipenem, imipramine hydrochloride , Imiquimod, Impramidine Hydrochloride, Indalidone, Indapamide, Indicarnide Hydrochloride, Indolozine Hydrochloride, Indigo Carmine Sodium, Indinavir, Indinavir Sulfate, Indole Cyanine green, indopril hydrochloride, indolidan, indomethacin, indomethacin sodium, indoprofen, indolamin, indoresate hydrochloride, indoxol, indroline hydrochloride, indomethacin Liximab, Inotetron, Enogatran, Izolimumab, Inositol Niacinate, Insulin, Interferon beta-1A, Intetrazole, Intratriptyline Hydrochloride, Iodobenzguanidine, Iodine benzoic acid, iodoxerol, iodine, iodomiloride, iodorubicin, ioprazol, iomeprol, iopentol, iopromide, iopyrol, ioxate, ioxilam, empalide, ipromide Sazone, ipidacline, amiodoprofen calcium, sweet potato bitter alcohol, ipratropium, ipratropium bromide, ipriflavone, iprindole, cumfen, ipronidazole, Isoproplatin, iproxamine hydrochloride, ixabepilone, irbesartan, irinotecan, ilofloxacin, iropla, irsogladine, itimazole, irbesartan, bis Buoxazole, ipogrel, isopamicin, isobengazole, isobutamben, isocarboxazid, isoconazole, ethyl isoproterenol, isofloxythepin, isoflurane acetate, isoflurane, isoflurane Phosphorus, isohomohalicondrin B, isoleucine, isomazole hydrochloride, isopentamine hydrochloride, isoniazid, isopropylamine iodine, isopropanol, isopropyl unoprostone, isoproterenol hydrochloride, isosorbide Alcohol, Isosorbide Mononitrate, Exoquinamide, Isotretinoin, Isoket Acid, Ixoxicam, Isoxalin Hydrochloride, Isradipine, Itameline, Itasetron, Ita Gray, itopride, itraconazole, ivermectin, ixabepilone, jasplakinolide, Jemefloxacin, Jesopitron, josamycin, kahalalide F, carafungin, kanamycin sulfate, ketamine, Ketaserin, Ketozocin, Ketazolam, B Oxybutanol, oximipramine fumarate, ketoconazole, ketoprofen, ketomorphol, ketorolac, ketotifen fumarate, kitamycin, labetalol hydrochloride, lacis Dipine, lacidipine, lactitol, lativexin, lactobionic acid, larenec, lafutidine, l-alpha hydroxyvitamin D2, lamellarin-N triacetate, lamifibant, lamiv Lamotrigine, lanoconazole, digoxin, lanpirisone, lanreotide, lanreotide acetate, lansoprazole, lapatinib, laropiran, latanoprost, lateritin , laurocapram, lauryl isoquinoline bromide, lavotidine succinate, lazabemide, lesifibrate, leinamycin, lemidipine, leminprazole, lenercept, leni Quincin, legrastim, lenpirone, lentinan sulfate, leptin, leptolstatin, lercanidipine, ergonitrile, lerisetron, letimide hydrochloride, letrazuril, letrozole, leptide Leuprolide, leucomyzin, leuprolide, leuprolide acetate, leuprolide, levalbuterol, levamphetamine succinate, levamisole, levodobutamine lactobionate, Leveromakalim, levetiracetam, Leveycloserine , Levobetaxolol, Levobunolol, Levobupivacaine, Levocabastine, Levocarnitine, Levocetirizine, Levocetirizine Dihydrochloride, Levodopa, Levohydroxyproline Piperazine, Levofloxacin, Levofuraltazone, Calcium Levofolinate, Levoacetylmethadone Acetate, Levoacetylmethadone Acetate, Levomoprol, Levofloxacin Hydrochloride, Levoisonephrine, Levonorgestrel , Levopropoxyphene, Lepraxicillin Potassium, Levomeroxifene, Levorphanol Tartrate, Levosimendan, Levosulpiride, Levothyroxine, Levothyroxine Sodium, Levothyroxine Hydrochloride, Lexipavan , erythromycin, riazol, lisbenpril, lidamidine hydrochloride, lidocaine, lidobenine, lidoflurazine, Lifarizin, libet, rifeberol, linarotene, linco Linoxetine, linezolid, linoxetrol, linopridine, linoxtroban, lincidomine, lintitript, lintopride, liothyronine I-125, iothyronine sodium , compound thyroxine, lisapride, dexamfetamine dimesylate, lisinopril, insulin lispro, lissoclinamide, risazinone sulfate, lobaplatin, clobenzalide sodium, lobucavir, locarmate glucose Amine, locarmic Acid, lodamide, chlordraphenyl, lodipamide meglumine, lodixanol, lodoantipyrine I-131, lodocholesterol I-131, lodohippurate Sodium I-131, lodopyracet I-125, lodoquinol, lodoxamate meglumine, lodoxamide, lodoxamie Acid, lofemidazole hydrochloride, lofentanil oxalate, lofepa hydrochloride Ming, lofetamine hydrochloride I-123, lofexidine hydrochloride, logl icicAcid, loglucol, loglucomide, loglycamic Acid, logulamide, lohexol, earthworm lecithin, lomefloxacin, lomerizine, lomethinI-125, lometraline hydrochloride, Lometrexol, lomonomycin, Lomoxicam, lomustine, lonapalene, clonazolic acid, lonidamine, ioramic acid, lopanoic acid, loperamide hydrochloride, lophendylate, lopina Wei, loprocemic Acid, lopronic Acid, lopydol, lopydone, loracarbef, lorazamine hydrochloride, loratadine, lorazepam, lobamate, locanide hydrochloride, clorizole, Loreinadol, chlorpentamide Lormezepam, Lornoxicam, Lornoxicam, Chlortalamine, Clozafene, Losartan, Losartan Potassium, Losefamic Acid, Loseric Acid, Chlorxigadone, Losoxanthraquinone, losulamide meglumine, lothiazine hydrochloride, losumetic Acid, lotasul, loteprednol, lotetric acid, lothalamate sodium, lothalamic Acid, lotrolan, lotroxic Acid, lovastatin, ioversol, loviramide, loxagiate Sodium, loxaglate Meglumine, loxaglic Acid, loxapine, loxoribine, loxotrizoic Acid, lubeluzole, Lucanthone Hydrochloride, Ruferonib, Lurosetron Mesylate, Letotecan, Lutetium, Acetic Acid Luterelin, 2-phenyl-N-acetyltryptamine, sodium apoate, hexylamine, lydemycin, lydicomycin, linegestrel, lysinopressin, lysine, lysofylline , lysostaphin, maduramycin, sulfamelon, magganin 2 amide, magnesium salicylate, magnesium sulfate, magnolol, maytansin, polymalein, mallotoaponin, sycamore chromene, horse Lotilate, malotirate, mangafodipir, manidipine, maniwamycin A, mannitol, mannostatin A, chiromycin E, chiromycin F, mapestine, maprotiline, maraviroc , marimastat, dronabinol, masorol, maspin, massetolide, maytansine, mazapertine succinate, mazindol, mebendazole, mebeverine hydrochloride, mebrofenine, mebutamine Esters, mecamylamine hydrochloride, nitrogen mustard hydrochloride, meclozine hydrochloride, meclocycline, meclofenac sodium, mecloquinone, meclofenac dibutyrate, medazepam hydrochloride, medolinone, Drogesterone, Methalol, Medroxyprogesterone, Medrison, Meclizine Hydrochloride, Mefenamic Acid, Mebendil, Mefenex Hydrochloride, Mefesamide, Mefloquine Hydrochloride, Mefox Citrate, Megamycin Potassium Dihydrogen Phosphate, Megestrol Acetate, Meglumine, Meglutol, Methylestradiol Acetate, Meloxicam, Melphalan, Memantine, Memotine Hydrochloride , Mecanitan Hydrochloride, Menomoctone, Menolil, Tocopherol, Mephenidine Sulfate, Mepatrexine, Mepentate Ammonium Bromide, Pethidine Hydrochloride, Mephentermine Sulfate, Mephen Toin, methylphenidate, mepivacaine hydrochloride, Anning tablets, meptafol hydrochloride, mequintox, sodium mercurin, merbarone, mercaptopurine, chlorophenol mercury, hydroxy-(2-hydroxypropyl)mercury , meropenem, mesalamine, mexirazone, mesoridazine, mesterolone, mestranol, mesulamine hydrochloride, metavolol hydrochloride, orcinalene complex, metaraminol tartrate, metasalate Methadol, metformin, metformin, methacholine, oxytetracycline, methadone, acemethadol, methathiazine, methamphetamine hydrochloride, metformin, acemethazole, Meclizine, urotropine, primobolan acetate, methenolone, methicillin sodium, methimazole, methioninase, methionine, metintizox, mepenthixol hydrochloride, methocarbamol , Methorbital Sodium, Methoxyphene, Methotrexate, Levapromazine, Methoxatone, Methoxypolyethylene Glycol-Erythropoietin Beta, Methoxyflurane, Mesuximide, Meclothiazine Methazine, Methyl Pamolate, Nimethatropine, Methylbenzethonium Chloride, Methyldopa, Methyldopa Hydrochloride, Methylene Blue, Methylergonovine Maleate, Methylhistamine, Methylsarcosinophosphate Glycosides, Methylphenidate, Methylprednisolone, Methyltestosterone, MethynodiolDiacelate, Methysergide, Methysergide Maleate, Methimide, Methiopine, Metiprine, Metipamide, Metyrolol, Metezoline hydrochloride, mecfamide acetate, metoclopramide, iodomethicone, 16,16-dimethanolone, metolazone, metoperazine, chlorpheniramine, metoprolone Metoprolol, Metoprolol Tartrate, Metouizine, Metrifosate, Meglumine, Metrizoate Sodium, Metronidazole, Metopipa, Metyrapone, Metyrosine, Mexiletine Hydrochloride, Pregnancy Potassium methyl propionate, mezlocillin, mianserin hydrochloride, miberadil hydrochloride, miberadil dihydrochloride, mibordone, michellamine B, dacryline, microcolin A, midaflu, midazol hydrochloride mifepristone, midodrine, mifepristone, mifolate, miglitol, miracetamide, miramerine, meldonium, mirenpirone, miliperine, milnacipran, milrinone , Miltefosine, Mimoben Hydrochloride, Minapruline, Minasolone, Minoromi, Minocycline, Minocycline, Minoxidil Hydrochloride, Mefluroxyl Hydrochloride, Mikamycin Su, mipraglucoside, mifentanil, miristim, milinmycin hydrochloride, mirisetron maleate, mirtazapine, misonidazole, misoprostol, milimidamide, rice Tokesin, Mitosin, Mitoclean, Mitoguanidine Hydrazone, Dibromodulcitol, Mitomacin, Mitomycin, Mitonaphthamide, Mitospex, Mitotane, Mito Anthraquinone, Mivacurium, Mivazerol, Mixanpril, Mixidine, Mizolastine, Mizoribine, Moclobemide , Modafinil, Modarine Sulfate, Modicainide, Moexipril, Mofarotine, Mofegiline Hydrochloride, Mobendazole Acid, Molastim, Molinazone, Molindone Hydrochloride , morphomine, furoic acid, monapiril maleate, monensin, caprylic and capric glycerin mixture, montelukast, montelukast sodium, montirelin, mopipe Dagol, morcizine, morantel tartrate, morcizine, maniflumate, morphine, sodium morrhate, mosapamine, mosapride, motilide, motretinide, latamoxef disodium, moxazocine, moxifloxacin, moxiprine, manidazole, moxonidine, mumps skin test antigen, mozolomide, mycaperoxide B, mycophenolate mofetil, mycophenolic acid, myriaporone , Cannabinol, Nabilone, Cannabis Hydrochloride, Cannabigram Hydrochloride, Nabumetone, N-acetyldinaline, Nadide, Nafloxacin, Nadolol, Nadroparin Calcium, Nafadotri, Nabumetone Sestat, Nafarelin, Nafcillin Sodium, Naftopin, Namidone Hydrochloride, Nafecort, Naphthyramine Malate, Nafaxidine Hydrochloride, Nafuramide Oxalate, Naftifine Hydrochloride, natopidil, nateglitavana, nagrestip, nalbuphine hydrochloride, Nalidixate Sodium, nalidixic acid, nalmefene, nalmedone hydrochloride, naloxone, naltrexone, nalmoret, norphenidate Long, nanquidol hydrochloride, napatadine hydrochloride, naphthalene disulfonate, nepamizole hydrochloride, napaviin, naphazoline hydrochloride, naphterpin, naproxen, naproxen sodium, naproxol, nexagatran , Narapranor Hydrochloride, Methylsalinomycin, Naratriptan, Natograstim, Nasaprase, Natalizumab, Natamycin, Nateplase, Nagolide Hydrochloride, Nebivolol Niramycin, nedaplatin, nedocromil, nefazodone hydrochloride, nefluzide hydrochloride, nefopam hydrochloride, nelezaline maleate, nemazoline hydrochloride, nemorubicin Star, Neomycin Palmitate, Neostigmine Bromide, Neridronic Acid, Netilmicin Sulfate, Neutramycin, Nevirapin, Necilidine Hydrochloride, Niacin, Nibroxan, Nicardipine Hydrochloride, Ergoline, Niclosamide, Nicorandil, Nicotinamide, Nicotinic Alcohol, Nifedipine, Nifirmerone, Nifluridine, Nifuridine, Nifuridilzone, Nifuratel, Nifurone, Nifedipine Furadazil, Nifuramide, Nifurpirazole, Nifurquiazole, Nifurthiazole, Nifurtimox, Nilotinib, Nilotinib Hydrochloride Monohydrate, Nilutamide, Nivadipine, Nimazon, nimodipine, nipertidine, niravorine, niridazole, nisamycin, nisterol mesylate, nisin, nisolbamate, nisoldipine, nisoxetin, nisamycin Sterling Acetate, Nifeterine, Nitrazoxanide, Nitecapone, Nifurate Hydrochloride, Nitramine Hydrochloride, Nitramidazole Hydrochloride, Nitrazepam, Nitrendipine, Nitrocydine, Nitrate, Nitrofurantoin , nitrofurazone, nitroglycerin, nitrocresol, nitromet, nitromephene citrate, nitrous oxide, nitrous oxide antioxidant, nit Rullyn, Nivacol, Dimetridone Sodium, Nizatidine, Norperastine, Thibamate, Noramycin, Norilium Bromide, Nomifensine Maleate, Nordazole Hydrochloride Methadol, Diethinorone, Norepinephrine Tartrate, Norethindrone, Norethindrone, Norfiurane, Norfloxacin, Norgestimate, Norgestimate, Norgestrel, Nortriptyline Hydrochloride, Nascodine, Nylestriol, Novobiocin, Nystatin, Bisphosphonate, Ocaperidone, Oxiprone Hydrochloride, Oxipron, Caprylic Acid, Otamide, Octenidine Hydrochloride, Otodrine , octreotide, octiline phosphate, ofloxacin, orfunine, okicenone, Olanzepine, olmesartan, olmesartan medoxomil, olopatadine, olopatadine hydrochloride, oxaprinone, olsalazine, Olsalazine sodium, olvanib, omalizumab, omega-3 acid ethyl ester, omeprazole, onapristone, ondansetron, onzolastil, opipramol hydrochloride for oocytes , oracin, occonazole nitrate, ogulin, Orlislat, omaplatin, omeprene, ornidazole, opanosine, orphenadrine citrate, oxatron, oseltamivir, orten toss Pa , oxacillin sodium, oxyglycerate, oxaliplatin, oxacoumarin hydrochloride, oxamisolate, oxaniquine, oxandrolone, octyl pamoate, hydroxyprotriptyline hydrochloride , oxaprozin, oxabazole, oxamide, oxaunomycin, oxazepam, oxcarbazepine, oxantrolone, ethoxyrazine, oxetolone fumarate, oxfendazole, hydroxy Phenylglycine, Obendazole, Oxiconazole, Hydroxydopamine, Oxyfronate, Oxyfungin Hydrochloride, Oxyphane, Oximonan, Oximonan Sodium, Opimidone, Oxiracetam, Oxylamil, Oxysulam, Ometidine Hydrochloride, Oxordipine, Oxorgestrel Phenylpropionate, Oxolinic Acid, Oxyprenolol Hydrochloride, Cholephylline, Oxybutynin Chloride, Oxyclosan, Oxycodone, Oxycodone Hydrochloride, Oxymetazoline Hydrochloride, Oxymetholone, Oxymorphone Hydrochloride, Oxypertine, Oxybuzone, Allopurinediol, Oxytetracycline, Oxytocin, ozagrel, Ozlinone, paclitaxel, palauamine, padenomycin, palinavir, palivizumab, palmitoylrhizoxin, sodium pamolate, pamaside, pamalol sulfate, pamigrel, Pamidronate Disodium, Pamidronate, Panaprolon, Panamesin, Panaxatriol, Pancorpride, Pancuronium Bromide, Panipenem, Pannorin, Panomiphene, Panthion Ethylamine, pantoprazole, papaverine hydrochloride, parabactin, paracetamol, p-chlorophen, paraldehyde, paramethasone acetate, renitoline hydrochloride, bromoparapentate, parafuran pamoate, Pabendazole, paconazole hydrochloride, compound camphor tincture, paritide sulfate, pagiline hydrochloride, parheparin sodium, paromomycin sulfate, paroxetine, paroxetine hydrochloride, parthenolide, patroxacin, Paulomycin, Paziptin, Paziclon, Pazoxide, Pazufloxacin, Pefloxacin, Pegaspargase, Pegotine, Pegylated Interferon α-2a, Pegylated Hydrochloride Lanserin, Peidesing, Peliomy cipelretin, pelinone hydrochloride, pemetrexed acid, pemelide nitrate, pemetrexed, pemirolast, pemoline, penacillin, penburol sulfate, penciclovir, penfluridol, Penicillamine, Benzathine Penicillin G, Penicillin G Potassium, Procaine Penicillin G, Penicillin G Sodium, Penicillin VHydrabamine, Benzathine Penicillin V, Penicillin V Potassium, Pentacarbamide, Pentaerythritol Tetranitrate, Pentafucicil , Pentamidine, Pentomorphone, Neostigmine Bromide, Methionium, Pentazocine, Triamine Pentaacetic Acid, Penthiapine Maleate, Pentegitide, Pentilmicin, Amylamine Zazolone sodium, pentobarbital, pentolone, pentopril, pentosan, pentostatin, pentoxifylline, pentonitrol, pentrozole, pelomycin sulfate, pepstatin, whole Halobromide, perfofamide, perfosfamide, pergolide, perhexiline maleate, perillyl alcohol, perindopril, perindoprilat, Perlapin Permethrin, perospirone, perphenazine, benzo Acetylurea, phenaridine, phenazinomycin, napyridine hydrochloride, glyceryl phenylbutazone sodium, fencamid, phencyclidine hydrochloride, phenmetrazine tartrate, phenelzine sulfate, phenformin, phenmetrazine hydrochloride, Phenobarbital, phenbenzamine hydrochloride, phenprocoumon, phenserine, phensuccinal, phensuccinide, phentermine, phentermine hydrochloride, phentolamine mesylate, Phentoxifylline, phenylaminosalicylic acid, Phenylacetic acid, phenylalanine, phenylalanylketoconazole, phenylbutazone, phenylephrine hydrochloride, phenylpropanolamine hydrochloride, phenylpropanolamine Polistirex, pheniradol hydrochloride, phenytoin, phenytoinal, physostigmine, methphenidine Phenol, biscibani, diethanolamine picotrene, berberine, picuroterol, pidotimod, pefanine, pilocarpine, pixicaridinide, pimagidine, pimetine hydrochloride, pimedine Mitoprost, pimobendan, pimozide, pinacidil, pinadoline, pindolol, pinnenol, pinocebrin, piroxpine hydrochloride, pioglitazone, pampaperone, cepiperazine, Pipecuronium Bromide, Pipecitazine, Piperacillin, Piperacillin Sodium, Piperamamide Maleate, Piperazinc, Piperbromide, Piposulfan, Pibothiazine Palmitate, Peposolam Hydrochloride , Piprazoline, Piquantel Hydrochloride, Piperquinzil, Piperazol Hydrochloride, Piracetam, Pyrandamine Hydrochloride, Pirarubicin, Piramonan Sodium, Pyrazole Acid, Pyrazole Benzicillin sodium, pirbuterol acetate, pirenpirone, pirenzepine hydrochloride, piretanide, pirfenidone, pyridicillin sodium, piridronate sodium, pirprostin, pitroxine, piremycin hydrochloride Pyrexine, pyrindole, pimogrel, pimenol hydrochloride, tetracresyl ester, octopyrone, pirodavir, pyrrolast, piroglitrate tartrate, piproxate, piramide, P hydrochloride Piroxantrone, piroxicam, piroxidone, pirofen, praquinolazole, peridamine, hydrochloric acid Pimicillin, Pivopril, Pizotidin, Placetin A, Pleucamycin, Plomestane, Porbinast Ethylenediamine, Podofilox, Pacific Sumac Extract, Boldine Methosulfate, Glucosamine, Polignate Sodium, Polymyxin B Sulfate, Polythiazide, Ponarestat, Porphyrin Sodium, Pofhimycin, Potassium Chloride, Potassium Iodide, Potassium Permanganate, Povidone-Iodine , Pranolol, pravastatin, pramipexole, pramiracetam hydrochloride, pramoxine hydrochloride, pradoxime chloride, pradoline maleate, pravastatin, pravastatin sodium, pravastatin Zepam, prazosin, prazosin hydrochloride, prednisone, prednisone, prednimustine, prednisone, prednisolone, quetiapine fumarate, prednisone, prednisone Pregnenolone succinate, pregabalin, pregnenolone succinate, preterol hydrochloride, prenylamine, prididine hydrochloride, produracic acid, profado hydrochloride, progatamide, prodifine hydrochloride , prifefenone, prilocaine hydrochloride, omeprazole, primaquine phosphate, primolol, primidone, lisinopril, primidone tromethamine, prinsoldan, pritosufloxacin, Puzidilol hydrochloride, prodipine hydrochloride, probenecid, proclomil calcium, probucol, procainamide hydrochloride, procaine hydrochloride, procarbazine hydrochloride, procaterol hydrochloride, propane Chloroperazine, Psinonide, Proclonol, Procyclidine Hydrochloride, Pridilidine Hydrochloride, Prodolac, Profado Hydrochloride, Halogabine, Progesterone, Proglutamine, Proinsulin (Human), Proline Acid, Prolintan Hydrochloride, Promethazine Hydrochloride, Promethazine, Promethazine Hydrochloride, Propafenone Hydrochloride, Propagermanium, Propanidine, Promethamine Bromide, Proparacaine Hydrochloride, Propatyl Nitrate, Propental Theophylline, Cyclophenidate Hydrochloride, Propivacacin, Propionylmazine, Propionic Acid, Propionylcarnitine, Propiram, Propiram, Propiverine, Propofol, Proponolol Hydrochloride, Propoxycaine Hydrochloride, Propoxyphene hydrochloride, propranolol hydrochloride, cisapride, propylbis-acridone, propylhexadrine, propiodarone, propylthiouracil, proquinazone, potassium propionate, proxanone hydrochloride, sea Allanthiside, prostaline, prostratin, protamine sulfate, endogenous antimicrobial peptides, prorelin, protriptyline hydrochloride, proxazole, proxazole citrate, proxeromib, proporphan tartrate , Prulifloxacin, Pseudoephedrine, Pseudoephedrine Hydrochloride, Puromycin, Pyrabulone, Pyrantel Pamoate, Pyrazinamide, Pyrazomycin, Pyrazolinacridine, Pyridostigmine, Pyridoxine Hydrochloride Alcohol, Trimethoprim Maleate, Pyrimethamine, Pirenolin, Sodium Pyrithione, Zinc Pyrithione, Pyrrovalerone Hydrochloride, Pyrroxamine Maleate, Pyrrocaine, Pyrrolephenpropyl Hydrochloride, Pyrrole Nitrin, Piroline, Quadazocine Mesylate, Quazepam, Quizidone, Quazodine, Quizolast, Quetiapine, Quetiapine Fumarate, Quinflapine, Quincolide Special, quinapril blue, quinapril, quinapril hydrochloride, quinazosin hydrochloride, quibolone, Quinctolate, quindicamine acetate, quinadolinium bromide, quinolore hydrochloride, ethinylestradiol, quinazolone Law Met, quinuregrol acetate, quingestrol gluconate, quinielorane hydrochloride, quinine sulfate, quinpirole hydrochloride, quinpronaline sulfate, quinucinium bromide, quinupristin, quiprazine maleate, radium Beprazole, rabeprazole sodium, racemic thiamphenicol, racemic epinephrine, rafoxanide, ralitolin, raloxifene, raltegravir, raltitrexed, ramatrex Ban, ramipril, ramoplanin, ramosetron, ranelic acid, ranymycin, ranitidine, ranitidine hydrochloride, ranolazine, rauwolfia serpentine, rekanan , recanan hydrochloride, reclozepam, recombinant factor VIII, regavirumab, rislastim, relaxin, relomycin, remacemide hydrochloride, remifentanil hydrochloride, reprostol, Remopride, reppirast, repromicin, reproterol hydrochloride, reserpine, resinferatoxin, resorcinol, retapamulin, demethylated reteprotin, reticulon, raviparin Sodium, ravizinon, rhenium etidronate, rhizomycin, RI retinamide, ribaminol, ribavirin, ribadenosine, licasetron, ridogrel, rifabutin, rifabutin Formestane, rifaxime, riformide, rifampicin, rifapentine, rifaximin, rilopirase, riluzole, rimantadine, lincazole hydrochloride, rimexolone, Rimeterol hydrobromide, rimonabant, rimeroquine, riodipine, rioprost, lipazepam, lipisartan, risedronate, risedronate, risedronate Sedronic acid, lisocaine, lisoride hydrochloride, risperidone, risperidone, ritanserin, ritipenem, ritodrine, ritoxast, ritonavir, rituximab , rivastigmine, rivastigmine tartrate, rizatriptan, rizatriptan benzoate, rocastine hydrochloride, rocuronium bromide, rhodocaine, roflurane, roglutine, rohitukine , Rotamycin, Roletamicide, Rogamidine, Rolipurine, Rolipram, Ralecycline, Rolodine, Clomazaride, Romotide, Ronidazole, Ropinirole, Robital Hydrochloride British, ropivacaine, ropizine, roquinegram, rosamicin, rosiglitazone, rosiglitazone maleate, rosoxacin, rosuvastatin, rotavirus vaccine, Rosiglitazone Tigotine, rotoxamine, roxaitidine, roxaxan, roxindole, roxithromycin, rubiginone B1, ruboxyl, rufloxacin, rupatidine, arutamycin, luzardolam, sabelu oxazole, safinagol, safironib, saintopin, albuterol, salbutamol sulfate, sultilax, diethyldine maleate, salicyl alcohol, salicylamide, meglumine salicylate, salicyl Acid, Salmeterol, Salnacetin, Salicylate, Salmelidine, Sepatrilat, Sancycline, Sanfepenem, Seraconazole, Prisartan, Saprenium Pterin, sapropterin hydrochloride, saquinavir, sarafloxacin hydrochloride, sapropterin, myophytol A, sargragrastim, samoxicillin, sapecillin, sagrester, saruplase , Satelinone, Satigrelor, Satomerumab Pendipeptide, Secofungin, Scopolamine Hydrobromide, Scrazaipine Hydrochloride, Secalcitol, Secobarbital, Seelzone, Segiline, Sagglitide Acetate, Selegiline Hydrochloride, Selenium Sulfide, Selenium-75 Selenomethionine, Sefortidate, Segiline Merit, Sendomicin, Semodil, Semustine, Tribendazole Chloride, Chlorhaloxetine Hydrochloride, Suprelose, Ceroxetine Hydrochloride, Seractide Acetate, Ergocrine Maleate Sertraline, serine, semetacin, sermorelin acetate, sertaconazole, sertindole, sertraline, sertraline hydrochloride, S-ethynyluracil, sportiline, stopperone, sevelamer , Sevirumab, Sevoflurane, Sezolamide, Cibopiridine, Sibutramine Hydrochloride, Silicon Androsterone, Sildenafil, Sildenafil Citrate, Celipide, Ceteplase , silver nitrate, simendan, sinetrazine, simvastatin, sincalide, sinefungin, cnitrodiil, sinnabidol, sipatril, rapamycin, sisomicin, sitalide Tin, Citoglucoside, Cizoran, Sobuxozan, Sodium Nitroprusside, Sodium Iodide I-123, Sodium Nitroprusside, Sodium Oxybate, Sodium Phenylacetate, Sodium Salicylate, Sodium Valproate, Sophie That, solverol, soripertine tartrate, porcine alanine auxin, somantine hydrochloride, somatomodulin B, somatomodulin C, somatostatin, human ghrelin, growth hormone, porcine auxin, bovine Auxin, Sobinil, Solivudine, Sotalol, Soteretol HCl, Sparfioxacin, Sodium Phosphoacetylaspartate, Phosphonaspartate, Sparsomy, Spartin Sulfate, Spectinomycin HCl , spicamycin D, Spiroperone, Spirodolene Mesylate, Spiramycin, Spiropril Hydrochloride, Spiroprilat, Germanospiramine Hydrochloride, Spiromustine, Spironolactone, Spiroplatinum, Spiroxazone , splenopentin, spongistatin, dysprosium diamine, squalamine, stamycin hydrochloride, stannous pyrophosphate, tin sulfur colloid, stanozolol, stolonidin, staurosporine, stavudine, stiltymycin Streptomycin, Stenbolone Acetate, Stirronine, Stilonium Iodide, Slodonium Iodide, Stipiamide, Stippentyl Alcohol, Stobadine, Streptomycin Sulfate, Streptomycin Isoniazid, Streptomycin, Streptomycin Ureamycin, strontium chloride Sr-89, succibun, dimercaptosuccinate, succinylcholine chloride, sucralfate, sucralfate potassium, sudoxicam, sufentanil, sufutidine, sulfur Zepam, sulbactam cilexetil, sulconazole nitrate, sulfabenzidine, sulfabenzoyl, sulfacetamide, sulfapyriidine, sulfadiazine, sulfadoxine, sulfaline, sulfamethazine, sulfamethoxine, Sulfamethazine, Sulfamethazine, Sulfamethoxazole, Sulfamethoxine, Sulfaxazole, Zinc Sulfamate, Sulfanitrobenzene, Sulfasalazine, Sulfaisothiazole, Sulfapyrazole, Sulfur Hydrochloride Oxolol, sulfinosine, sulfinpyrazone, sulfisoxazole, sulfomixin, sulfomixin, sulfonyterol hydrochloride, sulfoxamine, Sulinldac, thiomarin, sunidazole, sulodil, sulfonylurea Chlorfenuron, Thiopenem, Suloxifen Oxalate, Sulpiride, Thioprostone, Sultacillin, Sutimet, Sutopride, Thiofirukast, Sumarotene, Sumatriptan, Succinic Acid sumatriptan, sencillin sodium, suprotone, suprofen, suradista, suramin, suformin, sulikanid maleate, suritozole, sulacridine maleate, succinyl sulfate Esters, swainsonine, symakalim, clooxytriazine, ximetine hydrochloride, Taciamine hydrochloride, tacrine hydrochloride, tacrolimus, tadalafil, thalidomide hydrochloride, levocyclotetradecone phenol, other Limycin, Tamustine, Tamethacin, Taniflumate, Talopram Hydrochloride, Tasaloxate, Tamettraline Hydrochloride, Tamoxifen, Tamoxifen Citrate, Fumaric Acid Tamampamine, Tamsulosin, Tamsulosin HCl, Tandamine Hcl, Tandospirone, Tapgen, Taprosten, Tasosartan, Iodomustine, Taxane, Taxoid, Succinate Tazadoline, Tazamilast, Tazarotene, Tazil Theophylline, Tazofylline Hydrochloride, Tazobactam, Tazofelon, Tazarolol Hydrochloride, Terbufelone, Tebuquine , Teclozan, Tecogalan Sodium, Teecleukin, Teflurane, Tegafur, Tegaserod, Carbamazepine, Teicoplanin, Tilenzepine, Tellurapyrylium, Telmestane, Telmisartan, Hydrochloride Tiloxantrone, Tirudipine Hydrochloride, Temafloxacin Hydrochloride, Tematropium Methyl Sulfate, Temazepam, Temestine, Temopril, Temoxicillin, Temoporfin, Temozolomide, Temsirolimus, Temopril Nidapr, teniposide, tenofovir, tenoxalud, tenoxicam, tipindole, tipoxalin, teprotide, terazosin, terazosin hydrochloride, terbi Nafine, terbutaline sulfate, terconazole, terfenadine, terfiavoxate, tergeride, teriparatide, teriparatide acetate, teragiren, terlipressin, terodiline , terozaline hydrochloride, tiroxiron, tertalol, texicam, benzylidene isoquinone, testosterone, testosterone, tetracaine, tetrachlorodecaoxide, tetracycline, tetracycline hydrochloride, tetrahydrozoline hydrochloride, Tetramisole hydrochloride, meglumine tetrazoleast, tetrazomine, tetrofosmin, tetrahydroquinone, tetraoxoprine, tetrahydromethindamine, thalidomide, thalidomide, estrogen, theophylline, Thiabendazole, Thiamethoprine, Thiamphenicol, Thiamphenicol, Thiamphenone, ThiazinamiumChloride, Thiethylperazine, Thiithixene, Thiomerbesyl Sodium, Thimerosal, Thiacolaline, Thiofedrine, Thioguanine, thiomarinol, thiopental, thiopramide, thioridazine, thiotepa, thiophene hydrochloride, Thiphencillin Potassium, thiram, tozalinone, threonine, thrombin, thrombopoiesis Thyroxine, Thymofasin, Thymopentin, Thymotrinan, Thyromidan Hydrochloride, Thyroxine, Sulfurast, Sulfurast Sodium, tiagabine, tiamenidine, tianeptine, tiapafant, tiapamil hydrochloride, thiamide hydrochloride, thiazole carboxamide nucleoside, thiobelast sodium, tibolone, tibexic acid, propionate Ticabesone Acid, Ticabidine, Ticacillin Cresyl Sodium, Ticaclrone, Ticlopidine, Tinic Acid, Tenolol, Tifuronate Sodium, Tegemonan Dicholine, Ticegrol , Tilentamine Hydrochloride, Tilidine Hydrochloride, Tilirolol, Tiprofen Axate, Tivolone Hydrochloride, Tiludronate Disodium, Tiludronic Acid, Temethfurone, Temobesone Acetate , Timolol, Timolol Maleate, Tecannabinol, Tinidazole, Tinzaparin Sodium, Tioconazole, Thialazosin, Chlorphenidium Chloride, Thioperidone Hydrochloride, Sulfur Pingacid, tispirone hydrochloride, tiotidine, Tiotropium, tiotropium bromide, thiacidazole, tipentoxine hydrochloride, tipranavir, tippredane, teprolol hydrochloride, meglumine substitute Premilast, teprodil hydrochloride, tiquiam, tiquinamide hydrochloride, tirandalydigin, tirapazamine, tirapazate, tirofiban, benzamide cinnamon, titanocene dichloride, cobalt sulfoxide Acid, Tecortisone Pivalate, Tizanidine Hydrochloride, Tnmethobenzamide Hydrochloride, Tobramycin, Tocainide, Tolcamfil, Tolfenacin Hydrochloride, Tolarol, Tolasulfonylurea, Tobramycin Hydrochloride Rasulin, tolbutamide, tolcapone, toxilate, tofamide, tolgabit, tolimidone, tolinda ester, tolmetin, tolnaphthate, iodobenzyl polyvinylpyrrolidone, Tolsulamide, Torrestat, Tolterodine, Tolterodine Tartrate, Tolukast, Atomoxetine Hydrochloride, Tonazocine Mesylate, Topiramate, Topotecan, Topoxetine Hydrochloride Kang, topsentin, topandrosterone, toquizine, torsemide, toremifene, torsemide, torsifene, tofloxacin, totipotent stem cell factor (TSCF), tracazolate, Triformin, Trelonide, Tramadol, Tramadol Hydrochloride, Tramazoline Hydrochloride, Trandolapril, Tranexamic Acid, Tranilast, Trenscarinide, Trastuzumab, Tranilast Zanol, trazodone hydrochloride, tribenzolamine hydrochloride, trefentanil hydrochloride, treproxate, tripipam maleate, tritorolone acetate, tretinoin, glyceryl triacetate, triacetyluridine, triazinefungin , Triamcinolone, Triampyrazine Sulfate, Triamterene, Triazolam, Tribenzyl Glycoside, Tricaprilin, Trimethoxybenzamide, Trichlorothiazide, Trichohyalin, Tricilibine, Tricitrates, Triclosan Phenopiprazine, triclofors sodium, trientine, triphenylgrel, triflavin, trifluloxine, triflubuzam, triflumidate, trifluoperazine hydrochloride, trifluoperidol, triflupromazine, Triflupromazine Hydrochloride, Trifluridine, Trihexyphenidyl Hydrochloride, Trilosteine, Trimazosin Hydrochloride, Trimegestone, Alimazine Tartrate, Trimethadone, Teofene Camphorsulfonate, Methoxy Benzidine, Trimetazine, Trimethrexate, Trimipramine, Trimoprost, Trimoxamine Hydrochloride, Glyceryl Trioleate, Trivoxifen Mesylate, Tripamide, Tripinax Hydrochloride Min, triprolidine hydrochloride, triptorelin, trisulfapyrimidine, triclosine Potassium, troglitazone, triethanolamine, troleandomycin, trombodipine, tromethamine, tropaserin hydrochloride, tropicamide, scopolamine, tropisetron, spectinomycin, trovaxat Star, travirdine, tryptophan, tuberculin, myostatin, tobrazole hydrochloride, tucarcsol, tulobuterol, torosterure, tibabamate, tylogenin, piropec sodium , tyrosine, gramicillin, tyrphostins, ubenimex, udazepam, undecylenic acid, uramustine, urapidil, urea, uretipa, uridine triphosphate, urofollistin, Urokinase, ursodeoxycholic acid, valaciclovir, valaciclovir hydrochloride, valine, pentanolamide, valproate semisodium, valproic acid, valsartan, valamidine, vanadeine, vancomycin Vaninolol, valperprost hydrochloride, vapreotide, vardenafil, varenicline, variolin B, vasopressin, vecuronium bromide, viraresol, vitacridine maleate, venla Faxine, venlafaxine hydrochloride, veradoline hydrochloride, veratramine, verapamil hydrochloride, verdins, veropam hydrochloride, verirukast, verofylline, veroxan, verteporfin, Vesrinone, vexibinol, vidarabine, vigabatrin, vildagliptin, viloxazine hydrochloride, vinblastine sulfate, vinblastine citrate, vinylphosphonate, vinblastate, vincristine sulfate, Vindesine, Vindesin Sulfate, Vinblastine Sulfate, Vinblast Glycerin Sulfate, Vinblastine Sulfate, Vinorelbine, Vinpocetine, Vincaperol, Vinxaltine, Vinblastine Sulfate, Viprostol, Virginie Ya, chloridin, verroxime, vitaxin, voglibose, vorazocine, voriconazole, vorozole, vogolide, Wafarin, zamoterol, xanomeline, isopropoxyanthracene Sodium nicotinate, zorphanol nicotinate, gemmilofiban, bifenolepine, biphenylbutyric acid, shiloban, shimoprofen, xipamide, zorphanol mesylate, p-toluenesulfonic acid Xylamidine, xylazine hydrochloride, xylomedaline hydrochloride, xylose, yangambin, zabipril, zacopride, zafirlukast, zalcitabine, zaleplon, zalpirone, zotihydrochloride Ding, Zaltoprofen, Zanamivir, Zangiren, Zanotron, Zatec, Zaltibradine, Zaltibradine, Zaltosetron, Zaltosetron Maleate, Zenar Sestat, Zelaixoxin mesylate, Zergniplatin, Zearalanol, Zidovudine, Zirosilicone, Zilental, Subbenzyl Vitamin C, Zileuton, Zimedine Hydrochloride, Ten Zinc monoenoate, Zidotrene, Zinoconazole Hydrochloride, Netastatin, Netterol Hydrochloride, Netvexime, Ziprasidone, Zobolt, Zofenopril Calcium, Zofenprilat, Zofenprilat Hydrochloride Lamin, Zolazepam Hydrochloride, Zoledronate, Zoletine Hydrochloride, Zolmitriptan, Zolpidem, Zometate Sodium, Clofenac, Zonidazole Hydrochloride, Zonisamide, Zopiclone, zopolrestat, zoerbumycin, zorubicin hydrochloride, zotepine, zucasecin, zidometacin, and pharmaceutically acceptable salts thereof.

Example 1

The capsules described herein are used to administer leuprolide acetate for the treatment of prostate cancer. Leuprolide acetate (USP 31) is a synthetic nonapeptide agonist analogue of luteinizing hormone releasing factor (LNHR). The molecular weight of leuprolide acetate is about 1209 Daltons and the size is 2-3 nanometers. It is soluble in aqueous media at a concentration of about 10 mg/mL. A prior method of administering leuprolide by extended release is disclosed in U.S. Patent 5,728,396, filed January 30, 1997, which is incorporated herein by reference.

Nanochannel delivery device chips were mounted into capsules and filled with 5 mg/mL leuprolide acetate solution (NDC No. 0703-4014-18) for the treatment of prostate cancer as described herein. The size of the capsule was about 2.8 mL such that the filled capsule contained about 14 mg of leuprolide acetate. If a stronger concentration of leuprolide acetate solution is used, the volume of the capsule can be reduced accordingly. The capsule is implanted subcutaneously inside the upper arm or thigh or into the abdomen. The capsule is implanted through a small incision during an outpatient clinic procedure, optionally using a tissue separator, and removed 2-3 months later through a small incision. For implantation and grafting, a small amount of anesthetic is used, eg, 1% lidocaine is injected at the site.

In some embodiments, the nanochannel delivery device is selected for its small and nanochannel size (e.g., according to [Grattoni, A. Ferrari, M., Liu, X. Quality control method for micro-nano-channels silicon devices. US patent application 61/049,287 (April 2008)]), to provide a release rate of about 120 μg/day, which can last for about 90 days.

In this example, the configuration of the nanochannel delivery device with this behavior uses a chip size of 6 x 6mm, with 161 large channels, and each channel has an opening of 190X190 μm, and each channel has about 23 rows of A nanochannel structure consisting of 10 inlet and outlet microchannels each connected by about 20 nanochannels as described herein. The cross section of the inlet and outlet is about 5×5 μm, the inlet is about 30 μm long, the outlet is about 1.6 μm long, the nanochannel is about 5 μm long, 5 μm wide and 13 nm high. Other configurations with different dimensions can be generated by mathematical modeling, resulting in about the same release rate and duration in other embodiments.

Example 2

Capsules and nanochannel delivery devices were constructed and implanted as described in Example 1. However, instead of administering leuprolide acetate, the capsule and nanochannel delivery device administered letrozole for the treatment of breast cancer. The limited success of chemotherapy in the treatment of breast cancer emphasizes the need for new preventive strategies to reduce cancer incidence. Recent studies have demonstrated that aromatase inhibitors are promising chemopreventive agents for breast cancer by inhibiting estrogen biosynthesis. In particular, the study suggests that letrozole is an ideal candidate for chemoprevention in high-risk groups such as BRCA1-positive women. However, the low efficacy and side effects associated with conventional systemic administration of letrozole are limiting factors for its long-term administration.

The growth of breast cancer is highly dependent on estrogen, so inhibiting estrogen is very effective in preventing breast cancer. Recent studies have shown that aromatase inhibitors such as anastrozole, letrozole and exemestane are promising molecules for the chemoprevention of breast cancer. Aromatase Mediates the biosynthesis of estradiol, the most potent form of estrogen, from androgens via the cytochrome P450 enzyme complex (aromatase). Aromatase is present in breast tissue, and non-steroidal and steroidal aromatase inhibitors, respectively, reduce circulating estrogen levels to 1%-10% of pretreatment levels. Therefore, inhibition of aromatase is an important way to reduce the growth-stimulating effects of estrogen in estrogen-dependent breast cancers, which account for about 60-70% of breast cancers. Among the aromatase inhibitors, letrozole is a very potent non-steroidal inhibitor, inhibiting about 99% of estrogen biosynthesis. In addition, several studies and clinical trials of chemotherapy in metastatic breast cancer have shown that letrozole is more potent and has fewer side effects than tamoxifen. Therefore, the study suggests that letrozole is a candidate for investigational chemopreventive therapy in women at increased risk of breast cancer. However, regular oral letrozole has been shown to increase the risk of heart problems and osteoporosis. The key to successful chemoprevention of breast cancer relies on long-term delivery of specific drugs while preventing side effects. Sustained local release of a chemopreventive agent (i.e., letrozole) in breast tissue significantly reduced the incidence of breast tumors and systemic side effects, in contrast to ineffective oral administration. This shows promise for improving quality of life for patients.

We believe that the implantable nanochannel device according to the present invention enables sustained and long-term local release of letrozole in breast tissue and significantly reduces estrogen-dependent epithelial cell proliferation with reduced toxicity.

Preclinical studies have used letrozole at a daily dose of 2.5 mg. We believe that sustained local release of letrozole in breast tissue (using the nanochannel device of the present invention) requires only lower doses compared to oral delivery. In the first analysis, we believed that a daily topical delivery range of 35-50 μg was effective.

Accomplishing effective chemopreventive therapy through local administration of chemopreventive agents using long-term, sustained-release implants significantly improves the quality of life of women in high-risk groups. We believe that the use of the nanochannel delivery device of the present invention will lead to improved therapeutic efficacy, effective drug dosage reduction and reduced side effects through true sustained release. Fewer breast cancers also have a positive economic impact on patients, their employers and insurance companies through lower treatment costs, fewer medical visits and less lost work time due to effective preventive therapy.

The development of a reliable extended-release implantable technology adds a new approach to drug delivery in breast cancer. Tumor therapy and inhibition of metastasis and/or tumor recurrence are ongoing research. Technological enhancements to the initial platform provide adjustable and programmed release, including remote, interactive control of implanted devices, further enabling the ability to administer multiple drugs simultaneously. In vivo refilling also prolongs the function of the nanochannel device and reduces adverse events associated with transplantation. As a general method of drug delivery, additional indications could be identified, extending the scope of this innovation.

Example 3

The capsules and nanochannel delivery devices were constructed and implanted in patients as described in Example 1. However, instead of administering leuprolide acetate, the capsule and nanochannel delivery device administered lapatinib to treat breast cancer.

Example 4

The capsules and nanochannel delivery devices were constructed and implanted in patients as described in Example 1. However, instead of administering leuprolide acetate, the capsule and nanochannel delivery device administered bupenorphine to treat opioid dependence.

Example 5

Capsules and nanochannel delivery devices were constructed and implanted in patients as described in Example 1. However, instead of administering leuprolide acetate, the capsule and nanochannel delivery device administered interferon alpha implants for giant cell hemangioblastoma.

Example 6

The capsules and nanochannel delivery devices were constructed and implanted in patients as described in Example 1. However, instead of administering leuprolide acetate, the capsule and nanochannel delivery device administered zidovudine in vaginal therapy to prevent HIV transmission from pregnant women to their infants.

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As used herein, the term "direct fluid communication" should be interpreted as fluid communication between two directly connected objects, eg such that fluid can exit one object and immediately enter the second object without passing through an intermediate object. For example, in the embodiment shown in FIGS. 3A-3G , outlet 70 is in direct fluid communication with nanochannel 25 . However, the outlet 70 is not in direct fluid communication with the inlet 30 because the fluid must pass through an intermediate body (nanochannel 25) after exiting the inlet 30 and before entering the outlet 70

Furthermore, the term "inlet" as used herein should be interpreted as a chamber or reservoir of a nanochannel delivery device that holds a substance prior to delivery through the nanochannel delivery device. Similarly, "outlet" should be interpreted as a chamber or reservoir within a nanochannel delivery device that holds a substance that is about to leave the nanochannel delivery device.

All of the devices, systems and/or methods described and claimed herein can be made and accomplished without undue experimentation in light of the present disclosure. Although the devices, systems and/or methods of the present invention have been described in terms of specific embodiments, it will be apparent to those skilled in the art that changes may be made to the steps of these devices, systems and/or methods or steps of the methods described herein. sequence without departing from the concept, spirit and scope of the present invention. Such similar alterations and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and conceptual scope of the invention as defined by the appended claims.

references

The contents of the following references are incorporated herein by reference:

[1] Santen, R.J., Yue, W., Naftolin, F., Mor, G., Berstein, L. The potential of aromatase inhibitors in breast cancer prevention. Endocrine-Related Cancer. 6, 235-243 (1999).

[2] Goss, P.E., Strasser, K. Aromatase Inhibitors in the Treatment and Prevention of Breast Cancer. J. Clin. Oncol. 19, 881-894 (2001).

[3] Chlebowski, R.T. Reducing the Risk of Breast Cancer. N. Engl. J. Med., 343, 191-198 (2000).

[4] Dowsett, M., Jones, A., Johnston, S.R., Jacobs, S., Trunet, P., Smith, I.E. Invivo measurement of aromatase inhibition by letrozole (CGS 20267) in postmenopausal patients with breast cancer. Clin . Cancer Res. 1, 1511 1515 (1995).

[5] Brueggemeier, R.W., Hackett, J.C., Diaz-Cruz, E.S. Aromatase Inhibitors in the Treatment of Breast Cancer. Endocrine Reviews 26, 331-345(2005).

[6] Coates, A.S., Keshaviah, A., Thürlimann, B., et al. Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98 . J. Clin. Oncol. 25, 486 492 (2007).

[7] Goss, P.E., Ingle, J.N., Martino, S., et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N.Engl.J.Med.349 , 1793 1802 (2003).

[8] Garreau, J.R., Delamelena, T., Walts, D., Karamlou, K., Johnson, N. Side effects of aromatase inhibitors versus tamoxifen: the patients' perspective. Am. J. Surg. 192, 496-8( 2006).

[9] Luthra, R., Kirma, N., Jones, J., Tekmal, R.R. Use of letrozole as achemopreventive agent in aromatase overexpressing transgenic mice. The Journal of Steroid Biochemistry and Molecular Biology.86, 461-467 (2003 ).

[10] Harper-Wynne, C., Ross, G., Sacks, N., Salter, J., Nasiri, N., Iqbal, J., A'Hern, R., Dowsett, M. Effects of the aromatase Inhibitor letrozole on normal breast epithelial cell proliferation and metabolic incisions in postmenopausal women: apilot study for breast cancer prevention. Cancer Epidemiol. Biomarkers Prev.11, 614-21(2002).

Claims (23)

1. a kind of method for manufacturing nanochannel delivery apparatus, methods described include：

First substrate is provided；

Multiple nanochannels are formed in first substrate；

First expendable material is filled into the multiple nanochannel；

Multiple inlet microchannels are formed in first substrate；

Second expendable material is filled into the multiple inlet microchannel；

Form the cap layers for covering the multiple nanochannel；

Multiple outlet microchannels are formed in the cap layers；

The first expendable material is removed from the multiple nanochannel；With

The second expendable material is removed from the multiple inlet microchannel,

Wherein carry out removing first from the multiple nanochannel after the cap layers for covering the multiple nanochannel are formed Expendable material.

2. the method for claim 1 wherein formed after multiple inlet microchannels to carry out from described more in first substrate The first expendable material is removed in individual nanochannel.

3. the method for claim 1 or 2, wherein inlet microchannel are arranged orthogonally to the principal plane of first substrate.

4. the method for claim 1 or 2, its middle outlet microchannel is arranged orthogonally to the principal plane of first substrate.

5. the method for claim 1 or 2, wherein inlet microchannel are directly in fluid communication with nanochannel.

6. the method for claim 1 or 2, its middle outlet microchannel is directly in fluid communication with nanochannel.

7. the method for claim 1 or 2, wherein first substrate includes silicon on insulator type wafer, the wafer includes interior Oxide skin(coating).

8. the method for claim 1 or 2, wherein building entrance and exit microchannel with photoetching process.

9. the method for claim 7, wherein forming multiple inlet microchannels is included from the first substrate etching material, wherein institute State etching and end at internal oxidition nitride layer.

10. the method for claim 9, wherein forming the big passage of multiple entrances is included from the first substrate back side etch material, Wherein described etching ends at internal oxidition nitride layer.

11. the method for claim 10, wherein in etching material so as to removing institute after forming inlet microchannel and the big passage of entrance State the path between inner oxide layer open inlet microchannel and the big passage of entrance.

12. the method for claim 1 or 2, wherein each nanochannel is about 1-10 nanometers depth.

13. the method for claim 1 or 2, wherein each nanochannel is about 10-20 nanometers depth.

14. the method for claim 1 or 2, wherein the first expendable material then can be removed by selective etch.

15. the method for claim 1 or 2, wherein first expendable material is tungsten.

16. the method for claim 1 or 2, wherein the second expendable material then can be removed by selective etch.

17. the method for claim 16, wherein second expendable material is selected from：Tungsten, copper, the glass of doping and undoped glass Glass.

18. the method for claim 1 or 2, wherein second expendable material is filled into the multiple inlet microchannel, so that Second expendable material extends on the top of inlet microchannel, and makes it by chemical-mechanical flat technology (CMP) Become flat.

19. the method for claim 1 or 2, wherein the cap layers are selected from silicon nitride, silica, carbonitride of silicium, carborundum and silicon.

20. the method for claim 1 or 2, wherein the cap layers include the multiple deposition thing of material, it includes tensile stress and pressure Contracting stress, so that the net impact of the cap layers is draftability.

21. the method for claim 1 or 2, wherein the cap layers are about 0.5-1.0 microns thickness.

22. the method for claim 1 or 2, wherein the cap layers are about 1.0-2.0 microns thickness.

23. the method for claim 1 or 2, wherein the cap layers are about 2.0-4.0 microns thickness.